Exam #3

Question 1

general characteristics of viruses

Answer 1

three shapes:
icosahedral
helical
complex

protein coat capsid: protects nucleic acids, carries required enzymes
composed of identical subunits capsomeres

capsid plus nucleic acids called nucleocapsid

non-enveloped (naked) viruses
lack envelope; more resistant to disinfectants

enveloped viruses have lipid bilayer envelope

matrix protein between nucleocapsid and envelope

Question 2

Names of viruses

Answer 2

Viruses often referred to informally

groups of unrelated viruses sharing routes of infection
respiratory route: respiratory viruses
oral-fecal route: enteric viruses

zoonotic viruses cause zoonoses (animal to human)

arboviruses (from arthropod borne) are spread by arthropods; often can infect widely different species
important diseases:
dengue fever
yellow fever
West Nile encephalitis
Zika virus
Chikungunya

Question 3

animal virus replication

Answer 3

5-step infection cycle:
1.attachment
2. penetration and uncoating
3. synthesis (replication)
antigenic shift, antigenic drift, reverse transcription
4. assembly
5. release

Question 4

1. Attachment

Answer 4

1. attachment
   viruses bind to receptors
   usually glycoproteins on cytoplasmic membrane
   often more than one required (for example, HIV binds to two)
   normal function unrelated to viral infection
   specific receptors (tropism) required; limits range of virus
   -dogs don’t contract measles from humans…

Question 5

Nonstructural proteins

Answer 5

Nonstructural proteins include enzymes and transcription factors that are needed for viral replication but are not part of the viral particle

Variants have many mutations in a key region of the viral spike protein called the receptor binding domain, which is required to infect cells

Question 6

penetration and uncoating: fusion

Answer 6

Enveloped viruses can fuse with host cell membrane.

non-enveloped viruses cannot fuse, enter host cell by endocytosis

Question 7

Synthesis

Answer 7

expression of viral genes to produce viral structural and catalytic genes (capsid proteins, enzymes required for replication)

synthesis of multiple copies of genome

most DNA viruses multiply in nucleus

enter through nuclear pores following penetration

three general replication strategies depending on type of genome of virus
1. DNA viruses
2. RNA viruses
3. reverse transcribing viruses

replication of DNA viruses
usually in nucleus (poxviruses - exception: replicate in cytoplasm, encode all enzymes for DNA, RNA synthesis)

dsDNA replication straightforward - follows central dogma

Question 8

replication of ssDNA viruses

Answer 8

ssDNA similar except complement
first synthesized to generate double-stranded DNA.

                                                      Newly synthesized strand acts as  template to produce more ssDNA

Question 9

Replication of RNA viruses

Answer 9

majority single-stranded; replicate in cytoplasm

require virally encoded RNA polymerase (replicase - RNA directed RNA polymerase),
- uses RNA template to synthesize new RNA strand

which lacks proofreading, allows antigenic drift
->influenza viruses

replication of RNA viruses
majority single-stranded; replicate in cytoplasm
require virally encoded RNA polymerase (replicase - RNA directed RNA polymerase),

ss (+) RNA

Viral RNA binds host ribosomes and gets translated to make viral proteins, including a viral replicase that is used to synthesize more copies of the viral genome.

To do this, it
makes multiple copies of the complementary (-) strand using the original (+) strand as a template.
these (-) strands act as templates to produce more viral (+) strand RNA packaged as genomes into new virons that are forming.

genomes are functional mRNAs
Polio virus, Rhinovirus, Coronavirus, Flaviviruses:

Question 10

Synthesis of SS(-) RNA

Answer 10

replication of RNA viruses
require virally encoded RNA polymerase (replicase - RNA directed RNA polymerase),
- lacks proofreading – generates mutations during replication.

ss (–) RNA cannot be directly translated
must be copied into a (+) strand.
Measles virus, Ebola virus Influenza virus:
A replicase is carried into host cell.

Once (+) strand produced, it can also be
translated to make viral proteins and
used as template for synthesizing
new (-) RNA strands.

Question 11

RNA-dependent RNA polymerase (RdRp)

Answer 11

synthesis of complementary strand of RNA in single-stranded RNA viruses requires replicase not found in host cells:
virally encoded RNA polymerase lacks proofreading, allows antigenic drift

Dengue viral architecture of
RNA-dependent RNA polymerase
(NS5) consisting of fingers, palm, and thumb structure characteristic of known polymerase structures

catalytic site
divalent metal ions Zn2 and Mg2

high rate of error during copying (≈10−4)

Question 12

antigenic drift

Answer 12

mechanism for variation in viruses

involves accumulation of mutations in genes that code for antibody-binding sites.

continuous, ongoing process resulting in emergence of new strain variants.

example: influenza viruses can change through antigenic drift, a process in which mutations to the virus genome produce changes in the viral H or N.

Hemaglutinin - glycoprotein on surface, binds cells
with sialic acid on membrane

Neuraminidase - surface protein - enables viral release from cell.
Oseltamivir (Tamiflu) - neuraminidase inhibitor

Question 13

Why RNA viruses recombine

Answer 13

Recombination in RNA viruses involves the formation of chimeric molecules from parental genomes of mixed origin. – requires that 2 or more viruses infect the same host cell.

Co-infection of a cell by genetically distinct viral strains can lead to the generation of recombinant viruses.

Coronavirus is an unsegmented RNA virus.
natural selection acts on recombinants

Question 14

Antigenic shift

Answer 14

some RNA viruses segmented
reassortment results in
antigenic shift

Reassortment of segmented viruses genomes causes antigenic shift – there is a sudden change in spikes because the virus acquires a new genome segment.

-two or more different strains of a virus, or strains of two or more different viruses, combine to form new subtype having mixture of surface antigens of original strains.

Question 15

replication of reverse-transcribing viruses

Answer 15

encode reverse transcriptase: makes DNA from RNA
retroviruses have ss (+) RNA genome (HIV)
reverse transcriptase synthesizes single DNA strand
complementary strand synthesized

dsDNA integrated into host cell chromosome
can direct productive infection or remain latent
cannot be eliminated

If RNA virus is retrovirus, different enzyme required, not found in host cells:

reverse transcriptase – synthesizes strand of DNA from RNA template.

Question 16

reverse transcription and genome integration

Answer 16

HIV-encoded reverse transcriptase makes DNA copy of viral RNA genome

RNA template degraded; cDNA strand is made, yielding double-stranded DNA copy of viral RNA
copy circularized, then moved into host nucleus

Integrase inserts in linear form into host chromosome
no specific host sequence needed
once inserted, provirus is permanent part of that cell’s genome
RNA slides into the reverse transcriptase through a path where polymerase and Rnase H active sites are located

reverse transcriptase frequently makes mistakes, lacks proofreading ability

allows HIV to evolve quickly, avoid immune response

Question 17

Assembly and release

Answer 17

assembly
protein capsid forms; genome, enzymes packaged
takes place in nucleus or in organelles of cytoplasm

release
most via budding
viral protein spikes insert into host cell membrane; matrix proteins accumulate; nucleocapsids extruded
covered with matrix protein and lipid envelope
-some obtain envelope from organelles
non-enveloped viruses released when host cell dies, often by apoptosis initiated by virus or host

Question 18

acute and persistent infections

Answer 18

acute:
rapid onset
short duration

persistent:
continue for years
or lifetime

persistent infections chronic or latent
chronic infections: continuous production
of low levels of virus particles

may or may not
have symptoms

latent infections: viral genome (provirus)
remains silent in host cell; can reactivate

some viruses exhibit both
(HIV)

Question 19

Hepatitis B

Answer 19

Hepatitis B virus infection may be either acute (self-limiting) or chronic (long-standing) - persons with self-limiting infection clear the infection spontaneously within weeks to months

Virus transmitted through contact with the blood or other body fluids of an infected person.
-> occupational hazard for health workers; can be prevented by currently available safe and effective vaccine. (CDC)

virus replicates and circulates in blood for years, often asymptomatically, which increases spread

Children less than 6 years of age who become infected with the hepatitis B virus are the most likely to develop chronic infections.

first vaccine approved in early 1980s, administered to all infants before leaving hospital

Question 20

viruses and human tumors

Answer 20

cancerous or malignant can metastasize; benign do not

proto-oncogenes and tumor suppressor genes work together to stimulate, inhibit growth and cell division

mutations cause abnormal and/or uncontrolled growth
usually multiple changes at different sites required

viral oncogenes similar to host proto-oncogenes; can interfere with host control mechanisms, induce tumors

Question 21

Tumor suppressor genes

Answer 21

Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (apoptosis or programmed cell death).

When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer.

Question 22

Proto-oncogene

Answer 22

proto-oncogene: often encodes proteins that stimulate cell division, prevent cell differentiation or regulate programmed cell death (apoptosis)
Src was first discovered as an oncogene in a chicken retrovirus:

An oncovirus is a virus that causes cancer.

Studies of avian Rous sarcoma virus (RSV) led to the discovery of the viral oncogene src.

productive infections, latent infections, tumors
virus-induced tumors rare; most result from mutations

Question 23

Plant viruses

Answer 23

plant viruses - common
don’t attach to cell receptors; enter via wounds in cell
wall, spread through cell openings (plasmodesmata)

plants rarely recover, lack specific immunity - many viruses
extremely hardy

transmitted by soil, humans, insects, contaminated seeds, tubers, pollen, grafting

Question 24

Viroids

Answer 24

viroids: small single-stranded RNA molecules
-246–375 nucleotides, about 1/10th smallest RNA virus
-forms closed ring; hydrogen bonding gives ds look
-thus far only found in plants; enter through wound sites

Question 25

Prions

Answer 25

composed solely of protein; no nucleic acids linked to slow, fatal human diseases; animal diseases usually transmissible only within species mad cow disease in England killed >170 people prion proteins accumulate in neural tissue neurons die tissues develop holes brain function deteriorates characteristic appearance gives rise to general term for all prion diseases: transmissible spongiform encephalopathies cells produce normal form PrPC (prion protein, cellular) proteases readily destroy infectious prion proteins PrPSC (prion protein, scrapie) resistant to proteases; become insoluble, aggregate unusually resistant to heat, chemical treatments hypothesized that PrPSC converts PrPC misfolding to PrPSC

Question 26

Innate and adaptive immunity

Answer 26

innate immunity is routine protection, present at birth although considered non-specific, involves pattern recognition of specific molecules Innate immunity is an evolutionarily ancient defense system that provides multicellular organisms with immediate defense mechanisms without requiring prior exposure. adaptive immunity develops throughout life in response to exposure to microbes and foreign material antigens cause response, system produces antibodies to bind can also destroy host cells

Question 27

overview of the innate defenses

Answer 27

first-line defenses are barriers blocking entry if invaders breach, sensor systems detect, send out signals sentinel cells use pattern recognition receptors (PRRs) effector actions: innate defenses work to destroy invaders

Question 28

first-line defenses

Answer 28

skin difficult for microbes to penetrate epidermis: many layers of epithelial cells outermost cells are dead, filled with keratin repels water, maintains dry environment continually slough off along with any attached microbes dermis: tightly woven, fibrous connective tissue mucus membranes line digestive, respiratory, and genitourinary tracts bathed with mucus and other secretions constant turnover of epithelial cells that are shed with any attached microbes mucociliary escalator propels mucus, trapped particles out of respiratory tract normally keeps lower respiratory tract free of microbes cilia of epithelial cells beat synchronously

Question 29

upper respiratory system

Answer 29

nose and nasal cavity, pharynx (throat), epiglottis lined by mucous membranes Goblet cells produce mucus, a slimy glycoprotein traps air-borne dust and particles including microbes

Question 30

The BAM model Bacteriophage adhering to mucus provide a non–host-derived immunity

Answer 30

Mucus is produced and secreted by the underlying epithelium. (2) Phage bind variable glycan residues displayed on mucin glycoproteins via variable capsid proteins (Ig-like domains). (3) Phage adherence creates an antimicrobial layer that reduces bacterial attachment to and colonization of the mucus, which in turn lessens epithelial cell death. (4) Mucus-adherent phage are more likely to encounter bacterial hosts, thus are under positive selection for capsid proteins that enable them to remain in the mucus layer. (5) Continual sloughing of the outer mucus provides a dynamic mucosal environment.

Question 31

first-line defenses antimicrobial substances

Answer 31

protect skin, mucous membranes salt accumulates from perspiration lysozyme degrades peptidoglycan peroxidase enzymes break down hydrogen peroxide lactoferrin- binds iron AMPs (antimicrobial peptides) defensins - form pores in microbial membranes short antimicrobial peptides found within mucous membranes and phagocytes nonspecific antimicrobial factors

Question 32

Innate immune defenses – antimicrobial substances

Answer 32

Lactoferrins and defensins in the cervical plug protect the fetus and separate the vagina, which is normally colonized with multiple microorganisms, from the normally sterile intra-uterine compartment. transferrin - limits pathogen access to iron normal microbiota (flora) competitive exclusion of pathogens cover binding sites, consume available nutrients production of toxic compounds Propionibacterium degrade lipids, produce fatty acids E. coli synthesizes colicins in intestinal tract Lactobacillus in vagina produce low pH disruption of normal microbiota (antibiotic use) can predispose person to infections Clostridium difficile in intestine Candida albicans in vagina

Question 33

Skin - normal microbiota

Answer 33

adapted to dry, salty, cool habitat use substances in sweat, sebum as nutrients produce by-products that inhibit other microbes breakdown of sebum yields fatty acids - toxic to many bacteria outermost layers bathed in secretions sweat evaporates, leaves salty residue that inhibits microbes sebaceous glands open into hair follicles, secrete oily sebum too dry, salty, acidic, and toxic for most pathogens… those that tolerate often shed with dead skin cells

Question 34

production of toxic compounds

Answer 34

A colicin is produced by and toxic to some strains of E. coli. Colicins are released into the environment to reduce competition from other bacterial strains. Colicins bind to outer membrane receptors, using them to translocate to the cytoplasm or cytoplasmic membrane, where they exert their cytotoxic effect, including depolarisation of the cytoplasmic membrane, DNase activity, RNase activity, or inhibition of murein synthesis. Virtually all colicins are carried on plasmids.wikipedia

Question 35

cells of the immune system

Answer 35

red blood cells (erythrocytes) carry O2 platelets (from megakaryocytes) involved in clotting white blood cells (leukocytes) important in host defenses formation, development termed hematopoiesis blood cells originate from hematopoietic stem cells -found in bone marrow -induced to develop by colony-stimulating factors (CSFs) move around body, travel through circulatory system always found in normal blood -numbers increase during infections some reside in various tissues

Question 36

four types of leukocytes (white blood cells)

Answer 36

1. granulocytes contain cytoplasmic granules neutrophils highest numbers, engulf and destroy bacteria, other material – most abundant, first responders basophils involved in allergic reactions, inflammation mast cells similar; found in tissues eosinophils fight parasitic worms also involved in allergic reactions

Question 37

Mononuclear phagocytes

Answer 37

comprise mononuclear phagocyte system (MPS) includes monocytes (circulate in blood) and cell types that develop as they leave blood stream macrophages differentiate from monocytes often named after location where found in body The growth and differentiation of macrophages depends on lineage-determining cytokines, and interactions with supporting tissue in haematopoietic organs.

Question 38

Dendritic cells and lymphocytes

Answer 38

3. dendritic cells sentinel cells, function as “scouts” engulf material in tissues, bring it to cells of adaptive immune system for “inspection” usually develop from monocytes 4. lymphocytes responsible for adaptive immunity B cells, T cells highly specific in recognition of antigen generally reside in lymph nodes, lymphatic tissues natural killer (NK) destroy certain types of cells

Question 39

What is the role of the sensor systems in innate immunity?

Answer 39

They detect invasion by microbes.

Question 40

How are the roles of neutrophils and macrophages similar?

Answer 40

They are both phagocytic cells. Macrophages descend from monocytes.

Question 41

cell communication

Answer 41

communication allows coordinated response surface receptors serve as “eyes” and “ears” of cell usually span membrane, connect outside to inside binding to specific ligand induces response adhesion molecules allow cells to adhere to other cells - endothelial cells can adhere to phagocytic cells, allow them to exit bloodstream cytokines are “voices” of cell produced by cells, diffuse to others, bind appropriate receptors to induce changes: growth, differentiation, movement, cell death act at low concentration; effects local, regional, systemic

Question 42

Cytokines

Answer 42

chemokines: chemotaxis of immune cells colony-stimulating factors (CSFs): multiplication and differentiation of leukocytes interferons (IFNs): control of viral infections, regulation of inflammatory response interleukins (ILs): produced by leukocytes; important in innate and adaptive immunity tumor necrosis factor (TNF): inflammation, apoptosis …act together to promote response

Question 43

pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs)

Answer 43

cell wall components (lipopolysaccharide, peptidoglycan, lipoteichoic acid, lipoproteins), flagellin subunits, viral RNA molecules may be called MAMPs (for microbe-associated)  some are DAMPs (for danger-associated), which indicate host cell damage

Question 44

pattern recognition receptors (PRRs)

Answer 44

cells “see” PAMPs in extracellular environment others in phagosomal or endosomal membranes of organelles - characterize ingested material following detection, signal transmitted to nucleus where it induces gene expression, inflammatory response, antiviral response

Question 45

Toll-like receptors (TLRs)

Answer 45

recognize a variety of pathogen-associated molecular patterns (PAMPs). Recognition of lipopolysaccharide (LPS) by TLR4/TLR2 recognizes a broad range of structurally unrelated ligands and functions in combination with other TLRs, including TLR1 and TLR6. TLR3 - double-stranded (dsRNA) TLR5 - bacterial flagellin TLR9 - unmethylated CpG motifs, abundant in bacterial DNA. G+, Gram-positive; G–, Gram negative; GPI, glycophosphoinositol; RSV, respiratory syncytial virus.

Question 46

(PRR) NOD like receptors

Answer 46

NOD-like receptors (NLRs) found in cytoplasm detect bacterial components indicating cell has been breached; some detect damage unleash series of events to protect host - some at expense of cell some NLRs join cytoplasmic proteins to form an inflammasome - activates inflammatory response by cytokine expression NOD-like receptors – growth cycle of some pathogenic microorganisms involves infection of the cytoplasm Viral genes are often transcribed and translated in the cytoplasm, and virus particles are assembled. In addition, some bacteria and parasites have a series of escape mechanisms, such as making holes in the phagosome membrane and entering the cytoplasm. nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs)

Question 47

Inflammasome

Answer 47

a subset of NLRs (named NLRP1) are able to assemble and oligomerize into a common structure Inflammasomes play an important role in the induction of inflammatory cascades and coordination of host defenses, both via the activation and secretion of pro-inflammatory cytokines and the induction of a specialized form of immune-stimulatory programmed cell death termed pyroptosis.

Question 48

RIG-like receptors (RLRs) found in cytoplasm

Answer 48

detect viral RNA indicating infection, produce interferons viral RNA often 3 phosphates at 5′ end (no capping as in cytoplasmic RNA), often double-stranded interferons cause neighboring cells to express inactive antiviral proteins (iAVPs) (protein kinase R, RNase L) activated by dsRNA to degrade mRNA, stop protein synthesis, undergo apoptosis effector action – destroy invader

Question 49

Interferon response

Answer 49

Interferons are proteins that are part of your natural defenses. They tell your immune system that germs or cancer cells are in your body. And they trigger killer immune cells to fight those invaders. Interferons got their name because they "interfere" with viruses and keep them from multiplying. Interferons (IFNs) — the body's first line of antiviral defence — are cytokines that are secreted by host cells in response to virus infection. By inducing the expression of hundreds of IFN-stimulated genes, several of which have antiviral functions, IFNs block virus replication at many levels.

Question 50

complement system

Answer 50

Three pathways lead to three different outcomes: opsonization - enhancing phagocytosis of antigens chemotaxis - attracting macrophages and neutrophils cell lysis - rupturing membranes of foreign cells

Question 51

Complement proteins

Answer 51

complement proteins: circulate in the blood and in the interstitial fluid. interact with each other in chain reactions (cascades). Complement acts as a linker between the innate and the adaptive immune response.

Question 52

complement system

Answer 52

complement activities of adaptive immune system proteins circulating in blood and bathing tissues proteins named in order discovered: C1 through C9 can split into fragments, for example, C3 splits to C3a and C3b activated by three different pathways that lead to formation of C3 convertase, which splits C3 Alternative pathway quickly triggered – provides early warning that an invader is present. Initiated by C3b binding a foreign cell surface. After C3b binds, other complement proteins attach, eventually forming the C3 convertase. C3 convertases are unstable (half-life 10 – 20 min)

Question 53

Three outcomes of formation of C3 convertase

Answer 53

inflammatory response: C5a attracts phagocytes to area; C3a and C5a increase permeability of blood vessels, induce mast cells to release cytokines, histamine 2. lysis of foreign cells: membrane attack complexes (MACs) formed by proteins C5b, C6, C7, C8, and C9 molecules assembling in cell membranes of Gram negatives 3. opsonization: C3b binds to bacterial cells and foreign particles, promotes engulfment by phagocytes

Question 54

How can C3b be both a product of complement activation and an activator of the complement system?

Answer 54

Small amounts of C3b are always present, so there will always be some available to activate the system. Large amounts of C3b are needed to function as opsonins, and this will only be available if the system is activated.

Question 55

Opsonization and migration - neutrophil

Answer 55

C3b – opsonin – triggers phagocytosis C5a – chemoattractant – neutrophil migration

Question 56

How do MACs cause cells to lyse?

Answer 56

They form pores in the cell membrane: Certain complement components assemble in cell membranes, forming a doughnut-shaped membrane attack complex (MAC). This creates pores in the membrane, disrupting the cell integrity.

Question 57

anaphylotoxins – complement peptides

Answer 57

Anaphylatoxins, or complement peptides, are fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defense. Anaphylotoxins cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability – and mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals. Anaphylotoxins trigger degranulation of mast cells or phagocytes. If the degranulation is widespread, it can cause a shock-like syndrome similar to that of an allergic reaction.

Question 58

complement system - recognizing self

Answer 58

regulation prevents host cells from activating molecules in host cell membranes bind regulatory proteins that inactivate C3b, preventing opsonization or triggering alternative pathway

Question 59

Some pathogens attract complement regulatory proteins to their surfaces. How would this help the pathogens avoid destruction?

Answer 59

The regulatory proteins inactivate C3b, thereby preventing the molecule from: activating the complement system (alternative pathway) and opsonizing the bacterium The complement system is an ancient innate immune system that provides protection from pathogen invasion by surface pattern recognition. C3 is present in Cnidaria, suggesting a primitive version of the alternative pathway was established more than 500 million years ago.

Question 60

Phagocytosis

Answer 60

phagocytes engulf and digest material, pathogens chemotaxis: phagocytes recruited by chemoattractants (products of microorganisms, phospholipids from injured host cells, chemokines, C5a) recognition and attachment: direct (receptors bind mannose) and indirect (binding to opsonins) engulfment: pseudopods surround, form phagosome phagosome maturation and phagolysosome formation: endosomes fuse, lower pH; lysosomes bring enzymes destruction and digestion: toxic ROS* and nitric oxide produced; pH decreases; enzymes degrade; defensins damage membrane of invader; lactoferrin ties up iron exocytosis: vesicle fuses with cytoplasmic membrane, expels remains leukocytes: defense mediators and sentinels. Phagocytosis in immune cells is activated by attachment to pathogen-associated molecular patterns (*PAMPS)

Question 61

Macrophages

Answer 61

macrophages are scavengers and sentinel cells phagocytize dead cells, debris, destroy invaders live weeks or months; regenerate lysosomes always present in tissues; can call in reinforcements TLRs on surfaces and in phagosomes detect invaders cytokines produced in response can become activated macrophages to increase power if insufficient, can fuse to form giant cells macrophages, giant cells, T cells form granulomas wall off and retain organisms or material resistant to destruction prevent escape but interfere with normal tissue function tuberculosis and other diseases

Question 62

phagocytosis - neutrophils

Answer 62

specialized attributes of neutrophils neutrophils: rapid response - move into area and eliminate invaders critical role in early stages of inflammation first to be recruited from bloodstream to site of damage more powerful than macrophages, but short life span of 1–2 days in tissues die once granules used kill microbes via phagocytosis and release of granule content can release DNA to form *neutrophil extracellular traps* (NETs) catching microbes, allow enzymes and peptides from granules to destroy

Question 63

NET (Neutrophil Extracellular Trap)

Answer 63

Neutrophils release granule proteins and DNA into extracellular space to trap bacteria or viruses during infection: NETs (neutrophil extracellular traps). NETs disarm pathogens with antimicrobial proteins such as neutrophil elastase and histones bound to DNA. NETs also serve as physical barrier that prevents spread of pathogens.

Question 64

avoiding host defenses

Answer 64

Avoiding recognition and attachment capsules: interfere with opsonization; some bind host’s regulatory proteins that inactivate C3b Streptococcus pneumoniae

Question 65

MECHANISM OF DNA UPTAKE during transformation

Answer 65

dsDNA bound to the cell surface fragmentation of dsDNA occurs upon binding ssDNA fragments transported across the membrane via transformation pseudopilus, evolutionarily related to type IV pili transport possibly driven by proton motive force. retraction (disassembly) of pseudopilus allows exogenous DNA to cross peptidoglycan All components of the DNA uptake machine are encoded by genes belonging to the competence regulon except EndA. EndA contributes to virulence by allowing pneumococci to escape from neutrophil extracellular traps, which are made of DNA

Question 66

inflammatory response

Answer 66

tissue damage results in inflammation purpose is to contain site of damage, localize response, eliminate invader, and restore tissue function results in swelling, redness, heat, pain, sometimes loss of function pattern recognition receptors (TLRs, NLRs) trigger detect PAMPs, DAMPs host cells release inflammatory mediators (cytokines, histamine, TNF acts on liver to release acute-phase proteins) inducers include microbes, tissue damage blood vessel damage starts two enzymatic cascades lead to coagulation and increased permeability 1.redness (erythema) 2. swelling (edema) 3. heat 4. pain 5. altered function

Question 67

inflammatory response

Answer 67

histamine is produced by mast cells. -increases permeability of capillaries to white blood cells -allows them to target pathogens in infected tissues Inflammatory process involves cascade of events dilation of small blood vessels greater blood flow (heat, redness); slower flow rate leakage of fluids (swelling, pain) migration of leukocytes from bloodstream to tissues endothelial cells “grab” phagocytes, slow them down phagocytes squeeze between cells of vessel (diapedesis or extravasation) clotting factors wall off site of infection dead neutrophils, tissue debris accumulate as pus

Question 68

Chemotactic response to inflammatory stimulus – diapedesis (extravasation)

Answer 68

endothelial cells "grab" circulating phagocyte phagocytes make adhesion molecules in response, causing them to tumble to a halt they squeeze between the endothelial cells

Question 69

Which type of phagocyte is the first to be recruited to a site of inflammation?

Answer 69

Neutrophil acute inflammation is short term, mainly neutrophils; macrophages clean up damage by ingesting dead cells and debris If acute fails, chronic inflammation results; macrophages, giant cells accumulate, and granulomas form

Question 70

Fibrogenesis

Answer 70

During fibrogenesis, monocytes are recruited to the inflamed liver by their chemokine receptors forming a pro-fibrotic macrophage population. These cells express pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1β which perpetuate hepatocellular injury and enhance the survival of hepatic myofibroblasts. Chemokine expression by these macrophages promotes recruitment of monocytes, other inflammatory cells and hepatic stellate cells. resolution Pro-resolution macrophages remove cellular debris and express TNF-related apoptosis-inducing ligand which promotes myofibroblast apoptosis. This removes the source of scar production Finally, pro-resolution macrophages are a rich source of fibrolytic proteases. Hepatic dendritic cells may also promote the resolution of fibrosis.

Question 71

damaging effects of inflammation

Answer 71

- process can be likened to fire sprinkler system: prevents spread, but damages build - enzymes and toxic compounds from phagocytic cells are released, damage tissues - if limited (cut on finger) then damage minimal -if in delicate system (membranes surrounding brain, spinal cord) then can be severe, even life-threatening

Question 72

Cell death

Answer 72

apoptosis: programmed cell death; doesn’t trigger inflammatory response pyroptosis: if pattern recognition receptors are triggered, cell may undergo cell death with inflammatory response

Question 73

Inflammasomes

Answer 73

play an important role in the induction of inflammatory cascades and coordination of host defenses, both via the activation and secretion of pro-inflammatory cytokines and chemokines, and the induction of a specialized form of immune-stimulatory programmed cell death termed pyroptosis.

Question 74

fever

Answer 74

fever - important host defense mechanism strong indicator of infectious disease, especially bacterial temperature-regulation center in brain normally holds at 37°C but raises during infection in response to pyrogens cytokines produced by macrophages following detection of microbial products by TLRs are endogenous pyrogens exogenous pyrogens produced by microbes growth rates of bacteria optimized for 37°C typically drop sharply above optimum, allows more time for defenses moderate temperature rise increases rates of enzymes enhances inflammatory response, phagocytic killing, multiplication of lymphocytes, release of attractants for neutrophils, production of interferons and antibodies, release of leukocytes from bone marrow

Question 75

adaptive immunity develops throughout life

Answer 75

~week to build following first exposure innate immunity protects meanwhile in some cases, person may not survive long enough adaptive immunity has memory stronger response to re-exposure vaccination relies upon this ability response has molecular specificity must distinguish between “healthy self” and “dangerous” pathogens, cancerous cells

Question 76

Antigen

Answer 76

antigen – a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies.

Question 77

strategy of adaptive immune response

Answer 77

first response to antigen is primary response two strategies for countering foreign materials: *verification usually required humoral immunity eliminates extracellular antigens bacteria, toxins, viruses in bloodstream, tissue fluids 2. cellular immunity deals with antigens within a host cell invading virus

Question 78

humoral immunity

Answer 78

B lymphocytes or B cells responsible develop in bone marrow triggered to proliferate, differentiate into plasma cells in response to extracellular antigens produce Y-shaped proteins called antibodies bind to antigens with specificity many different antibodies needed for wide array of antigens some B cells form memory B cells B-cell receptor: membrane-bound version of B-cell’s specific antibody; binding antigen triggers response *usually needs confirmation from helper T cell respond quickly if antigen encountered again

Question 79

Antibodies

Answer 79

antibody molecules have two functional regions two identical arms and stem of molecule arms bind specific antigen stem functions as “red flag” to tag antigen, enlist other immune system components to eliminate antibodies protect both directly and indirectly directly: bind to antigen, prevent attachment to cell indirectly: tag antigen for elimination

Question 80

cell-mediated immunity

Answer 80

T lymphocytes, or T cells, mature in thymus two subsets: cytotoxic T cells and helper T cells both have multiple surface copies of T-cell receptor (TCR) analogous to BCR, but does not recognize free antigen antigen must be presented by body’s own cells third subset: regulatory T cells have TCR, but role is to prevent immune system from mounting a response against “self”molecules

Question 81

helper T cells and cytotoxic T cells

Answer 81

activated before they can multiply confirm antigen signifies danger dendritic cells responsible for T-cell activation activated, T cell proliferates, differentiates forms effector helper T cells (TH cells) or effector cytotoxic T cells (TC cells) both form memory cells TC cells respond to intracellular antigens, induce apoptosis (virally infected cell) TH cells orchestrate humoral and cell-mediated immunity: activate B cells, macrophages produce cytokines to direct and support T cells

Question 82

How is the humoral response different from that of the cell-mediated response?

Answer 82

The humoral response is geared towards eliminating invaders that are in body fluids whereas the cell-mediated response is directed towards eliminating invaders that are within host cells. Humoral response produces antibodies specific to toxins, free bacteria and viruses present in body fluids - antibodies are produced and secreted as soluble proteins that circulate in blood or lymph. Cell-mediated response – a response to intracellular infection by viruses, bacteria - depends on direct action of lymphocytes.

Question 83

adaptive immune response - lymphocyte receptors

Answer 83

B cells and T cells have membrane-bound receptors function to recognize specific antigens BCR is specific antibody the B cell is programmed to make TCR does not recognize free antigen; must be presented by body’s own cells (antigen-presenting cells - APC’S)

Question 84

lymphatic system tissues and organs

Answer 84

lymphatic organ system - unique to vertebrates composed of draining lymphatic vessels, lymph nodes, and associated lymphoid organs. lymphatic vessels are one-way, absorptive vessels that transport interstitial fluid, immune cells, and macromolecules to lymph nodes, and from these back to the blood circulation

Question 85

anatomy of the lymphatic system

Answer 85

lymphatic vessels carry lymph contains white blood cells, and antigens from tissues moves to lymph nodes lymph empties back into circulatory system inflammatory response: more fluid enters tissues, more antigen-containing fluids enter lymphatic system

Question 86

lymphatic capillaries

Answer 86

lymph formed when interstitial fluid enters initial lymphatic vessels of lymphatic system hydrostatic pressure of tissue fluid drives lymph into lymphatic capillaries Lymphatic capillaries absorb interstitial solutes, macromolecules, and immune cells that extravasate from the blood vascular system. The discontinuous basement membrane and button-like endothelial junctions allow passive cell to cell flow to form lymph

Question 87

lymphatic vessels

Answer 87

Collecting lymphatic vessels contain zipper-like junctions, lymphatic valves, and contractile smooth muscle cells (SMCs) that enable the unidirectional propulsion of lymph. Lymph drains into venous circulation through 4 distinct lymphovenous valves located where the internal jugular vein (IJV) and external jugular vein (EJV) drain into the subclavian vein (SCV).

Question 88

anatomy of the lymphatic system

Answer 88

primary lymphoid organs include bone, thymus hematopoietic stem cells reside in bone marrow; give rise to all blood cells including lymphocytes B cells mature in bone marrow T cells migrate to thymus and mature there brings population of B cells and T cells into contact with antigens lymphocyte must encounter appropriate antigen important because lymphocytes specific to only one or a few antigens

Question 89

lymphocyte development – B cells

Answer 89

negative selection of self-reactive B cells B cells are exposed to “self” in bone marrow; if bind, induced to undergo apoptosis this negative selection removes most B cells; critical for preventing immune system from attacking body

Question 90

T cells migrate to thymus and mature there

Answer 90

positive and negative selection of T cells in thymus positive selection: T cells must recognize MHC eliminated if unable to recognize negative selection: T cells also eliminated if recognize “self” peptides presented on MHC molecules positive selection – CD4 or CD8 negative selection – apoptosis of self-recognizing T cells process is so stringent that over 95% of developing T cells undergo apoptosis in thymus

Question 91

secondary lymphoid organs

Answer 91

once mature, lymphocytes gather in secondary lymphoid organs and wait to encounter antigen secondary lymphoid organs sites where lymphocytes contact antigens-lymph nodes, spleen, tonsils, adenoids, appendix situated throughout body lymph nodes filter and monitor lymph sites where lymphocytes proliferate secondary lymphoid organs sites where lymphocytes contact antigens mucosa-associated lymphoid tissue (MALT) mucosal immunity prevents microbial invasion via mucous membranes

Question 92

anatomy of the lymphatic system- immune surveillance of the intestinal lumen

Answer 92

Peyer's patches small masses of lymphatic tissue found throughout ileum region of small intestine. Peyer’s patches allow intestinal content sampling by specialized M cells monitor intestinal bacteria populations, prevent growth of pathogenic bacteria in intestines. SED=subepithelial dome TDA=thymus-dependent area MLN=mesenteric lymph node oval or round lymphoid follicles (similar to lymph nodes) located in submucosa layer of ileum , extend into mucosa layer

Question 93

Germinal centers

Answer 93

germinal centers in the B cell follicles of secondary lymphoid tissues sites within secondary lymphoid organs where mature B cells proliferate, differentiate, and mutate antibody genes (through somatic hypermutation (affinity maturation) aimed at achieving higher affinity) and switch the class of their antibodies (example: IgM to IgG) during normal immune response to infection. (Wikipedia)

Question 94

MALT and SALT

Answer 94

*MALT: mucosa-associated lymphoid tissue MALT drained by efferent lymphatics but there are no afferent lymphatics lymphocytes exposed in MALT regions go through regional lymph nodes then return to the MALT region after activation lymphoid tissues under skin: skin-associated lymphoid tissue (SALT) Langerhans cells: specialized dentritic cells in skin that sample bacteria both anti-inflammatory and activatory, depending on context

Question 95

antigens

Answer 95

antigen comes from antibody generator reacts specifically with antibody, B-cell receptor, or T-cell receptor great variety of antigens (microbes, pollen) two general categories T-dependent antigens: B cell requires *confirmation from TH cell to be activated 2. T-independent antigens: activate B cells without TH cell help; include lipopolysaccharide (LPS) and molecules with repeating subunits (some carbohydrates)

Question 96

antigens

Answer 96

response to antigens varies depending on type proteins generally elicit strong response; lipids weak small molecules usually not antigenic epitopes trigger response called antigenic determinants regions of macromolecules 10 or so amino acids; three-dimensional shapes bacterial cell has many different epitopes

Question 97

What are antigenic determinants?

Answer 97

Specific regions on an antigen molecule to which the immune response is directed. epitopes

Question 98

antibodies

Answer 98

antibodies also called immunoglobulins Y-shaped proteins with two general parts two identical arms (Fab regions) bind antigen stem (Fc region) named from early studies that yielded two types of fragments: antigen-binding (Fab) fragments and those that could be crystallized (Fc) antibodies have basic Y-shape: antibody monomer two copies of heavy chain and light chain amino acids fold into characteristic domains light chains have two; heavy chains usually four fork of Y is flexible hinge region disulfide bonds join heavy, light chains and two halves

Question 99

Antibodies region

Answer 99

variable region at ends of Fab regions; accounts for specificity antigen-binding site attaches to specific epitope fit precise but reversible: numerous non-covalent bonds constant region includes Fc and part of two Fab regions allows immune system components to recognize otherwise diverse antibody molecules

Question 100

protective outcomes of antibody-antigen binding

Answer 100

neutralization: prevents toxins, viruses from binding opsonization: enhancement of phagocytosis complement system activation: classical pathway immobilization and prevention of adherence: binding to bacterial flagella or pili interferes aggregation: two arms of antigen bind separate antigens antibody-dependent cellular cytotoxicity: targets cell for destruction by natural killer (NK) cells

Question 101

immunoglobulin (Ig) Classes

Answer 101

five major classes: IgM, IgG, IgA, IgD, IgE have same basic monomeric structure each class has different constant region of heavy chain some form multimers of basic monomeric structure each class has distinct functions and properties

Question 102

IgM

Answer 102

IgM 5–13% of circulating antibodies first class produced during primary response main class produced in response to T-independent antigens pentamer five monomeric subunits give 10 antigen-binding sites aggregates effectively large size prevents crossing from bloodstream to tissues primary role in bloodstream infections most efficient class in triggering classical pathway of complement system IgM production begins at birth; infected fetus can make

Question 103

MALT and antibodies

Answer 103

*MALT: mucosa-associated lymphoid tissue mostly IgA in the intestines and respiratory tract to protect against pathogens that may gain access to underlying tissues IgG and IgM secreted into lamina propria to counteract pathogens that have gained access to connective tissue IgE secreted into lamina propria; mediates the release of histamine from mast cells MALT drained by efferent lymphatics but there are no afferent lymphatics lymphocytes exposed in MALT regions go through regional lymph nodes then return to the MALT region after activation

Question 104

IgG

Answer 104

IgG 80–85% of total serum immunoglobulin also exits vessels to enter tissues provides longest-term protection: half-life is 21 days generally first, most abundant circulating class produced during secondary response protect via neutralization, aggregation, opsonization, complement activation, and antibody-dependent cellular cytotoxicity transported across placenta to fetus’s bloodstream maternal IgG protects fetus and newborn degrades gradually over 6 month period infant begins producing IgG found in colostrum (first breast milk) absorbed by newborn’s intestinal tract

Question 105

IgA

Answer 105

IgA IgA is most abundant immunoglobulin class produced monomeric form is 10–13% of serum antibodies dimer: secretory IgA secreted form important in mucosal immunity gastrointestinal, genitourinary, and respiratory tracts secretions: saliva, tears, breast milk protects breast-fed infants against intestinal pathogens protection primarily via neutralizing toxins, viruses and interfering with attachment of microbes to host cells produced by plasma cells of mucosa-associated lymphoid tissue (MALT); secretory component (polypeptide) added to attach antibody to mucus

Question 106

Why should B cells residing in the mucosa-associated lymphoid tissues produce IgA?

Answer 106

Because antigen that enters MALT tissues originated from a mucosal surface such as the lining of the intestinal tract or respiratory tract. IgA is the class of antibody that is secreted, thereby protecting these surfaces.

Question 107

How would mucosal immunity prevent diarrheal disease?

Answer 107

It neutralizes virus and toxins in the intestinal tract and prevents microorganisms from traveling through mucus and adhering to the mucous membranes, thereby blocking the action of intestinal pathogens

Question 108

IgD

Answer 108

IgD <1% of serum immunoglobulins involved with development and maturation of antibody response function in blood not clearly defined

Question 109

IgE

Answer 109

IgE barely detectable in normal blood tightly bound via Fc region to basophils and mast cells allows these cells to detect, respond to antigens antigen binds two adjacent IgE molecules carried by mast cell, cell releases histamine basophils and mast cells also release chemicals when IgE binds to normally harmless foods, dusts, pollens, yielding allergic reactions of coughing, sneezing, swelling some allergic (hypersensitivity) reactions can be life-threatening

Question 110

lymphocyte development

Answer 110

gene rearrangement generates diversity process similar for B cells and T cells each B cell responds to only 1 epitope, but population in body responds to >100 million epitopes V (variable), D (diversity) and J (joining) regions joined by deleting sections of DNA imprecise joining: nucleotides often added, deleted; changes reading frame, adds further diversity light, heavy chains formed separately; combination of two chains creates diversity of antigen-binding site

Question 111

lymphocyte development - B cells

Answer 111

negative selection of self-reactive B cells B cells are exposed to “self” in bone marrow; if bind, induced to undergo apoptosis this negative selection removes most B cells; critical for preventing immune system from attacking body

Question 112

Activation of T cells

Answer 112

effector functions of TH (CD4) cells recognize antigen presented on MHC class II from antigen-presenting cells (APCs) activates with cytokines; may recognize different epitope. B cell likely recognized epitope on pathogen’s surface; TH could recognize peptide from within

Question 113

role of TH cells in macrophage activation

Answer 113

TH cells can recognize peptides presented on MHC class II; activate macrophage to increase power, inflammatory response increases size, metabolism, number of lysosomes produces nitric oxide and other toxic compounds activated macrophages can fuse to form giant cells

Question 114

Tuberculin test: Mantoux tuberculin skin test (TST),also called purified protein derivative (ppd)

Answer 114

The TB skin test is done in two parts. During one visit to a doctor’s office or clinic, a tiny amount of tuberculin is injected into the skin, usually the forearm. tuberculin: a sterile extract purified protein derivative made from the bacteria that causes TB. After receiving the injection, a small, pale bump will form at the site of the injection.

Question 115

Why is it important that B cells and T cells become activated before they can begin multiplying in response to an antigen?

Answer 115

To ensure that they do not mount a response against the body's own tissues.

Question 116

effector functions of TC (CD8) cells

Answer 116

cells present internal proteins on MHC class I; binding by TC indicates recognition of pathogen or cancer TC cells don’t recognize peptides presented by healthy self cell TC induces apoptosis: proteases, cytotoxins (perforin) If an effector CD8 cell recognizes antigen presented on an MHC class I molecule, how should it respond? Induce apoptosis in the presenting cell. Why would a “self” cell not display MHC class I molecules? Some viruses interfere with the process of antigen presentation, so that the cell lacks MHC class I molecules on its surface.

Question 117

natural killer (NK) cells

Answer 117

natural killer cells induce apoptosis in “self” cells NK cells recognize host cells with foreign proteins in membrane bound by antibodies antibody-dependent cellular cytotoxicity (ADCC) NK cells have FC receptors for IgG molecules NK cells bind, deliver perforin- and protease-containing granules to cell, initiating apoptosis also recognize host cells lacking MHC class I some viruses interfere with antigen presentation Why might a virus encode its own version of an MHC class I molecule? It would trick NK cells so that they wouldn't kill the cell that lacks host-encoded MHC class I molecules

Question 118

cancer immunotherapy: T cells are employed to affect tumor cells This creates a memory in the T cells so if the cancer returns, they can act again, and on their own.

Answer 118

CAR-T cells chimeric antigen receptor T cells bypass MHC restriction of the T-cell receptor (TCR) instead acquire TCR-independent, predetermined specificity for a defined cell surface antigen expressed by the target cell of interest using a disarmed virus, T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors, or CARs. these special receptors allow the T cells to recognize and attach to an antigen on tumor cells. recognize and kill cancer cells that have the antigen on their surfaces

Question 119

Natural killer cells in cancer immunotherapy

Answer 119

Specific recognition and elimination of cancer cells by natural killer (NK) cells can be markedly enhanced through expression of chimeric antigen receptors (CARs) which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy.

Question 120

Applications of Immune Response: vaccination

Answer 120

adaptive immunity develops throughout life adaptive immunity has memory - stronger response to re-exposure vaccination relies upon this ability response has molecular specificity must distinguish between “healthy self” and “dangerous” naïve lymphocyte: never encountered antigen activated lymphocyte: received specific signals, proliferates, produces effector lymphocytes: short lived, primary response memory lymphocytes: secondary response characteristics of secondary response significantly faster, more effective than primary pathogens usually eliminated before causing harm vaccination exploits this natural phenomenon

Question 121

Principles of immunization

Answer 121

Immunization is process of inducing immunity has probably had greatest impact on human health of any medical procedures Immunity acquired naturally or artificially via normal events (exposure to infectious agent) or by inducing via immunization passive or active active immunity: follows antigen exposure natural (infection) or artificial (immunization) passive immunity: antibodies from another natural: during pregnancy, mother’s IgG antibodies cross placenta; breast milk contains secretory IgA no memory; protection is lost once antibodies degrade artificial: injection of antiserum (contains antibodies) can prevent disease before or after likely exposure limit duration of certain diseases block action of microbial toxins antitoxin is antiserum that protects against a toxin anti venom What is antitoxin? A preparation of antibodies that neutralize a given toxin.

Question 122

Tetanus example

Answer 122

Tetanus immune globulin is used to prevent tetanus infection Tetanus immune globulin works by giving your body the antibodies it needs to protect it against tetanus infection. This is called passive protection. This passive protection lasts long enough to protect your body until your body can produce its own antibodies against tetanus. What would be a primary advantage of passive immunity with diseases such as tetanus or botulism? Time. You can quickly neutralize the toxin with a passive administration of antibodies to save the patient's life when no time is available for them to make their own active immune response

Question 123

Vaccines

Answer 123

A vaccine is a preparation of a pathogen or its products used to induce active immunity. Vaccines can not only protect an individual against disease, they can also prevent diseases from spreading in a population. For over a hundred years vaccination has been effected by one of two approaches: either introducing specific antigens against which the immune system reacts directly or introducing live attenuated infectious agents that replicate within the host without causing disease and synthesize the antigens that subsequently prime the immune system.

Question 124

ATTENUATED VACCINES

Answer 124

attenuated vaccines: weakened form of pathogen (live organisms) replicates in recipient; disease undetectable or mild grown under conditions resulting in mutations, or genetically manipulated to replace genes advantages: single dose usually induces long-lasting immunity due to microbe multiplying in body may inadvertently immunize others by spreading disadvantages: can sometimes cause disease in immunosuppressed individuals can occasionally revert or mutate, become pathogenic not recommended for pregnant women usually require refrigeration to keep active measles, mumps, rubella, chickenpox, yellow fever, Sabin vaccine against polio – examples In the case of viruses or intracellular microorganisms where cell-mediated immunity is usually desired, attenuated pathogens are capable of replicating within host cells.

Question 125

INACTIVATED VACCINES

Answer 125

inactivated vaccines: unable to replicate advantage: cannot cause infections or revert to pathogenic forms disadvantage: no replication, so no amplification in vivo; immune response is limited booster doses usually needed often contain adjuvant to enhance immune response Inactivated vaccines – multiple different types: inactivated whole agent vaccines: contain killed microorganisms or inactivated viruses treated with formalin or other chemical that doesn’t significantly change surface epitopes includes influenza, rabies, Salk polio vaccine (cholera vaccine)

Question 126

Adjuvants

Answer 126

Adjuvant - pharmacological or immunological agent that modifies effect of other agents. Adjuvants may be added to a vaccine to modify immune response by boosting it to give higher amount of antibodies and longer-lasting protection, minimizing amount of injected foreign material.

Question 127

Inactivated vaccines – toxoids

Answer 127

Toxoid - bacterial toxin whose toxicity is inactivated by formalin or heat treatment, while immunogenicity is maintained. During vaccination, immune response mounted and immunological memory formed against molecular markers of toxoid without resulting in toxin-induced illness. Used in vaccines against diptheria. toxoids: toxins treated to destroy toxic part, retain antigenic epitopes Includes diphtheria, tetanus, (cholera vaccine (B subunit))

Question 128

Other kinds of inactivated vaccines

Answer 128

subunit vaccines: consist of key protein antigens or antigenic fragments from pathogen avoids cell parts that may cause side effects for example, acellular pertussis (aP) vaccine recombinant vaccines: subunit vaccines produced by genetically engineered microorganisms for example, hepatitis B virus; yeast cells produce part of viral protein coat VLP (virus-like particle) vaccines: empty capsids produced by genetically engineered organisms human papillomavirus (HPV) polysaccharide vaccines: made from capsules not effective in young children; polysaccharides are T-independent antigens, elicit poor response pneumococcus vaccines for adults conjugate vaccines: polysaccharides linked to proteins converts polysaccharides into T-dependent antigens Haemophilus influenzae type b (Hib)- nearly eliminated Hib meningitis in children; Streptococcus pneumoniae vaccine promising

Question 129

B-cell response: humoral immunity - T-independent antigens

Answer 129

response to T-independent antigens can activate B cells without aid of TH cells pathogen-specific molecules with numerous identical evenly spaced epitopes (polysaccharide capsules) are bound by clusters of B-cell receptors ->leads to activation of B cells but not very immunogenic in young children effector functions of TH (CD4) cells: recognize antigen presented on MHC class II from antigen-presenting cells (APCs) activates with cytokines; may recognize different epitope B cell likely recognized epitope on pathogen’s surface; TH could recognize peptide from within

Question 130

development of conjugate vaccines

Answer 130

Can make conjugate vaccine against T-independent antigen (capsule of H. influenzae) converts to T-dependent antigen by covalently attaching protein; B cell responds to capsule, TH responds to protein component, activates B cell

Question 131

Herd immunity and vaccines

Answer 131

Vaccine is preparation of pathogen or its products used to induce active immunity protect individual; prevent spread in population herd immunity develops when critical portion of population is immune to disease; infectious agent unable to spread due to insufficient susceptible hosts responsible for declines in childhood diseases diseases sometimes reappear and spread as result of failure to vaccinate children effective vaccines should be safe, have few side effects give long lasting protection low in cost, stable, easy to administer

Question 132

mRNA vaccines

Answer 132

Elicit both humoral and cell-mediated response High rate and magnitude of protein expression Cannot integrate into the genome – no chance of insertional mutagenesis

Question 133

Current immunization progress

Answer 133

current progress in immunization recent advances yielding safer, more effective vaccines for example, conjugate vaccines that enlist T-cell help new adjuvants being developed administering of cytokines with vaccine novel types being actively studied peptide vaccines (key antigenic peptides from pathogens) edible vaccines (transfer genes for key antigens into plants; could eliminate global difficulties of transport, storage) DNA-based vaccines (inject into muscle tissue, which expresses for a short time)

Question 134

Principles of epidemiology

Answer 134

Epidemiology is study of disease patterns in populations epidemiologists collect, compile data about sources of disease and risk factors (health detectives) design infection control strategies, prevent or predict spread of disease diverse disciplines: ecology, microbiology, sociology, statistics, psychology many daily habits (handwashing, waste disposal) based on work communicable (contagious) diseases can be transmitted from one host to another measles, colds, influenza transmission determined by interactions between environment, pathogen, and host control of any of these factors may break infection cycle improved sanitation (prevent infection) antimicrobial medications (kill or inhibit pathogens) vaccination (increase host resistance) non-communicable diseases do not spread from host to host Microorganisms often arise from individual’s normal microbiota or environment (Clostridium tetani)

Question 135

principles of epidemiology - rates of disease in a population

Answer 135

rate = # cases/size of population per unit of time A rate is a measure of the frequency an event occurs in a defined population in a defined time (number of deaths per hundred thousand in one year). It has a time dimension, while a proportion (number with cancer divided by the total population) doesn’t.

Question 136

Attack rate

Answer 136

is percentage of people who become ill in population after exposure reflects infectious dose, immune status of population Infectious dose: the amount of a pathogen that is required to establish an infection. Attack rate: the attack rate is the proportion of an at-risk population that contracts the disease during a specified time interval.

Question 137

R0

Answer 137

R0 (R naught) is defined as the expected number of secondary cases produced by a single (typical) infection in a completely susceptible population. It is the ability to transmit the disease; high R0 leading to a higher rate of transmission and a thus higher number of cases in a susceptible population. For example, if R0 of a disease introduced in a susceptible population is 5, it implies that, on average, the disease is likely to be transmitted by an infectious case to five susceptible hosts. With an R0 value of more than 1, the transmission is likely to continue in a population, and in case the R0 is below 1, the transmission will probably wane off because one infectious case will infect less than one person on average. R0 - basic reproduction number. It can measure disease severity and also gives an estimate about the herd immunity required to reverse an epidemic. Easily transmissible infections have a higher R0.

Question 138

Incidence rate

Answer 138

incidence rate is number of new cases/time/population measure of risk of an individual contracting a disease

Question 139

prevalence

Answer 139

Prevalence = number of people with the disease (the total number of cases) at a given time / number of people at risk in a given population both expressed as cases per 100,000 people reflects overall impact of disease on society includes old and new cases, as well as duration of disease Prevalence is a proportion, rather than a rate. PREVALENCE. "How many people actually have the disease at any point in time?” Prevalence provides a good way to indicate the burden of disease in a population. It is influenced by the incidence and by the duration of the condition: under most circumstances, prevalence = incidence × disease duration.

Question 140

Explain the difference between incidence of a disease and prevalence of the disease.

Answer 140

Incidence describes the number of new cases in a region during a specific time period; prevalence describes the total number of cases in a region during a specific time period. Incidence conveys information about the risk of contracting the disease, whereas prevalence indicates how widespread the disease is.

Question 141

rates of disease in a population

Answer 141

morbidity is incidence of disease in population at risk contagious diseases (influenza) often have high morbidity rate: infected individual may transmit to several mortality is overall death rate in population in developed countries, most often associated with non-communicable diseases (cancer, heart attack) communicable diseases major cause of death in developing countries case-fatality rate is percentage of population that dies from a specific disease plague, Ebola feared because of very high case-fatality rate case-fatality rate for AIDS has decreased from improved treatment; prevalence has increased as more with disease survive

Question 142

Endemic diseases

Answer 142

endemic diseases constantly present in population common cold, measles in United States sporadic – only occur from time to time epidemic is unusually large number of cases can be from introduced or endemic disease outbreak is group of cases at specific time and population

Question 143

Reservoir

Answer 143

The reservoir of an infectious agent is the habitat in which the agent normally lives, grows, and multiplies. Reservoirs include humans (includes carriers), animals, and the environment The term zoonosis refers to an infectious disease that is transmissible under natural conditions from vertebrate animals to humans Plants, soil, and water in the environment are also reservoirs for some infectious agents.

Question 144

chain of infection

Answer 144

reservoirs of infection natural habitat in which pathogen lives in or on animal, human, or in environment (soil, water) identification important in disease control control of rats, mice, prairie dogs (reservoirs of Yersinia pestis) prevents plague epidemics in U.S. human reservoirs only in humans or in other animals, environment often easier to control if only in humans smallpox symptomatic or asymptomatic human reservoirs symptomatic infections: obvious source of pathogens asymptomatic infections: harder to identify, carriers may not realize, can spread to others many people carry Staphylococcus aureus non-human animal reservoirs common (gastrointestinal pathogens, rabies virus) zoonoses (zoonotic diseases) exist in mostly in animals, can be transmitted to humans (examples, plague, rabies) - more severe in humans environmental reservoirs difficult or impossible to eliminate (Clostridium)

Question 145

Portal of exit is the path by which a pathogen leaves its host.

Answer 145

portals of exit and portals of entry body surface or orifice: entry, exit route for pathogen respiratory tract: exit in droplets of saliva, mucus (Mycobacterium tuberculosis, respiratory viruses) skin: shed on skin cells (Staphylococcus aureus) intestinal tract: shed in feces (example, Vibrio cholerae) genital pathogens: semen, vaginal secretions (Neisseria gonorrhoeae) to cause disease, must be transmitted also colonize surface or enter host

Question 146

Transmission

Answer 146

direct direct contact skin-to-skin contact, kissing, and sexual intercourse. droplet spread spray with relatively large, short-range aerosols produced by sneezing, coughing, or even talking. indirect airborne carried by dust or droplet nuclei suspended in air. Airborne dust includes material that has settled on surfaces and become re-suspended by air currents as well as infectious particles blown from the soil by the wind vehicle-borne food, water, biologic products (blood), and fomites (inanimate objects such as handkerchiefs, bedding, or surgical scalpels). vector-borne (mechanical or biologic) mosquitoes, fleas, and ticks may carry an infectious agent through purely mechanical means or may support growth or changes in the agent vertical transmission: pregnant woman to fetus, or mother to infant during childbirth, breast feeding horizontal transmission: person to person via air, physical contact, ingestion of food or water, or vector

Question 147

Infectious dose

Answer 147

infectious dose: that amount of a pathogenic agent that will cause infection in susceptible subjects ID is number of cells that infects 50% of population or, the number of organisms that will cause 50% of exposed individuals to become ill.. The infectious dose of most pathogens is NOT equal! direct contact: handshake, sexual intercourse infectious dose important (Shigella is 10–100 cells) from hands, can be ingested: fecal-oral transmission handwashing considered single most important measure for preventing spread of infectious disease some pathogens cannot survive in environment, require intimate sexual contact (Treponema pallidum, Neisseria gonorrhoeae) droplet transmission: respiratory droplets generally fall to ground within a meter from release densely populated buildings (schools, military barracks) spread minimized by covering mouth when sneezing indirect contact air: respiratory diseases commonly transmitted particles larger than 10 µm usually trapped by mucus smaller particles can enter lungs, carry pathogens talking, laughing, singing, sneezing, coughing generate droplet nuclei (microbes attached to dried material) remain suspended number of bacteria in air proportional to number of people difficult to control ventilation systems, negative pressure, HEPA filters

Question 148

Vehicle and vector borne

Answer 148

vectors: living organisms that can carry pathogen most commonly arthropods: mosquitoes, flies, fleas, lice, ticks; can carry internally or externally can be mechanical or biological vector control important in preventing diseases disease transmission: vehicle-borne fomites: inanimate objects clothing, table-tops, doorknobs, drinking glasses food and water: can become contaminated animal products (meat, eggs) cross-contamination: transfer from one food to another municipal water systems can distribute to large numbers Cryptosporidium parvum outbreak in Milwaukee, Wisconsin (1993)

Question 149

Portal of entry and susceptible host

Answer 149

Portal of entry - how a pathogen enters a susceptible host - must provide access to tissues in which the pathogen can multiply or a toxin can act. Infectious agents may use the same portal to enter a new host that they used to exit the source host, or many follow a “fecal-oral” route: they exit source host in feces, are carried on hands to a vehicle such as food, water, or utensil, and enter a new host through the mouth. Susceptible host - depends on genetic or constitutional factors, specific immunity, and nonspecific factors that affect an individual’s ability to resist infection or to limit pathogenicity. An individual’s genetic makeup may either increase or decrease susceptibility.

Question 150

characteristics of the pathogen

Answer 150

virulence: ability to cause disease factors that allow pathogen to adhere to or penetrate host cell, thwart immune defenses, damage host dose: minimum number of pathogens required doses below minimum necessary may produce asymptomatic infection: immune system eliminates organism before symptoms appear very large dose (laboratory accident) may produce serious disease even in normally immune individual incubation period: influences extent of spread long incubation period can allow extensive spread 10,000 individuals drank water containing Salmonella enterica serotype Typhi 10–14 day incubation period allowed spread of typhoid fever to at least 6 different countries (1963; ski resort in Switzerland)

Question 151

Course of infectious disease

Answer 151

incubation period: time between infection and onset varies: few days for common cold to years for leprosy depends on growth rate, host’s condition, infectious dose illness: signs and symptoms of disease may be preceded by prodromal phase (vague symptoms) convalescence: recuperation, recovery from disease carriers may harbor and spread infectious agent for long periods of time in absence of signs or symptoms Depending on the microbe and the illness, an asymptomatic carrier in the incubation period might be shedding infectious microbes to his/her surroundings. In such a case, a longer incubation period would lead to a greater spread of the disease as the carrier comes into contact with more individuals while he/she is generally appearing to be healthy.

Question 152

Characteristics of host

Answer 152

immunity to pathogen: previous exposure, immunization herd immunity protects non-immune individuals in population; >90% immunity typically sufficient antigenic variation can overcome (avian influenza) general health: malnutrition, overcrowding, fatigue developing world more susceptible: crowding, poor food, sanitation age: very young, elderly generally more susceptible Immune system less developed in young; wanes in old Elderly also less likely to update immunizations

Question 153

Epidemiological studies

Answer 153

descriptive studies Used to identify potential risk factors that correlate with the development of disease. Determining the time that the illness occurred helps distinguish a common-source epidemic from a propagated epidemic. Some epidemics are seasonal. analytical studies Designed to determine which risk factors are relevant to disease development. A case-control study compares the past activities of cases with controls to determine the cause of the epidemic. Cross-sectional studies survey a range of people at a given time. Cohort studies compare groups to determine if the identified risk factors predict a tendency to develop disease. experimental studies Used to evaluate the effectiveness of a treatment or intervention in preventing a disease.

Question 154

Descriptive studies

Answer 154

descriptive studies: data collected following outbreaks clues about disease the person: affected individuals – defines population at risk age, gender, ethnicity, occupation, personal habits, previous illnesses, socioeconomic class, marital status ….may all yield clues about risk the place: geographic location helps pinpoint source, yield clues about potential reservoirs, vectors, or boundaries …. that might affect transmission the time: season important; also rate of spread propagated epidemic: slow rise in cases suggests contagious disease spreading in population; first case is called index case common-source epidemic: rapid rise in cases suggests exposure to single source of pathogen

Question 155

normal microbiota

Answer 155

normal microbiota resident microbiota inhabit sites for extended periods transient microbiota inhabit temporarily protective role of normal microbiota protection against pathogens cover binding sites - prevent attachment consume available nutrients produce compounds toxic to other bacteria when killed or suppressed (during antibiotic treatment), pathogens may colonize, cause disease antibiotics inhibit Lactobacillus; results in vulvovaginal candidiasis antibiotics inhibit intestinal microbiota, allow overgrowth of toxin-producing Clostridium difficile

Question 156

Hygiene hypothesis

Answer 156

development of oral tolerance immune system learns to lessen response to many microbes that routinely inhabit gut as well as food hygiene hypothesis: insufficient exposure to microbes can lead to allergies

Question 157

Colonization and infection

Answer 157

Colonization: microbe establishing itself on body surface infection used to refer to pathogen subclinical: no or mild symptoms infectious disease - noticeable impairment symptoms: subjective effects experienced by patient (pain and nausea) signs: objective evidence (rash, pus formation, swelling) initial infection = primary infection damage can predispose individual to developing secondary infection (respiratory illness impairing mucociliary escalator)

Question 158

Pathogenicity

Answer 158

Pathogenicity – potential capacity to cause disease primary pathogen: microbe or virus causes disease in healthy individual plague, malaria, measles, influenza, diphtheria, tetanus, tuberculosis opportunistic pathogen causes disease only when body’s innate or adaptive defenses are compromised or when introduced into unusual location can be members of normal microbiota or common in environment (Pseudomonas) virulence - degree of pathogenicity virulence factors - traits that allow microorganism to cause disease

Question 159

Infectious dose

Answer 159

communicable or contagious diseases easily spread infectious dose - number of microbes necessary to establish infection ID50 is number of cells that infects 50% of population or, the number of organisms that will cause 50% of exposed individuals to become ill… Shigellosis results from ~10–100 ingested Shigella Salmonellosis results from ~106 ingested Salmonella enterica serotype Enteritidis (difference reflects ability to survive stomach acid) incubation period: time between infection and onset varies: few days for common cold to years for leprosy depends on growth rate, host’s condition, infectious dose illness: signs and symptoms of disease preceded by prodromal phase (vague symptoms) convalescence: recuperation, recovery from disease carriers - may harbor and spread infectious agent for long periods of time in absence of signs or symptoms

Question 160

Distribution of pathogens

Answer 160

distribution of pathogen localized infection: microbe limited to small area (boil caused by Staphylococcus aureus) systemic infection: agent disseminated throughout body (measles) suffix -emia means “in blood” bacteremia: bacteria circulating in blood not necessarily a disease state viremia: viruses circulating in bloodstream toxemia: toxins circulating in bloodstream septicemia or sepsis: acute, life-threatening illness caused by infectious agents or products in bloodstream

Question 161

Adherence and colonization

Answer 161

adhesins attach to host cell receptor located at tips of pili (called fimbriae) can be component of capsules or various cell wall proteins binding highly specific; exploits host cell receptor growth in biofilms siderophores – bacterial iron-binding molecules (host uses lactoferrin and transferrin to bind iron and limit the growth of microbes) avoid secretory IgA (protects mucosal surfaces) rapid pili turnover (to shed any bound antibody) antigenic variations IgA proteases (enzymes that cleave IgA antibodies) compete with normal microbiota, tolerate toxins

Question 162

avoiding host defenses

Answer 162

hiding within host cell avoid complement proteins, phagocytes, and antibodies Shigella - transfer from intestinal epithelial cell to adjacent cells by causing host cell actin polymerization Listeria monocytogenes (meningitis) does same avoiding killing by complement system proteins serum resistant bacteria resist killing by the complement system Neisseria gonorrhoeae hijacks mechanisms of host system prevent encounters with phagocytes C5a peptidase: degrades chemoattractant C5a resulting in decreased accumulation of phagocytes. Streptococcus pyogenes (causes strep throat) capsules: interfere with opsonization M protein: cell wall of Streptococcus pyogenes binds regulatory protein that inactivates C3b Fc receptors: bind Fc region of antibodies Staphylococcus aureus, Streptococcus pyogenes

Question 163

surviving within phagocytes

Answer 163

escape from phagosome: before lysis with lysosomes Listeria monocytogenes produces molecule - forms pores in membrane; Shigella species lyse phagosome prevent phagosome-lysosome fusion: avoid destruction Salmonella sense ingestion by macrophage, make protein that blocks fusion process survive within phagolysosome: few survive destructive environment Coxiella burnetii (Q fever) can withstand; delays fusion

Question 164

avoiding antibodies

Answer 164

IgA protease: cleaves IgA, found in mucus, secretions Neisseria gonorrhoeae and others produce antigenic variation: alter structure of surface antigens, stay ahead of antibody production Neisseria gonorrhoeae varies antigenic structure of pili mimicking host molecules: cover surface with molecules similar to those found in host cell, appear to be “self” Streptococcus pyogenes form capsule from hyaluronic acid, a polysaccharide found in tissues

Question 165

damage to host

Answer 165

exotoxins: proteins with damaging effects secreted into tissue following bacterial lysis foodborne intoxication results from consumption destroyed by heating; most exotoxins heat-sensitive act locally or systemically proteins, so immune system can generate antibodies many fatal before immune response mounted vaccines therefore critical: toxoids are inactivated toxin antitoxin is suspension of neutralizing antibodies to treat neurotoxins damage nervous system enterotoxins cause intestinal disturbance cytotoxins damage variety of cell types

Question 166

Exotoxins

Answer 166

A-B toxins have two parts A subunit is toxic, usually an enzyme B subunit binds to cell, dictates cell type to be infected structure allows novel approaches for vaccines and therapies; can use B subunit to deliver medically useful compounds to specific cell type membrane-damaging toxins – (proteins) cytotoxins disrupt plasma membranes, lyse cells hemolysins lyse red blood cells some insert into membranes, form pores streptolysin O from Streptococcus pyogenes phospholipases hydrolyze phospholipids of membrane α-toxin of Clostridium perfringens (gas gangrene)

Question 167

Exotoxins: superantigens bind MHC class II antigen on T cells

Answer 167

superantigens: simultaneously bind MHC class II and T-cell receptor T-cell interprets as antigen recognition toxic effect from cytokine release from TH include toxic shock syndrome toxin (TSST), several by Staphylococcus aureus, Streptococcus pyogenes

Question 168

Endotoxin

Answer 168

endotoxin, other bacterial cell wall components endotoxin is lipopolysaccharide (LPS) lipid A triggers inflammatory response when localized, response helps clear when systemic, causes widespread response: septic shock or endotoxic shock lipid A typically released following cell lysis phagocytosis, MAC formation, certain antibiotics activates innate and adaptive defenses toll-like receptors (monocytes, macrophages, others) induces cytokine production also T-independent antigen response of B-cells heat-stable; autoclaving does not destroy peptidoglycans, other components also trigger

Question 169

damage to host - comparison of exotoxins and endotoxin

Answer 169

exotoxins from Gram-positives and Gram-negatives protein; potent; usually heat-inactivated endotoxins only from Gram-negatives lipid A component of LPS; small localized amounts yield appropriate response, systemic distribution can be deadly; - heat-stable

Question 170

damage to host

Answer 170

damaging effects of the immune response damage associated with inflammation phagocytic cells can release enzymes and toxic products damage associated with adaptive immunity immune complexes: antigen-antibody complexes can form, settle in kidneys and joints, and activate complement system leading to inflammation acute *glomerulonephritis following skin, throat infections of S. pyogenes cross-reactive antibodies: may bind to body’s own tissues, promote autoimmune response acute rheumatic fever following S. pyogenes infection

Question 171

Chapter 16 Host-Microbe Interactions summary

Answer 171

Many microorganisms do not make their human host sick. Three categories of host-microbial symbiosis (mutualism, commensalism, and parasitism). Benefits are provided to the host by the normal microbiota, including aiding digestion, preventing infection, and helping immune system development and function. The effect of pathogenic microbes on the host In order to cause an infection, a pathogen must possess virulence factors that allow it to colonize the host, obtain nutrients, and avoid the immune system response. Terminology of infectious disease Strategies used by pathogens to attach to host cells, obtain nutrients such as iron, and enter host cells Strategies to avoid the immune system including avoiding phagocytes, complement, and antibodies. The damage caused by the pathogen to the host including direct damage through production of toxins, and indirect damage through overreaction of the host immune system to the pathogen Bacterial pathogens Viral pathogens (including some additional strategies viruses use to circumvent the adaptive immune response) Eukaryotic pathogens: malarial parasites and RBC’s