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Flashcards in exam 4 Deck (152):
1

The nervous system

a) Barriers at the surface of the human brain-Meninges: the three membranes (the dura mater, arachnoid, and pia mater) that line the skull and vertebral canal and enclose the brain and spinal cord.
b) Blood-brain barrier: is a highly selective semipermeable membrane barrier, separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS).
- is formed by brain endothelial cells and it allows the passage of water, some gases, and lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function.
-it prevents the entry of lipophilic potential neurotoxins by way of an active transport mechanism
-also has astrocytes which support the epithelial cells in maintaining the blood brain barrier
Microbes can enter the blood brain barrier through endothelial cells, can enter using “Trojan horse” by entering white blood cells
Can enter through the paracellular pathway- squeeze through junction between endothelial cells
Cause inflammatory response to cross blood-brain barrier
c) Blood-cerebrospinal fluid barrier: The blood–cerebrospinal fluid barrier is a pair of barriers that separates peripheral and cerebral blood from the cerebrospinal fluid (CSF); it is made of epithelial cells. The blood–CSF barrier serves the same purpose as the blood–brain barrier, but facilitates the transport of different substances into the brain due to the distinct structural characteristics between the two barrier systems.
The blood-cerebrospinal fluid barrier also modulates the entry of leukocytes from the blood to the central nervous system.

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b) Blood-brain barrier:

is a highly selective semipermeable membrane barrier, separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS).
- is formed by brain endothelial cells and it allows the passage of water, some gases, and lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function.
-it prevents the entry of lipophilic potential neurotoxins by way of an active transport mechanism
-also has astrocytes which support the epithelial cells in maintaining the blood brain barrier
Microbes can enter the blood brain barrier through endothelial cells, can enter using “Trojan horse” by entering white blood cells
Can enter through the paracellular pathway- squeeze through junction between endothelial cells
Cause inflammatory response to cross blood-brain barrier

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Blood-cerebrospinal fluid barrier

: The blood–cerebrospinal fluid barrier is a pair of barriers that separates peripheral and cerebral blood from the cerebrospinal fluid (CSF); it is made of epithelial cells. The blood–CSF barrier serves the same purpose as the blood–brain barrier, but facilitates the transport of different substances into the brain due to the distinct structural characteristics between the two barrier systems.
The blood-cerebrospinal fluid barrier also modulates the entry of leukocytes from the blood to the central nervous system.

4

1. Be able to describe the basic structures and functions of the nervous system that are pertinent to microbial infection.

Nasal cavity: through nose, directly to the brain- the olefactory epithelium cells, to the olfactory bulb in the CNS
Microglia: function as macrophages in the CNS. Pathogens will get into the CNS through “Trojan horse- use paracellular transport (the transfer of substances across an epithelium by passing through the intercellular space between the cells), and cause inflammation-induced damage to the nervous system
Through motor neurons-especially viruses
Infect sensor neurons and travel through peripheral nervous system to central

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2. What are the unique features of rabies virus infection and disease? What is the route through the human body? How does pre- and post-exposure prophylaxis work?

It’s a negative single stranded RNA genome, enveloped.
Has 5 proteins:
-Nucleoprotein (N)
Phosphoprotein (P)
Matrix protein (M)
Glycoprotein (G)
Large RNA polymerase protein (L)

It enters muscle tissue from a bite, replicates, enters the peripheral motor neurons at neuromuscular synapses, gets transported to the CNS, then spreads to salivary glands from the brain
-enters cell->gets transcribed-> then either gets translated or keeps replicating->then is released
Pre-exposure prophylaxis: control in reservoir: animal vaccination- oral vaccination in wildlife, live attenuated and subunit vaccines
Control in humans: pre-exposure vaccines- receive the inactivated virus
Treatment post-exposure prophylaxis: disease is preventable if treated before symptoms manifest by wound cleaning, rabies immunoglobulin infiltrated into wound and given intramuscularly, post-exposure vaccine which is just a booster if already given pre-exposure vaccine
After symptoms: nothing

6

Rabies
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control


Rabies Reservoir: humans, infected animals-canines, carnivores, livestock,
Rabies Basic biology and contribution of this to disease: has a negative single stranded RNA genome, is enveloped. Has 5 proteins named after their dominant function- each has multiple functions: Nucleoprotein(N), Phosphoprotein (P), Matrix protein (M)-forms shell, Glycoprotein (G)-major protein that is antigenic, Large RNA polymerase protein (L).
Rabies Mechanism of transmission: bite-saliva of infected animals
Rabies Major sites of colonization: muscle tissue and neurons, has an incubation period. It can replicate in neuron and spread from there
Rabies Major sites of disease: central nervous system, salivary glands
Rabies Main diseases: causes inflammation of the brain and spinal cord that can lead to encephalopathy and, coma and later, death. Also causes paralysis of legs, trouble breathing, Encephalopathy is any type of disease that changes the brain's function or structure
Rabies Major virulence factors: has Has 5 proteins which affect/inhibit innate immune response, which causes a delay in the adaptive immune response. It slows the innate response long enough for it to get ot the CNS: Nucleoprotein(N), Phosphoprotein (P), Matrix protein (M), Glycoprotein (G), Large RNA polymerase protein (L).
Rabies virus (RABV) inhibits innate immunity until late in infection to delay AMI
-N inhibits RIG-1 activation (which is a pattern recognition receptor)
-P inhibits IFN induction (Interferons are a group of signaling proteins made and released by host cells in response to the presence of several pathogens)
P also prevents nuclear import of STAT1/2 (a transcription factor that activates transcription of interferons etc)
Rabies Main disease symptoms: 2 types: furious and paralytic.
-Furious: behavior: hyperactivity, confusion, and agitation
exposure->first symptoms (1-2 days): fever, pruritus (severe itching) and paresthesia (pins and needles feeling due to damage to nervous system), followed by clinical expression (1-4 days): hydrophobia, hypersalivation, eventually death (1-7 days).
-Paralytic: “calmer” behavior: by drowsiness, lack of energy, coma and then death
Exposure->incubation 20-90 days-> first symptoms- fever, pruritus and paresthesia-> clinical expression: dysphagia, respiratory failure, hypersalivation->coma->death
Rabies Main treatment and control: control in reservoir: animal vaccination- oral vaccination in wildlife, live attenuated and subunit vaccines
Control in humans: pre-exposure vaccines- receive the inactivated virus
Treatment post-exposure: disease is preventable if treated before symptoms manifest by wound cleaning, rabies immunoglobulin infiltrated into wound and given intramuscularly, post-exposure vaccine which is just a booster if already given pre-exposure vaccine
After symptoms: nothing

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Rabies Reservoir

Rabies Reservoir: humans, infected animals-canines, carnivores, livestock,

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Rabies Basic biology and contribution of this to disease

has a negative single stranded RNA genome, is enveloped. Has 5 proteins named after their dominant function- each has multiple functions: Nucleoprotein(N), Phosphoprotein (P), Matrix protein (M)-forms shell, Glycoprotein (G)-major protein that is antigenic, Large RNA polymerase protein (L).

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Rabies Mechanism of transmission

bite-saliva of infected animals

10

Rabies Major sites of colonization

Rabies Major sites of colonization: muscle tissue and neurons, has an incubation period. It can replicate in neuron and spread from there

11

Rabies Major sites of disease

Rabies Major sites of disease: central nervous system, salivary glands

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Rabies Main diseases

Rabies Main diseases: causes inflammation of the brain and spinal cord that can lead to encephalopathy and, coma and later, death. Also causes paralysis of legs, trouble breathing, Encephalopathy is any type of disease that changes the brain's function or structure

13

Rabies Major virulence factors:

has Has 5 proteins which affect/inhibit innate immune response, which causes a delay in the adaptive immune response. It slows the innate response long enough for it to get ot the CNS: Nucleoprotein(N), Phosphoprotein (P), Matrix protein (M), Glycoprotein (G), Large RNA polymerase protein (L).
Rabies virus (RABV) inhibits innate immunity until late in infection to delay AMI
-N inhibits RIG-1 activation (which is a pattern recognition receptor)
-P inhibits IFN induction (Interferons are a group of signaling proteins made and released by host cells in response to the presence of several pathogens)
P also prevents nuclear import of STAT1/2 (a transcription factor that activates transcription of interferons etc)

14

Rabies Main disease symptoms

: 2 types: furious and paralytic.
-Furious: behavior: hyperactivity, confusion, and agitation
exposure->first symptoms (1-2 days): fever, pruritus (severe itching) and paresthesia (pins and needles feeling due to damage to nervous system), followed by clinical expression (1-4 days): hydrophobia, hypersalivation, eventually death (1-7 days).
-Paralytic: “calmer” behavior: by drowsiness, lack of energy, coma and then death
Exposure->incubation 20-90 days-> first symptoms- fever, pruritus and paresthesia-> clinical expression: dysphagia, respiratory failure, hypersalivation->coma->death

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Rabies Main treatment and control

control in reservoir: animal vaccination- oral vaccination in wildlife, live attenuated and subunit vaccines
Control in humans: pre-exposure vaccines- receive the inactivated virus
Treatment post-exposure: disease is preventable if treated before symptoms manifest by wound cleaning, rabies immunoglobulin infiltrated into wound and given intramuscularly, post-exposure vaccine which is just a booster if already given pre-exposure vaccine
After symptoms: nothing

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Rabies replication cycle

similar to influzenza, measles. Rabies infects neuron and muscles->virus binds receptos and is taken up via endocytosis->transcription of – RNA to + RNA strand which then makes more – RNA->once replication occurs, virus is released from cell

17

Herpes
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

Herpes Reservoir: humans, life long
Herpes Basic biology and contribution of this to disease: enveloped, has a capsid with DS linear DNA viruses- alpha, beta and gamma strains
Genome is about 150,000bp, and encodes about 80 genes, is about 150 nm in diameter- 50% needed for replication, 50% needed to interact with host cells= complex virus
Has a lipid bilayer, envelope glycoproteins, transmembrane proteins, envelope, capsid
Has its own DNA polymerase and nucleotide scavenging enzymes which allows replication in non-growing cells
Alpha: target are epithelial cells, latency occurs in neurons
Beta: immune cells are primary targets, latency in immune cells
Gamme: immune cells primary target, latency in B cells
Herpes Mechanism of transmission: neonatal transmission and disease
Herpes Major sites of colonization: initial infection in mucoepithelial cells,
Herpes Major sites of disease: most infections are limited to site/latency
Lytic infection: direct cytopathological effect and lesion at infection site
-avoidance of immune response by cell-to-cell spread and syncytia formation, establishes latency in neurons=neveous system, reactivated by stress and travels back to the lesion site for eruption
CMI required to control virus, cell-mediated immunopathology also contributes to symptoms
Lytic infection in epithelial cells
It can’t get to the CNS, but stays in PNS
Herpes Main diseases: complications include infections of eye or brain, systemic disease in immunocompromised people, neonatal transmission and disease
Neonatal herpes can affect skin, eyes and mouth, CNS or be disseminated
Herpes Major virulence factors
Herpes Main disease symptoms: complications inc
Herpes Main treatment and control: no vaccine, but antivirals that inhibit viral DNA polymerase can limit replication upon reactivation, but don’t affect latency

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Herpes Reservoir

: humans, life long

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Herpes Basic biology and contribution of this to disease

enveloped, has a capsid with DS linear DNA viruses- alpha, beta and gamma strains
Genome is about 150,000bp, and encodes about 80 genes, is about 150 nm in diameter- 50% needed for replication, 50% needed to interact with host cells= complex virus
Has a lipid bilayer, envelope glycoproteins, transmembrane proteins, envelope, capsid
Has its own DNA polymerase and nucleotide scavenging enzymes which allows replication in non-growing cells
Alpha: target are epithelial cells, latency occurs in neurons
Beta: immune cells are primary targets, latency in immune cells
Gamme: immune cells primary target, latency in B cells

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Herpes Mechanism of transmission

Herpes Mechanism of transmission: neonatal transmission and disease

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Herpes Major sites of colonization

Herpes Major sites of colonization: initial infection in mucoepithelial cells,
Alpha – mucoepithelial cells primary target, latency in
neurons

• Beta – immune cells primary target, latency in immune
cells

• Gamma - immune cells primary target, latency in B cells

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Herpes Major sites of disease

most infections are limited to site/latency
Lytic infection: direct cytopathological effect and lesion at infection site
-avoidance of immune response by cell-to-cell spread and syncytia formation, establishes latency in neurons=neveous system, reactivated by stress and travels back to the lesion site for eruption
CMI required to control virus, cell-mediated immunopathology also contributes to symptoms
Lytic infection in epithelial cells
It can’t get to the CNS, but stays in PNS

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Herpes Main diseases

complications include infections of eye or brain, systemic disease in immunocompromised people, neonatal transmission and disease
Neonatal herpes can affect skin, eyes and mouth, CNS or be disseminated

24

Herpes Main treatment and control

no vaccine, but antivirals that inhibit viral DNA polymerase can limit replication upon reactivation, but don’t affect latency

25

HSV-1

3.7 billion people infected, oral herpes, spread by oral secretions, increase in genital herpes

26

HSV-2

about 400 million people infected, genital herpes, spreads through sexual contact, infections increase susceptibility to HIV infection

27

3. What are the unique features of Human Herpes Simplex virus infection and disease? How and where is latency established?

replication in non-growing cells
Genome is about 150,000bp, and encodes about 80 genes, is about 150 nm in diameter
Site of latency established are neurons, but reactivated by stress, and travels back to lesion site for eruption
Infected individuals can produced virus without symptoms

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Polio
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

Polio virus Reservoir: humans (can affect some primates experimentally) so can be eradicated worldwide
Polio virus Basic biology and contribution of this to disease: part of picornaviruses- small naked RNA viruses, single stranded, + strand RNA virus
Viral particles ae about 30nm in diameter, resistant to environment, resilient viral capsule
Polio virus Mechanism of transmission: fecal-oral route- contaminated water, direct oral secretion ingestion
Polio virus Major sites of colonization: mucosal surface
Polio virus Major sites of disease: primarily gastrointestinal virus, but affects nervous system which is accidental. Spreads from mucosal surface to lymph nodes-> causes viremia-> spreads to spinal cord and motor neurons, and motor end plate, also spreads to extraneural tissue
Polio virus Main diseases: affects nervous system
Polio virus Major virulence factors: its receptor is a PVR protein, delivery of genome doesn’t require complete update, LPS promotes virion stability and infection, exit is destructive
Polio virus Main treatment and control: vaccine- live attenuated so don’t need booster

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Polio virus Reservoir

humans (can affect some primates experimentally) so can be eradicated worldwide

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Polio virus Basic biology and contribution of this to disease

part of picornaviruses- small naked RNA viruses, single stranded, + strand RNA virus
Viral particles ae about 30nm in diameter, resistant to environment, resilient viral capsule

31

Polio virus Mechanism of transmission

fecal-oral route- contaminated water, direct oral secretion ingestion

32

Polio virus Major sites of colonization

Polio virus Major sites of colonization: mucosal surface

33

Polio virus Major sites of disease:

Polio virus Major sites of disease: primarily gastrointestinal virus, but affects nervous system which is accidental. Spreads from mucosal surface to lymph nodes-> causes viremia-> spreads to spinal cord and motor neurons, and motor end plate, also spreads to extraneural tissue

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Polio virus Main diseases

Polio virus Main diseases: affects nervous system
Asymptomatic illness >90%
• Abortive poliomyelitis 5%
- Short term febrile illness
• Nonparalytic poliomyelitis/aseptic meningitis 2%
- Short term febrile illness
- Back pain and spasms
• Paralytic polio 0.1 - 2%
- Paralytic poliomyelitis – flaccid paralysis with no sensory loss
> Recovery, residual paralysis or death may result
- Bulbar poliomyelitis
> Death 75% of time – eating or breathing is affected
- Post-polio syndrome – may be decades later
> Deterioration of previously affected muscles

35

Polio virus Major virulence factors

Polio virus Major virulence factors: its receptor is a PVR protein, delivery of genome doesn’t require complete update, LPS promotes virion stability and infection, exit is destructive

36

Polio virus Main treatment and control

Polio virus Main treatment and control: vaccine- live attenuated so don’t need booster

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4. What is the typical route through the body for poliovirus? How is nervous system disease an outcome of this

Spreads from mucosal surface to lymph nodes-> causes viremia-> spreads to spinal cord and motor neurons, and motor end plate, also spreads to extraneural tissue

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5. What are the advantages and disadvantages of each type of polio vaccine

1) Inactivated polio vaccine: delivers inactivated polio virus
-more expensive
-safe for immunodeficient people
-no risk of vaccine related disease
-boosters needed
-lack of stimulation of secretory IgA
-higher level of vaccination needed for herd immunity

2) live attenuated vaccine
-replicates in GI tract but not capable of entry to CNS
-taken orally
-less expensive
-no booster needed
-more induction of secretory IgA
-virus sheds in feces-spreads to others
-may very rarely rever to virulence
-possible rare generation of circulating vaccine-derived poliovirus (cDPV) that can lead to outbreaks

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Neisseria meningitidis Reservoir

Neisseria meningitidis Reservoir: humans

40

Neisseria meningitidis Basic biology and contribution of this to disease

: gram neg, aerobic and anaerobic respiration, fastidious and fragile, called memingococcus
Has lots of genetic diversity- 13 serogroups based on cell surface molecules, some clonal complexes associated with invasive infection, others not
Has no core pathogenome

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Neisseria meningitidis Mechanism of transmission:

large droplets with close contact (not aerosols)

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Neisseria meningitidis Major sites of colonization:

nasopharynx of URT- excellent colonists of URT, epithelia

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Neisseria meningitidis Major sites of disease

URT from where it spreads to bloodstream and then brain- CNS
Can get from epithelia to epithelial space/past barrier
Mostly stays in nasal passages
If it gets past the epithelia, it can get into the blood and to the brain from the blood, and once in the bloodstream its virulence factors help it survive

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Neisseria meningitidis Main diseases:

meningitis- headache, stiff neck, fever are initial symptoms
meningococcal septicemia- thrombosis of small blood vessels and multi-organ involvement
meningococcal diseases are accompanied by disseminated vascular coagulation and skin lesions, also pneumonia, arthritis and urethritis
can be 70-90% fatal if untreated

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Neisseria meningitidis Major virulence factors:

: capsule, pili for attachment, LOP (LPS without long O-antigen) binds receptors and triggers release of inflammatory cytokines leading to endothelial damage, may be sialyated
Has outer membrance vesicles, IgA protease
Has antigenic variation in outer membrane proteins
Bacteria has to survive in nasopharynx, bloodstream and CNS

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Neisseria meningitidis Main disease symptoms

headache, stiff neck, fever are initial symptoms

47

Neisseria meningitidis Main treatment and control:

vaccines, prompt antibiotic treatment, antibiotic prophylaxis for close contacts of infected individuals. Risk for neurological complications following recovery and also paralysis, deafness, mental impairment, amputations, and seizures

48

Neisseria meningitidisReservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

Neisseria meningitidis Reservoir: humans
Neisseria meningitidis Basic biology and contribution of this to disease: gram neg, aerobic and anaerobic respiration, fastidious and fragile, called memingococcus
Has lots of genetic diversity- 13 serogroups based on cell surface molecules, some clonal complexes associated with invasive infection, others not
Has no core pathogenome
Neisseria meningitidis Mechanism of transmission: large droplets with close contact (not aerosols)
Neisseria meningitidis Major sites of colonization: nasopharynx of URT- excellent colonists of URT, epithelia
Neisseria meningitidis Major sites of disease: URT from where it spreads to bloodstream and then brain- CNS
Can get from epithelia to epithelial space/past barrier
Mostly stays in nasal passages
If it gets past the epithelia, it can get into the blood and to the brain from the blood, and once in the bloodstream its virulence factors help it survive
Neisseria meningitidis Main diseases:
meningitis- headache, stiff neck, fever are initial symptoms
meningococcal septicemia- thrombosis of small blood vessels and multi-organ involvement
meningococcal diseases are accompanied by disseminated vascular coagulation and skin lesions, also pneumonia, arthritis and urethritis
can be 70-90% fatal if untreated
Neisseria meningitidis Major virulence factors: capsule, pili for attachment, LOP (LPS without long O-antigen) binds receptors and triggers release of inflammatory cytokines leading to endothelial damage, may be sialyated
Has outer membrance vesicles, IgA protease
Has antigenic variation in outer membrane proteins
Bacteria has to survive in nasopharynx, bloodstream and CNS
Neisseria meningitidis Main disease symptoms: headache, stiff neck, fever are initial symptoms
Neisseria meningitidis Main treatment and control: vaccines, prompt antibiotic treatment, antibiotic prophylaxis for close contacts of infected individuals. Risk for neurological complications following recovery and also paralysis, deafness, mental impairment, amputations, and seizures

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6. What is the typical route through the body for Neisseria meningitidis? What are colonization features that allow it to survive in other parts of the body? What are the challenges in development of some of the meningococcal vaccines?

Typical route: nasopharyngeal colonization, followed by entry into the bloodstream, and then entry into the CNS
Colonizes the nasopharyngeal by being internalized via host receptor interactions
Gets into the blood, where its capsule and sialyated LOS reduce complement and antibody binding and phagocytosis. The host complement regulators are recruited in the blood->then passes the endothelium to get into the CNS, and inflammation and cytokine damage may increase bacterial transcytosis of all cell barriers->the bacteria interacts with the leptomeninges of the brain, and cytokines are released, leading to meningitis
Has pili for attachment and capsule and sialylated LOS to reduce complement
Challenges with vaccine development: the bacteria has a B serotype which is identical to the sialic acid in human so it is hard to make a vaccine for something humans also make. Another challenge is that vaccines target outer membrane proteins, and not the actual capside

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Naegleria fowleri Reservoir

Naegleria fowleri Reservoir: humans, warm freshwater like lakes and rivers

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Naegleria fowleri Basic biology and contribution of this to disease

Naegleria fowleri Basic biology and contribution of this to disease: has trophozoite (growing stage), flagellate and cyst
Brain eating bacteria

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Naegleria fowleri Mechanism of transmission

Naegleria fowleri Mechanism of transmission: accidental- water up the nose-> straight into brain
Can get it by swimming in infected water

53

Naegleria fowleri Major sites of colonization

nose

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Naegleria fowleri Major sites of disease

Naegleria fowleri Major sites of disease: brain and meninges

55

Naegleria fowleri Main diseases:

Naegleria fowleri Main diseases: primary and secondary meningoencephalitis
-primary fatal amoebic meningocephalitis: headache, stiff neck, seizures, coma. Strong inglammation in the brain and meninges-primary damage may be due to immunopathology such as excessive cytokine release, olfactory region macrophages recruit intense neutrophil influx
-secondary meningoencephalitis: occurs when an infection starts elsewhere in the body and then travels to your brain, such as due to herpes virus

56

Naegleria fowleri Major virulence factors

accidental pathogen, has no dedicated tocins, but once it gets to the brain it is very successful. It is also very big which is a challenge for phagocyte
-direct virulence factors: adhesion, ameobastomes degrading enzymes to avoid immune system/phagocytosis, have pore-forming proteins, hydrolytic enzymes
-indirect virulence factors: phenotypic switching, morphology, ubiquity, physiological tolerance, biofilms, chemotaxis, drug resistance, immune evasion, host factors

57

Naegleria fowleri Main disease symptoms

fever leading to seizures, coma, death, following damage to the brain

58

Naegleria fowleri Main treatment and control

antiparasitic and anti-inflammatory agents

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7. How does Naegleria fowleri enter the central nervous system? What is the distinction between primary and secondary amoebic meningoencephalitis?

accidental- water up the nose-> straight into brain
Can get it by swimming in infected water
-primary fatal amoebic meningocephalitis: headache, stiff neck, seizures, coma. Strong inglammation in the brain and meninges-primary damage may be due to immunopathology such as excessive cytokine release, olfactory region macrophages recruit intense neutrophil influx
-secondary meningoencephalitis: occurs when an infection starts elsewhere in the body and then travels to your brain, such as due to herpes virus

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8. Be able to describe the structures and functions of the gut, including environmental conditions, antimicrobial factors, and metabolic and immune functions.

-Where the most significant interactions with microbes occur
-One cell endothelial layer= prime for pathogens
-Intestinal epithelial cells are a great barrier, coated in mucus
-Mucus is where microbes interact with us, and can also be food for them-they can get their nutrients by degrading it (glycosylating and sulfurylating it)
-Environment in the GI tract: shedding surface- sheds about 2x10^11 cells per day, -flushing action-9L fluid per day enter SI
-IgA, bile, AMO- bile is a mix of cholesterol, phospholipids, bile acids, Ig
-Mucus coated surfaces
-Attachment to mucus or high rate of growth needed to sustain populations
-Has innate and adaptive immunity

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9. Describe the main microbial populations of the different parts of the GI tract, including types of microbes, locations, and diversity. Be able to list a few major inhabitants of the gut.

Native microbiota are mostly found in the mucus layer
Prominent microbiota of gut: 1) most dense-Bacteroidetes, Firmicutes, actinobacteria

Prominent gut microbes:
-Fungi: Candida, saccharomyces
-protists: Entamoeba, Blastocystis
-Archaea: typically methanogens
-viruses: human viruses, bacteriophage, plant viruses
-Helminth worms
-Bacteria:
-Bacteroidetes: Bacteroides,
-Firmicute: Faecalibacterium prausnitzii
-actinobacterium: bifidobacterium
Stomach doesn’t have a lot of microbes, small intestine microbes range from 10^3-10^8, large intestine is most densely colonized 10^11-10^12

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10. What is the benefit of mucus degradation by gut microbes? List a benefit to the microbe, the host and the other members of the microbial community.

Mucus is made of proteins and producing and secreting it is costly for us. Role of microbes is that they recycle mucus and return some of that energy to us in the form of metabolite
Benefit to microbe: frees up sugars etc from mucus allowing others to grow,
Benefit to us: free up short fatty acids which we can use

63

11. How are SCFA produced in the gut? What are a few roles that SCFA play in human biology?

SCFA are metabolic products of plant based product digestion, and microbes produce these and many other metabolites
SCFA impact:
- they act as direct signals- are metabolic water products, but are imp for us
-our cells have short chain fatty acid receptors-GPCR41 and GPCR43- for signals to communicate with interior of cells
-provides a mechanism for gut microbes and our cells to communicate
-GPCR41: C3, C4 mainly, less of C2 SCFA- present on immune cells, adipose tissue, pancrease, spleen, lymp nodes, bone marrow
-GPCR43: C2, C3 more than C4- highest level in neutrophils, monocytes and B cells. Also in skeletal muscle, adipose tissue

Other effects of short chain fatty acids:
-Propionate-induces satiety (sated/satisfied) hormone leptin and reduces food intake, reduces expression of inflammatory cytokines
-Butyrate: preferred energy source for IEC-colonic epithelial cells. Induces IEC proliferation in normal cells, yet is antiproliferative in tumor cells so decreases colon cancer (butyrate paradox)
Butyrate and propionate induce expression of MUC2, the main mucin protein in GI tract
Also regulates gut motility

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12. Be able to give a few examples of the role of the microbiota in maintaining the gut barrier, including colonization resistance.

Germ-free animals are more susceptible to infections/gut pathogens
Members of normal microbiota produce molecules that are defense molecules that inhibit pathogen growth
competitive effect/hypothesis-compete with pathogens for nutrients
Promote proper immune health-improve immune response so directly help

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13. What are some specific examples of the roles of gut microbes in the proper development of the innate and adaptive immune system? Be able to give specific examples, including microbial genera and host cell type/function involved

-they influence mucosal immunity and systemic immunity-stimulate immune development
-effects lymphoid tissue, IgA secretion, antimicrobial production by Paneth cells, T cell population
-help develop isolated lymphoid follicles- are clusters of immune cells, through secretion of peptidoglycan
-have an impact on T cells: SFB- in mice GI but not humans- imp for proper function of Th17 cells. In absence of these, Th17 cells don’t function properly
-clostridia: impact-regulate immune cells
-Bacteroides fragilis- has numerous effects on innate and adaptive response-can help splenic development, T cell deficiencies, help with cytokine imbalance
due to polysaccharide A (PSA) which is a zwitterionic polysaccharide which can recapitulate many of these effects

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14. Be able to define dysbiosis

Disruption of normal microbiota, leads to immune dysfunaction
Leads to increased intestinal permeability, disruption of immune tolerance, metabolic dysfunction, carcinogenesis
Causes diseases such as: irritable bowel syndrome, inflammatory bowel disease, type 2 diabetes

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15. What might be the role of gut microbes in malnutrition? Be able to describe the experiments done using microbiota transplantation

Severe type of malnutrition is kwashiorkor- subset of individuals who don’t respond to treatment with therapeutic food- have a cycle that is very hard to break
But transplanting microbes from healthy individuals into malnourished individuals can help them recover

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16. What is the proposed role of the microbiota that contributes to cardiovascular disease? How do Archaea contribute?

We produce phosphatidylecholine when breaking down protein, which is converted to TMA-> to TMAO (trimethylamine N-oxide) by gut flora which is linked to cardiovascular disease
The microbiota of vegans is different than carnivores- they did not show diet-induced TMAO increase upon consumption of steak
Some gut methanogens use TMA as electron acceptor for methanogenesis rather than CO2, leading to CVD

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17. What are probiotics?

They are pure cultures of microbial strain that yield health benefits when in controlled trials
-they take direct action against pathogens- Lactobacillus strains can make antimicrobials that control Listeria infection
-they enhance function of epithelial barrier- certain bacteria can protect against E. coli infection
-they modulate the host immune response- local and systemic effects

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18. What are the main strategies used by GI pathogens in the disease process? This refers to intestinal colonization by the pathogen.

They avoid killing in stomach- form cysts and acid tolerance. In the lumen of the gut, they secrete toxins, invade epithelial cell, and then trasit to elsewhere

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20. Helicobacter pylori Reservoir:

20. Helicobacter pylori Reservoir: human stomach- dominant stomach microbe when present, colonization is declining in western countries

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21. Helicobacter pylori Basic biology and contribution of this to disease:

21. Helicobacter pylori Basic biology and contribution of this to disease: epsilon-proteobacterium, curved morphology, polar flagella, microaerophile and fastidious, extreme genetic diversity

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22. Helicobacter pylori Mechanism of transmission

22. Helicobacter pylori Mechanism of transmission: fecal-oral or oral-oral route, by age 10 persists for life if not deliberately removed, asymptomatic colonization frequent outcome

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23. Helicobacter pylori Major sites of colonization

23. Helicobacter pylori Major sites of colonization: stomach, most cells live in the mucus layer and do not directly interact with host cells

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24. Helicobacter pylori Major sites of disease

24. Helicobacter pylori Major sites of disease: stomach

76

25. Helicobacter pylori Main diseases

peptic ulcers, gastric mucosa associated lymphoid tissue lymphoma, gastric adenocarcinoma

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26. Helicobacter pylori Major virulence factors

VecA- a vacuolating toxin, enters mitochondria and disrupts it causing cell death, disrupts epithelial cell-cell function, causes inflammation, disrupts activation and proliferation of t-cells.

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29. For Helicobacter pylori be able to define the site of colonization and colonization factors.

Site of colonization: stomach, most cells live in the mucus layer and do not directly interact with host cells
Colonization factors:
-BabA: adhesion protein
-CagA: a bacterial oncoprotein, causes disruption of cell-cell junctions, loss of cell polarity
-VacA: vacuolating cytotoxin A- enters mitochondria and disrupts it damages epithelial cells, disrupts tight junctions and causes apoptosis

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30. What is the role of VacA and CagA in colonization and/or damage by H. pylori?

VecA- a vacuolating toxin, enters mitochondria and disrupts it causing cell death, disrupts epithelial cell-cell hunction, causes inflammation, disrupts activation and proliferation of t-cells.
CagA-a bacterial oncoprotein, causes disruption of cell-cell junctions, loss of cell polarity

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32. What might be some potential benefits of an H. pylori infection?

There is an inverse correlation with H. pylori levels and many disorders:
-esophageal disease- gastroesophageal reflux disease and esophageal cancer
-allergic/inflammatory diseases- allergies and asthma
-infectious diseases
-effects on metabolism-affects appetite hormone such as ghrelin and leptin
H. pylori also induces T regulation population

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C. difficile
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

C. difficile Reservoir: mostly humans, some domestic animals
C. difficile Basic biology and contribution of this to disease: firmicute, obligate anaerobe-vegitative cells are very oxygen sensitive, forms endospores which are resistant to stomach acid, oxygen, and decontamination procedures
C. difficile Mechanism of transmission: spores shed from symptomatic or asymptomatic individuals
C. difficile Major sites of colonization: intestines
C. difficile Major sites of disease: intestines, but significant damage to intestines can occur and can allow bacteria to get into rest of body and cause systemic infection
C. difficile Main diseases: pseudomembranous colitis, others include mild diarrhea, bowel perforation, sepsis and shock and death
C. difficile Major virulence factors: toxin A and toxin B
Toxin A: disrupts signals for proper cytoskeleton formation including what keeps epithelial cells tight
Toxin B: disrupts tight junction formation, inflammation
Both toxins cause disruption of the intestines, causing diarrhea, cramps etc
C. difficile Main disease symptoms:
C. difficile Main treatment and control: susceptible to some antibiotics, but recurrent infections are common. Severe cases require surgery to remove colon
New treatment: bacteriotherapy aka fecal transplant- fecal sample is taken from donor, administered to patient and those new microbiota colonize intestines and clear C. diff

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C. difficile Reservoir

C. difficile Reservoir: mostly humans, some domestic animals

83

C. difficile Basic biology and contribution of this to disease

C. difficile Basic biology and contribution of this to disease: firmicute, obligate anaerobe-vegitative cells are very oxygen sensitive, forms endospores which are resistant to stomach acid, oxygen, and decontamination procedures

84

C. difficile Mechanism of transmission

C. difficile Mechanism of transmission: spores shed from symptomatic or asymptomatic individuals

85

C. difficile Major sites of colonization

C. difficile Major sites of colonization: intestines

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C. difficile Major sites of disease

C. difficile Major sites of disease: intestines, but significant damage to intestines can occur and can allow bacteria to get into rest of body and cause systemic infection

87

C. difficile Main diseases

C. difficile Main diseases: pseudomembranous colitis, others include mild diarrhea, bowel perforation, sepsis and shock and death

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C. difficile Major virulence factors

C. difficile Major virulence factors: toxin A and toxin B
Toxin A: disrupts signals for proper cytoskeleton formation including what keeps epithelial cells tight
Toxin B: disrupts tight junction formation, inflammation
Both toxins cause disruption of the intestines, causing diarrhea, cramps etc

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C. difficile Main treatment and control

susceptible to some antibiotics, but recurrent infections are common. Severe cases require surgery to remove colon
New treatment: bacteriotherapy aka fecal transplant- fecal sample is taken from donor, administered to patient and those new microbiota colonize intestines and clear C. diff

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33. What are the conditions needed for C. difficile infection to occur? What is proposed to be the role of the microbiota in protecting against CDI

Different parts of the intestine have different bile acids, and C. diff responds to these different acids and grows. Normal microbiota change these bile acids and prevent the C. diff from growing
Role of microbiota= colonization resistance

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34. What are the typical and novel treatments for CDI ?

It is susceptible to some antibiotics, but recurrent infections are common
Severe cases require surgery to remove
New treatment: bacteriotherapy- aka fecal transplant so these new microbes colonize the gut and prevent C. diff from growing

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V. cholerae Reservoir

V. cholerae Reservoir: environmental pathogen- colonizes warm tropical/semi tropical water around world

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Vibrio. cholerae Basic biology and contribution of this to disease:

: gram neg, motile- flagella, both anaerobic and aerobic respiration very genetically diverse
Its core genome- is chitin binding (uses chitin as C/N source), uses toxR gene,
Pan genome: has over 200 O antigen serogroups (variation within bacteria)
Very fast replication
Motile

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V. cholerae Mechanism of transmission:

: ingestion of contaminated food, marine water- how outbreaks originate

95

V. cholerae Major sites of colonization

V. cholerae Major sites of colonization: intestines

96

V. cholerae Major sites of disease

V. cholerae Major sites of disease: intestines

97

V. cholerae Major virulence factors

: CT (cholerrae toxin)—AB toxin- B component promotes uptake of A component which affects adenylate cyclase (which makes cAMP), affecting ion channels= massive dysregulation of ion concentrations- outside becomes more concentrated so water diffuses out due to gradient= massive water released from body. It is only made at certain time when its effects would be most beneficial to bacteria
Other virulence factors:
-Zot and Ha/p proteins: disrupt intestinal epithelial junctions
-Ace: directly affects Cl channels- causing Cl to leave cell
-VCC: is a Cl channel itself= allows Cl to exit cell
These all contribute to overall unbalance in cell

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V. cholerae
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control


V. cholerae Reservoir: environmental pathogen- colonizes warm tropical/semi tropical water around world
Vibrio. cholerae Basic biology and contribution of this to disease: gram neg, motile- flagella, both anaerobic and aerobic respiration very genetically diverse
Its core genome- is chitin binding (uses chitin as C/N source), uses toxR gene,
Pan genome: has over 200 O antigen serogroups (variation within bacteria)
Very fast replication
Motile
V. cholerae Mechanism of transmission: ingestion of contaminated food, marine water- how outbreaks originate
V. cholerae Major sites of colonization: intestines
V. cholerae Major sites of disease: intestines
V. cholerae Main diseases
V. cholerae Major virulence factors: CT (cholerrae toxin)—AB toxin- B component promotes uptake of A component which affects adenylate cyclase (which makes cAMP), affecting ion channels= massive dysregulation of ion concentrations- outside becomes more concentrated so water diffuses out due to gradient= massive water released from body. It is only made at certain time when its effects would be most beneficial to bacteria
Other virulence factors:
-Zot and Ha/p proteins: disrupt intestinal epithelial junctions
-Ace: directly affects Cl channels- causing Cl to leave cell
-VCC: is a Cl channel itself= allows Cl to exit cell
These all contribute to overall unbalance in cell

V. cholerae Main disease symptoms: vary depending on severity- watery diarrhea, vomiting
V. cholerae Main treatment and control: oral rehydration therapy, antibiotics may minimize shedding, vaccines and sanitation-but immunity is not long lasting with vaccines (several years

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35. Be able to describe the mechanism of action of cholera toxin and of the other toxins produced by V. cholerae

V. cholerae attaches to the epithelia and secretes AB toxin. The B component of the toxin promotes the uptake of the A component- A component affects adenylate cyclase activity of the cell (makes cAMP), affecting ion channels, causing a massive dysregulation of ion concentrations, so the outside becomes more concentrated than the inside of the cell, causing water to diffuse out of the cell and the body to release massive amounts of water
Other toxins: Zot, HA/P, Ace, VCC
All contribute to ion imbalance, and cholera toxin is only secreted at the most beneficial time to pathogen
-Zot and Ha/p proteins: disrupt intestinal epithelial junctions
-Ace: directly affects Cl channels- causing Cl to leave cell
-VCC: is a Cl channel itself= allows Cl to exit cell
These all contribute to overall unbalance in cell

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36. How does V. cholerae growth on chitin affect its diversity and its ability to cause disease?

V. cholerae and chitin interaction is important. Chitin binding requires a set of genes- GbpA. Chitin adds to its genetic diversity, allowing it to acquire new genes

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37. What is the role of the VPI, TCP, and CTX phage in V. cholerae diversity and disease?

Some strains have VIP -vibrio pathogenicity island- genes that come from somewhere else
-it has: TCP (toxin co-regulated pilus) which is a receptor for CTX phage, promotes binding to chitin, and promotes microcolony formation in intestines
-some strains have CTX phage with a gene for cholera toxin

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E. coli Reservoir:

commensals of humans and other animals, live in GI tract
-colonize large intestine of many mammals, humans: most abundant culturable facultative anaerobe
-minority in us
-present life-long
Certain strains only avian

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E. coli Basic biology and contribution of this to disease

metabolic diversity- aerobic/anaerobic respiration, fermentation, tremendous genetic diversity, commensals of humans and other animals
Pathovars: ETEC (Enterotoxogenic), EPEC/EHEC (enterophatic/enterohemorrhagic), EAEC (enteroaggregate E. coli)
InPEC- intestinal strain
ExPEC- extra intestinal
DAEC- associated with diarrhea in children, urinary tract infections, and pregnancy complication
AIEC- linked to Crohn’s disease

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E. coli Mechanism of transmission

fecal-oral rought- feces contaminate food/water-> get ingested

105

E. coli Major sites of colonization

E. coli Major sites of colonization: GI tract- intestines

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39. For each type of E. coli that we discussed, be able to list the main virulence factors (e.g. adhesins, toxins, etc).

ETEC
Adhesion: species specific pili
Toxin: LT and ST (label and stable)
Effector proteins: LT- like cholerae toxin- attach to small and large intestine and causes diarrhea

EPEC/EHEC
Adhesion: pili/fimbriae
Toxin: none for EPEC, EHEC produce shigga toxin
Effector proteins: LEE effector (locus enterocyte effacement)-encodes type 3 secretion system and other proteins responsible for attaching and effacing lesions in the large intestine

EAEC
Adhesion: aggregate adherence- allow adherence to intestinal surface with thick biofilms which can persist
Toxins: produce many toxins
Effector proteins: none

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ETEC
adhesion
toxin
effector proteins

Adhesion: species specific pili
Toxin: LT and ST (label and stable)
Effector proteins: LT- like cholerae toxin- attach to small and large intestine and causes diarrhea

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EPEC/EHEC
adhesion
toxin
effector proteins

Adhesion: pili/fimbriae
Toxin: none for EPEC, EHEC produce shigga toxin
Effector proteins: LEE effector (locus enterocyte effacement)-encodes type 3 secretion system and other proteins responsible for attaching and effacing lesions in the large intestine

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EAEC
adhesion
toxin
effector proteins

Adhesion: aggregate adherence- allow adherence to intestinal surface with thick biofilms which can persist
Toxins: produce many toxins
Effector proteins: none

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40. Be able to explain the attaching and effacing phenotype, both in terms of how the bacteria cause this and the effect it has on epithelial cells. What is the LEE pathogenicity island, what main genes are encoded, and how do they function? What is the role of Tir and imtimin?

EPEC and EHEC have LEE encoded proteins which encode the type 3 secretion system and other proteins responsible for attaching and effacing lesion in the large intestine
Both strains have distinct pili for attachment
LEE effector proteins have lots of redundant roles- so if one doesn’t work, they have others still

Intimin= outer membrane protein
Tir: the translocated intimin receptor

EHEC/EPEC attach to cell-> secretion through type 3 secretion system-> inject Tir into intestinal epithelium which becomes receptor protein for E.coli cell-> allows tight attachment-> ither injected prteins rearrange cells-> forms a pedestal on which the bacteria lands-> once landed, the bacteria injects more proteins-> remodel host’s cell-> causes loss of vili, among other things

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41. How are EHEC strains different than EPEC strains? What is the role of Shiga toxin in disease and how is it produced by EHEC strains?

EHEC strains produce the shiga toxin, introduced to it by a lysogenic phage. There is no specific mechanism for activating/injecting it- the toxin is released when the host cell bursts
Toxin is an AB toxin, and it binds and inhibits ribosomes,
Receptor for it is: Gb3, which cattle don’t have, so they can host the bacteria, but aren’t affected by it
Complication of EHEC is Hemolytic uremic syndrome (HUS)
-Siga toxin then enters the bloodstream, lysis RBCs, it effects the kidneys- its receptors are abundant of kidney cells, kidney damage and failure are possible
-Children, the elderly and immunocompromised people are most susceptible
-10% of those with EHEC get HUS

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42. The pathogenesis of Shigella is very different than other E. coli strains. Be able to explain how Shigella causes disease, in terms of its effects on or interactions with the following cell types: macrophages, epithelial cells, neutrophils

Its core genome is that of E. coli, but it has acquired virulence genes, and also lost a lot of genese, which has also made it more virulent
It gets into the small intestine (via fecal- oral route)-> gets taken up by M cells -> passed to macrophages-> but bacteria doesn’t get killed-> instead the bacteria kills macrophages-> the bacteria is then released into the subepithelial space-> enters epithelial cells at the bacolatral surface-> it then moves from cell to cell using actin based motility

-Shigella uses type 3 secretion system to: attach to cells, and uses the type 3 secretion system and T3SS to promote is own uptake via trigger mechanism- causes ruffling and envelopment of bacteria. Also uses type 3 secretion system to influence structure of epithelial barrier- most cells are shed after 2 days or less, but shigella uses this secretion system to enforce attachment fo epithelial cells to enforce attachment of epithelial cells to stop them from being releaed and stay attached to epithelia so it can survive.

Macrophages and shigella: cell death caused by pyropoptosis, which causes inflammation and further damage
Pyroptosis releases proinflammatory cytokines,
All this results in inflammation, the bacteria’s MAMPs are recognized by PAMPs, resulting in more inflammation
Shigella also produces its own anti-inflammatory proteins to prevent infection from being resolved

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Shigella
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

Shigella Reservoir: humans only
Shigella Basic biology and contribution of this to disease: intracellular pathogem, has lots of acquired and lost genes that contribute to its virulence
Shigella Mechanism of transmission: fecal oral route
Shigella Major sites of colonization: small intestines
Shigella Major sites of disease: small intestines
Shigella Major virulence factors: type 3 secretion system for promoting its own uptake via T3SS protein, influence/enforce epithelial barrier to prevent epithelial cells from being shed so it can survive
Uses actin-based motility, using VirG that polarly localizes to one enf of the bacteria and forms actin to allow it to be propelled from one cell to another- this is how it grows and spreads laterally
Shigella Main disease symptoms: blood in stool etc

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Shigella Reservoir

Shigella Reservoir: humans only

115

Shigella Basic biology and contribution of this to disease:

intracellular pathogem, has lots of acquired and lost genes that contribute to its virulence

116

Shigella Mechanism of transmission

Shigella Mechanism of transmission: fecal oral route

117

Shigella Major sites of colonization

Shigella Major sites of colonization: small intestines

118

Shigella Major sites of disease

small intestines

119

Shigella Major virulence factors

type 3 secretion system for promoting its own uptake via T3SS protein, influence/enforce epithelial barrier to prevent epithelial cells from being shed so it can survive
Uses actin-based motility, using VirG that polarly localizes to one end of the bacteria and forms actin to allow it to be propelled from one cell to another- this is how it grows and spreads laterally

120

Shigella Main disease symptoms

Shigella Main disease symptoms: blood in stool etc

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Entamoeba Reservoir

Entamoeba Reservoir: humans only

122

Entamoeba Basic biology and contribution of this to disease

: unicellular, “macrophage on steroids”
Has 2 stages: trophozoit- growth, development, and Cyst form- not active, mostly for transfer
Anaerobic fermenter, mitosomes (don’t have full mitochondira, have remnants of it)

123

Entamoeba Mechanism of transmission

: fecal contamination of food/water. Cysts are ingested and then low pH triggers development- forms 8 trophozoites per cyst. The trophozoites enter intestines and engaged in either commensal colonization, or invasive amoebiasis

124

Entamoeba Major sites of colonization

intestines

125

Entamoeba Major sites of disease

instestines, but can spread to othe organs such as the liver which is very dangerous

126

Entamoeba Main diseases:

intestinal amebiasis: invasion into the submucosa with lateral extension- forms flask shaped ulcers
causes inflammation, hemorrhage, seconday bacterial infections
natural infections don’t seem to result in long term immunity, children are especially vulnerable as they can suffer malnourishment and stunting as the result of repeated infection
extraintestinal amebiasis:
-invasion to deeper tissue
-infection of the liver and other organs
-live abscess about 1% of infections- often fala

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Entamoeba Main treatment and control:

: treatment with metronidazole (drug) or luminal agent; iodoquinol
Control with proper sanitation, clean water
No vaccines

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43. What is thought to be the main mechanism by which Entamoeba causes damage in the intestinal tract? What is the role of the amoebapores and proteases in this process? For trogocytosis?

It causes rapid rpithelial cell killing and inflammation-> then it kills other immune cells
Degrades Ig, ECM proteins, complement proteins, cytokines, and mucins
Makes pores- causing cell content to leak
Once epithelial cells are damaged, it gets into the subepithelial and damages cells there
Evades adaptive immune response by capping and shedding- when antibodies bind to it, they are shed and released, so it shakes them off = avoidance of immune response

Trogocytosis: mechanism of killing cells
-attaches to epithelial cells-> pinches the epithelial cells off little by little until nothing is left- “death by nipping”

129

Entamoeba
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

Entamoeba Reservoir: humans only
Entamoeba Basic biology and contribution of this to disease: unicellular, “macrophage on steroids”
Has 2 stages: trophozoit- growth, development, and Cyst form- not active, mostly for transfer
Anaerobic fermenter, mitosomes (don’t have full mitochondira, have remnants of it)

Entamoeba Mechanism of transmission: fecal contamination of food/water. Cysts are ingested and then low pH triggers development- forms 8 trophozoites per cyst. The trophozoites enter intestines and engaged in either commensal colonization, or invasive amoebiasis
Entamoeba Major sites of colonization: intestines
Entamoeba Major sites of disease: instestines, but can spread to othe organs such as the liver which is very dangerous
Entamoeba Main diseases:
intestinal amebiasis: invasion into the submucosa with lateral extension- forms flask shaped ulcers
causes inflammation, hemorrhage, seconday bacterial infections
natural infections don’t seem to result in long term immunity, children are especially vulnerable as they can suffer malnourishment and stunting as the result of repeated infection
extraintestinal amebiasis:
-invasion to deeper tissue
-infection of the liver and other organs
-live abscess about 1% of infections- often fala

Entamoeba Main treatment and control: treatment with metronidazole (drug) or luminal agent; iodoquinol
Control with proper sanitation, clean water
No vaccines

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43. What is thought to be the main mechanism by which Entamoeba causes damage in the intestinal tract? What is the role of the amoebapores and proteases in this process? For trogocytosis?

It causes rapid rpithelial cell killing and inflammation-> then it kills other immune cells
Degrades Ig, ECM proteins, complement proteins, cytokines, and mucins
Makes pores- causing cell content to leak
Once epithelial cells are damaged, it gets into the subepithelial and damages cells there
Evades adaptive immune response by capping and shedding- when antibodies bind to it, they are shed and released, so it shakes them off = avoidance of immune response

Trogocytosis: mechanism of killing cells
-attaches to epithelial cells-> pinches the epithelial cells off little by little until nothing is left- “death by nipping”

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Giardia Reservoir

Giardia Reservoir: many mammals

132

Giardia Basic biology and contribution of this to disease

has 2 stages: trophozoite and cyst- resistant to chlorine, cyst allows it to get from host to host
Anaerobic fermenters
Mitosomes
Have an adhesive ventral disk that lets it attach to intestinal epithelia
Not phagocytic

133

Giardia Mechanism of transmission

cyst allows it to get from host to host, cyst ingestion from contaminated food and water

134

Giardia Major sites of colonization

intestines

135

Giardia Major sites of disease

intestines

136

Giardia Main diseases:

Giardiasis: chronic infection may lead to failure to thrive, stunting, impaired cognitive function
Post-infectious complications include ocular pathology, reactive arthritis, post-infectious irritable bowel syndrome, chronic fatigue, food allergy, malnuitrition, cognitive impairement

137

Giardia Main disease symptoms

watery diarrhea, cramps, nausea, weight loss, bloating
Chronic infection may lead to failure to thrive, stunting, impaired cognitive function

138

Giardia Main treatment and control

treatment with metronidazole (drug)
Control with proper sanitation, clean water
No vaccine

139

44. What is the overall disease cycle for Giardia species?

Ingestion of cyst starts the cycle-> once it enters, acidic bile acids stimulate the trophazoite-it is noninvasive- only lives on the surface of the epithelial cells-> when it transfers to the large intestine, it reforms cysts

Mech of pathogenesis: promotes cell death- apoptosis (not pyropotosis)
Disrupts intracellular junctions- fluid disruption and diarrhea,
Ion disruption= diarrhea
Shortens microvilli= leads to improper nutrient abs = ion imbalance
-can lead to long-term malnuitrition and chronic damage

140

Giardia
Reservoir
Basic biology and contribution of this to disease
Mechanism of transmission
Major sites of colonization
Major sites of disease
Main diseases
Major virulence factors
Main disease symptoms
Main treatment and control

Giardia Reservoir: many mammals
Giardia Basic biology and contribution of this to disease: has 2 stages: trophozoite and cyst- resistant to chlorine, cyst allows it to get from host to host
Anaerobic fermenters
Mitosomes
Have an adhesive ventral disk that lets it attach to intestinal epithelia
Not phagocytic
Giardia Mechanism of transmission: cyst allows it to get from host to host, cyst ingestion from contaminated food and water
Giardia Major sites of colonization: intestines
Giardia Major sites of disease: intestines
Giardia Main diseases: chronic infection may lead to failure to thrive, stunting, impaired cognitive function
Post-infectious complications include ocular pathology, reactive arthritis, post-infectious irritable bowel syndrome, chronic fatigue, food allergy, malnuitrition, cognitive impairement
Giardia Major virulence factors
Giardia Main disease symptoms: watery diarrhea, cramps, nausea, weight loss, bloating
Chronic infection may lead to failure to thrive, stunting, impaired cognitive function
Giardia Main treatment and control: treatment with metronidazole (drug)
Control with proper sanitation, clean water
No vaccine

141

45. What is the One Health concept?

If you want to optimize human health than you need to think wholisticallly
Need to consider animals and the health of the environment- so a lot of additional factors need to be considered when considering human health

142

46. Be able to explain how antibiotic susceptibility/resistance is measure.

Measured using MIC- this is the smallest amount at which bacteria growth is inhibited- want as little of the antibiotic as possible
Kirby-Bauer disc diffusion assay- inoculate plate with a liquid culture of a test organism, and disc containing antimicrobial agents are placed on surface, incubated for 24-48 hours and then checked for zones of inhibition- the larger the zone of inhibition, the more susceptible the organism is to that antibiotic

143

able to explain the mechanism of action of the antibiotics discussed in class.

-any step in cell of bacteria that is unique can be a target for antibiotics
-Beta-lactam antibiotics target cell wall synthesis- prevent proper peptidoglycan crosslinking to occur= weak cell wall
Beta-lactams inhibit transpeptidase enzymes and inhibit their function
-other antibiotics that are not beta-lactams can also target the cell wall:
-Bacitracin: interferes with bactoprenol recycling
-Vancomycin: binds pentapeptide
-Cycloserine: interferes with pentapeptide synthesis
Other targets include topoisomerase and DNA grases- Quinolone antibiotics
RNA polymerase- Rifampicins are imp for treatment of TB
Ribosomes and protein synthesis- many antibiotics
Metabolic pathways- ex: sulfonamides (sulfa drugs) target folic acid synthesis
Membrane function

Translation inhibitors: many antibiotics inhibit translation. These don’t necessarily have similar structures, and they act on very specific parts of ribosomes/step of translation

Antibacterials that affect DNA- Fluoroquinolones, Quinolones, Novobiocin
Macrolides target protein synthesis

Antibacterials can also affect fatty acid biosynthesis- bacteria use several proteins in a type 2 fatty acid synthase (FAS) system, while eukaryotes use a single large, multifunctional polypeptide which is type 1, so the mechanism of synthesis differs enough that they can be targeted

Antibacterials can also affect the cell membrane

Metronidazole is effective against anaerobes- prodrug is inactive, but is converted to its active form by reduction by flavodoxin or ferredoxin, ETS components. Activated compound damages DNA non-specifically
-inside susceptible bug it becomes active- anaerobic microbes reduce its active form only
-exception- it can be used for anaerobic bacteria and protists as long as they have the reduction pathway needed to activate it.

144

Antibiotic non-target effects

Toxicity to host- side effects ex: kidney damage, hearing
Allergic reaction to antibiotic
Alteration of normal microbiota
Microbiota shift diseases ex: C. difficile infection after antibiotic treatment disrupts the nomal intestinal microbiota

145

48. Be able to explain the mechanisms of antibiotic resistance discussed in class

1) Intrinsic resistance:
a. The microbe lacks the target for the antibiotic to attack ex: lacking peptidoglycan for cell wall
b. Antibiotic is not permeable- due to presence of cell envelop, capsule
c. The bacteria pumps the antibiotic out using efflux pumps
2) Situational resistance also known as tolerance
i. Tolerance can be disrupted if we know the mechanism of tolerance. Ex: sometimes we add nutrients to promote growth of bacteria so the antibiotic can target it
b. Microbe not growing/in dormant state- many antibiotics target growing state
c. Microbe may be growing in a location that is not easily accessible to antibiotic- so it appears to be resistant while actually not being exposed to it
d. Microbe is growing in a biofilm-they are more resistant in biofilms, biofilms help sensitive cells resist killing due to the structure of the biofilm
3) Acquired resistance
a. You have a susceptible cell->it has a mutation /horizontal gene transfer->causes permanent change and resistance in it
i. Horizontal gene transfer is very problematic because it can result in resistance to multiple types of antibiotics

146

Overall mechanisms of antibiotic resistance:

-Prevent access of antibiotic to target with porins, membrance, capsule, or efflux prumps
-change in antibitiotic target
- change to original target,
-mutations at target site,
-modification of target site,
-acquire target substitute,
-protect target for example proteins that protect topoisomerases
-degrade or modify antibiotic

147

Resistance to one class of antibiotics is often acheieved through multiple mechanisms- mechanisms of antibiotic resistance to beta-lactams

1) Mutations
a. Pore gene: reduced permeability
b. Transpeptidase gene: decrease binding
c. Mutation to increase production of efflux pumps
2) Gene acquisition
a. Gene encoding degradative enzyme: Betal-lactamase
b. Gene encoding target replacement: MecA
c. Gene encoding efflux pump

Resistance mechanism 1: prevent access- antibiotic efflux
Resistance mechanism 2: alter target, - change target which reduces target’s affinity to antibiotic so it can still maintain its function but can be resistant
so target replacement or target protection- have another gene that does sme function as the antibiotic target that is not the target, so the target protein needed by bacteria is still being produced
Resistance mechanism 3: alter antibiotic
– so degradation of antibiotics by enzyme
-like beta-lactamase what degrades penicillin to penicilloic acid
-modify antibiotic

148

Beta-lactamase inhibitors:

they vary in substrate specificity
They bind to beta-lactamase and inhibit its function
Are not antibacterial themselves
Combination drugs= antibiotic plus inhibitor

149

Combating antibiotic resistance

-Development of new drugs
Will still have limited useful life
Focus on narrow spectrum antibiotics
Anti-virulence mechanisms
-Prudent antibiotic use- decrease selective pressure for resistance, combination therapy
-Surveillance to limit spread- take extra measures when dealing with resistant strains
-Infection control b other methods- vaccines, bacteriophages

150

clostridia
Bacteroides fragilis

clostridia: impact-regulate immune cells
-Bacteroides fragilis- has numerous effects on innate and adaptive response-can help splenic development, T cell deficiencies, help with cytokine imbalance
due to polysaccharide A (PSA) which is a zwitterionic polysaccharide which can recapitulate many of these effects

151

VecA

Helicobacteri pylori
a vacuolating toxin, enters mitochondria and disrupts it causing cell death, disrupts epithelial cell-cell function, causes inflammation, disrupts activation and proliferation of t-cells.

152

VirG amd VirA

Shigella uses VirG for actin based motility
VirG that polarly localizes to one end of the bacteria and forms actin to allow it to be propelled from one cell to another- this is how it grows and spreads laterally
VirA destabilizes host cell microtubules