Second half Flashcards
(281 cards)
1
Q
what condition is required to count microbes/bacteria
A
must be suspended in liquid
2
Q
3 ways to count microbes/bacteria (suspended in a liquid)
A
- direct microscopic counts via haemocytometry
- plate counts (dilution plating)
- optical density
3
Q
what is haemocytometry
A
- direct microscopic counts of bacteria
- can also distinguish between dead and live cells
4
Q
what is optical density
A
an indirect measurement of light scattered by the suspension at a specific wavelength to determine the concentration of microbial cells in liquid suspension
- higher the concentration of cells = the more turbid the suspension = more scattered light
5
Q
how is the microbial growth cycle analyzed
A
as cells density as a function of time
6
Q
what are the 4 phases of microbial growth in a batch liquid culture
A
- lag phase
- exponential/log phase
- stationary phase
- death
7
Q
Phase 1 of microbial growth: Lag phase
A
Bactria adapt themselves to growth conditions - maturation and synthesis of RNA, enzymes and other molecules
8
Q
Phase 2 of microbial growth: Exponential/log phase
A
characterized by cell doubling, number of cell divisions per unit time
can be split int 2 phases
1. early phase: cell growth is at maximum rate possible based on growth conditions
2. late phase: slowing of growth due to cell density, competition for nutrients, accumulating waste, etc.
9
Q
Phase 3 of microbial growth: Stationary phase
A
overall population growth plateaus due to a growth-limiting factor such as depletion of nutrients or formation of an inhibitory product
10
Q
Phase 4 of microbial growth: Death phase
A
without any new nutrients (and production of toxic byproducts) all cells eventually die off
11
Q
chemostat and continuous culture systems
A
- ensures continuous growth by adding and removing equal amounts of culture medium
- conditions of the culture approximate that of the native environment
12
Q
what is metagenomics
A
the study of metagenomes - collections of genetic material from a diverse group of organisms (microbial communities)
13
Q
overview of steps in metagenomic analysis
A
- gDNA isolation from environment/sample
- gDNA library construction
- sequencing
- analysis
14
Q
a more complicated way to identify species: ribosomal based
A
- 16S rRNA in prokaryotes and 18S rRNA in eukaryotes
- rRNA sequencing allows for identification of operational taxonomic units (OTUs)
- OTU can define a species when only DNA sequence data is available
15
Q
viral metagenomics is difficult as they…
A
- lack a unique rRNA-like region
- may be incorporated into the bacterial genome
16
Q
what are biofilms
A
specialized structures of microbes growing in communities/consortiums of different species that stick together on surfaces
17
Q
Extracellular polysaccharide (EPS) matrix of biofilms
A
- EPS is secreted by microbial cells and is a sticky adhesive that surrounds biofilms
- trapped within the EPS matrix are bacterial secreted proteins and extracellular DNA fragments
18
Q
how are biofilms formed (5 steps)
A
- attachment of planktonic bacteria
- attached bacteria form microcolonies
- EPS secretion
- biofilm elaboration and maturation
- dissolution and dispersal
19
Q
Life cycle of biofilms
A
- form when and where nutrients are plentiful
- bacteria attach to cell surfaces via cell envelop/appendages
- once nutrients are depleted microbes detach and look for new sources of nutrients
20
Q
true or false: biofilms can consist of multiple species or just one individual species
A
true
21
Q
what regulates biofilm formation
A
quorum sequencing
22
Q
what is quorum sequencing
A
the process of assessing bacterial density by secreting autoinducers into the surrounding environment
- QS is a mechanism for regulating density-dependent community behaviours - e.g. biofilm dissolution, expression of virulence factors, etc.
23
Q
how does quorum sequencing result in a co-ordinated response by ALL cells in the community
A
- autoinducer binds to a cytoplasmic receptor protein (transcription factor)
- at a certain “quorum” (aka inducer concentration) the transcription factor is activated and binds to DNA activating quorum-sensing regulated genes
- ONLY occurs when cell density (quorum) is high
24
Q
benefits of biofilms
A
- allows microbes to work together
- normal microbiota biofilms of plants/animals are essential
25
cons of biofilms
- may damage/degrade infrastructure
- colonize abiotic surface put into the body
- biofilms of pathogenic bacteria are a problem in medicine
- bacteria are highly resistant to antimicrobials and killing by the immune response defences
26
general information about viruses
- acellular entities
- obligate intracellular parasites
- display tropism (have specific hosts/ranges)
- interacts with host cell surfaces
- more viruses on the planet than any other organism
- impacts range from innocuous to lethal
27
narrow vs wide host range of viruses
narrow: binds to specific type of cell, e.g. cold and influenza infect human respiratory epithelial cells
wide: can bind to a wide variety of cells, e.g. rabies virus binds to dogs, foxes, racoons and humans
28
Risk group 4 viruses
- often untreatable, high individual and community risk
- include viruses such as filoviridae (e.g. Ebola virus)
- only viruses make it to risk level 4 (no bacteria, yeasts or fungi)
29
how can viruses be beneficial?
- bacteriophages can be used to control infections as an alternative to antibiotics or disinfectants
- viruses can be modified as delivery vehicles for gene therapy
- bacteriophages can be used in molecular cloning, as cloning vectors
- evolution: insertion and excision of viral genome
30
what is the general structure of viruses
capsid: protein coat that surrounds nucleic acid
envelope: if enclosed in a protein-containing membrane or nor
nucleic acid: either DNA or RNA encodes viral proteins
31
what are the 7 groups of viruses
I: double-stranded DNA virus
II: single-stranded DNA virus
III: double-stranded RNA virus
IV: (+) single-stranded RNA virus
V: (-) single-stranded RNA virus
VI: retrovirus
VII: double-stranded DNA pararetrovirus
32
group I: double-stranded DNA virus
- uses its own or host DNA polymerase for replication
- Bacteriophage lambda
- herpes virus: chicken pox, genital infections
33
group II: single-stranded DNA virus
- requires DNA polymerase to generate complementary strand
34
group III: double-stranded RNA virus
- requires RNA-dependent RNA polymerase to make mRNA and gRNA
- reoviruses: rotavirus
35
group IV: (+) single-stranded RNA virus
- requires RNA-dependent RNA polymerase to make a template for mRNA and genome replication
- flaviviruses: HepC, yellow fever
36
group V: (-) single-stranded RNA virus
-requires RNA-dependent RNA polymerase to make mRNA and replicate its genome
- orthomyxoviruses: influenza
37
group VI: retrovirus
- packages its own reverse transcriptase to make dsDNA
- lentiviruses: HIV (the cause of AIDS)
38
group VII: double-stranded DNA pararetrovirus
- requires plant host reverse transcriptase to make dsDNA
- caulimoviruses: infects vegetables
39
Classification of viruses is based on a combination of criteria...
1. nature of the genome (most important)
2. Viral structure
3. presence/absence of an envelope
4. size of viral particle
40
Structures of viruses
1. Filamentous: helical capsid symmetry - genome is coiled
2. Icosahedral capsid: rotational symmetry
3. Multiple helical packages: collection of several helical genome segments enables rapid evolution of new strains
4. Complex viruses: bacteriophages
5. Asymmetric: no capsid, DNA is enclosed by a core envelope surrounded by an OM
41
example of filamentous capsid virus
ebola virus
42
example of icosahedral capsid virus
human papilloma virus
43
example of multiple helical packages virus
influenza virus
44
examples of complex viruses
bacteriophages: T2, T4, and lambda phage
45
example of asymmetric viruses
vaccinia poxvirus
46
Basic process of viral infection and reproduction
1. Attach to the host cell
2. penetration of the host via endocytosis
3. Uncoating and release of viral contents
4. Biosynthesis of viral RNA
5. Assembly of new phages
6. Release of new viral particles
47
what makes biosynthesis of new viruses complicated
the presence of an envelope and the nature of the genome (especially RNA viruses and retrovirus)
48
how does phage genome get into the cell
- the virus attached to specific host cell receptors
- phage genome is injected through the cell wall and membrane and the capsid is shed
- phage structure becomes waste in the environment
49
2 types of bacteriophage life cycle
1. Lytic cycle
- rapid phage replication and lyses host cell
- lytic phages include T2, T4 and Ebola virus
2. Lysogenic cycle
- temperate phage infects and inserts the DNA into host chromosome
- activated to excise and follow lytic life cycle by certain triggers
- lysogenic phages include phage lambda
50
Mutualism example: lichen
- fungus provides minerals and protection from UV
- cyanobacteria/algae provide photosynthetic nutrients
51
synergism example: cow rumen microbiome
- rumen bacteria ferment complex polysaccharides from grass, making H2 and CO2
- methanogens convert these gases to methane
52
commensalism example: Beggiatoa and other sulfur spring microbes
- toxic H2S microbial mats contain Beggiatoa (a sulfur oxidizer).
- Beggiatoa reduce ecosystem toxicity and allows growth of other species
53
Amensalism example: Streptomyces and other soil bacteria
- streptomyces produce antibiotics and use these molecules to kill and lyse bacteria in soil, releasing their nutrients for consumption by streptomyces
- interaction is NON-specific
54
Parasitism example: legionella affecting amebas and human lung macrophages
- The causative agent of Legionnaire's disease
- can infect freshwater amebas and lung macrophages
- usually contaminate via air conditioning systems
- interaction is specific and usually obligatory for the parasite
55
what are endosymbionts
- intracellular bacteria that infect species (mostly insects)
- like "helpful parasites" (mutualism + parasitism)
56
endosymbiosis example: Wolbachia
- have symbiosis with 50% of insects
- can be transferred from mother to progeny
- useful to fight malaria - compete with viruses for colonization to lessen the viral load
- infections are localized to ovarian germ cells and testes
- females have an advantage for reproduction
57
Mutualism example: Photorhabdus luminescent and nematode worm
- the bacterium are bioluminescent and collectively make nematodes glow
- this attracts insect larvae predators to consume the worm
- once inside the insect, the bacteria are released from the nematode and use potent toxins to rapidly kill the insect
- both the worm and bacteria use the released nutrients from the dead insect and then reassociate to start the cycle again
58
parasitism and synergism example: helicobacter pylori and gastrointestinal tract
- the bacterial pathogen is the main causative agent of gastric ulcers and gastric cancer
- the bacteria utilize host cell energy stores for growth
59
commensalism example: staphylococcus epidermidis and skin cells
- the bacteria lives on human skin and used dead skin cells as nutrients
- unless you are immunocompromised in some way, they won't effect your body
60
mitochondria and chloroplasts have what type of symbiosis?
endosymbiosis (form of mutualism)
61
what are the 3 main questions of microbial ecosystems
1. who is there
2. what are they doing
3. how do microbiomes vary under different conditions
62
question 1: who is there? - determine using culture
- only supportive of a handful of bacterial species
- "the great plate count anomaly" states that many bacterial species int the lab conditions foreign and they cannot survive
- using "culturomics" can reside labor intensity with AI and robots, allows culture under many different conditions and picking of thousands of colonies into multi-well plates
63
question 1: who is there - determine using DNA sequencing
gDNA is extracted and subjected to either...
A) Amplicon sequencing - target gene is amplified, barcoded and sequenced (most common to amplify regions from 16S rRNA gene)
B) Metagenomic "shotgun" sequencing - gDNA is broken up into bits, barcoded and directly sequenced, computer is used to match genes to sequenced pool
- both methods reveal alpha diversity (species richness)
- amplicon sequencing is better and more accessible
64
question 1: who is there - determine using RNA sequencing
- extract mRNA from a community
- transcribe to DNA (using viral reverse transcriptase)
- barcode and sequence
- match transcripts to known genomes
key benefit = know the microbe is alive
65
question 2: what are they doing - predictive method
- a powerful computer assembles MAGs
- use the software to annote genes and predict their possible functions
- most famous program = pie crust
66
question 2: what are they doing - direct proteomics
- extract all the proteins in the sample, sequence peptide fragments using mass spectrometry
- use a computer to match peptides to proteins and proteins to genes
- pro: protein shows the genes are useful
- con: expensive
67
question 2: what are they doing - direct metabolomics
- extract all the molecules in a sample
- subject directly to mass-spectrometry or NMP spectroscopy
- use computer to match compound signatures to standards
68
question 2: what are they doing - direct metatranscriptomics (RNA-seq)
- mRNA content reflects active transcription - what the cells are doing/making in response to the environemt
69
question 3: how do microbes vary under different conditions
- microbes are dynamic systems - change in response to the environment
- sample longitudinally - at multiple points in time (multi-omics integration)
70
primary producers in oceans and freshwater ecosystems
bacteria and algae
71
which region of marine habitats contains the highest concentration of microbes
the neuston layer (surface layer)
- because of photosynthesis by primary producers
72
what extremophile category do most ocean microbes fall into
oligotrophs - do not need a lot of nutrients
73
major findings of tara oceans and tara pacific
- in the upper ocean layers temperature is that main determinant of microbiome composition
- in an era of climate change this could have major ramifications
74
mutualism within the ocean microbiome: Prochlorococcus and Alteromonas
- Prochlorococcus lost the catalyst in its genome to allow it to grow
- Altheromonas produce a catalayse for them
- Prochlorococcus removes H2O2 making a better environment for altheromonas
75
which extremophiles are found on the open ocean floor
barophiles - extreme pressure
psychrophiles - extreme cold
oligotrophs - extreme nutrient depletion
- these microbes have extremely slow metabolic rates and high concentration of heavy metal resistance genes
76
hydrothermal vent
- a deep ocean oasis with extreme pressure end extreme heat
- barophiles can live here
77
other carbon-rich sources that fuel marine microbiomes
- cold seeps
- whale fall
- ship wrecks
78
what is the most harmful treatment to soil microbes
- manufactured fertilizer pellets - introduce nitrogen into the soil
79
microbes found in the top layers of soil...
topmost = fungi, actinomycetes, slime molds
below = mycorrhizae (plan roots), aerobic bacterial biofilms and filaments
80
soil food web
producers: plants - leaves and roots, lithographs
consumers: protists and fungi
secondary consumers (predators): protists, nematodes, arthropods
decomposers: bacteria and fungi
81
each particle of soil supports miniature colonies, biofilms and filaments of bacteria and fungi that...
interact with each other and with plant roots
82
what are the streptomyces
- a major genus of soil bacteria notable for diversity of antibiotics they make
- also responsible for soil "smell"
83
microbes in the rhizosphere...
- help to protect plants from pathogens
- may fix nitrogen (diazotrophs)
- feed off nutrients provided by the plant
84
what are ectomycorrhizae
- grow outside plant cells
- colonize the rhizoplane
- form a thick, protective mantle around the root
- extend outward to absorb nutrients
- ectomycorrhizal hyphae do not penetrate cells
- eventually want to get into a cell and become an "endo"
85
what are endomycorrhizae
- grow inside plant cells
- dependent on their host
- lack sexual cycles
- exist entirely underground (e.g. root cells)
86
specialist endophytic relationship: plant roots and rhizobia
- bacterial cells adapt to life within nodules to form a nitrogen-fixing "organ" for the host plant
- leguminous plant
- leghemoglobin makes nodules pink and is there to allow O2 to be taken away (anaerobic environment)
87
what are commensal organisms
- microbes that are normally found at various non-sterile body sites
- can cause disease if they reach abnormal places
88
microbiota vs microbiome
microbiota = cell consortism
microbiome = the genetic potential of the consortium
89
some insects require microbes to allow digestion of their dietary substrates...
termites and demoted mites
90
how human are we?
1 : 1.3
human : bacteria
91
what are the most common bacteria found at various parts of the body
actinobacteria and firmicutes
92
which parts of the body can only host bacteria (as opposed to viruses and fungi)
nose and stomach
93
microbiome of the skin
- the skin is difficult to colonize because it is dry, salty, acidic and has protective oils
- most microbes found in moist areas such as scalp, ears, armpits, genitals and anal areas
- mostly gram-positive bacteria (more resistant to salt and dryness)
- e.g. S. epidermidis and C. acnes
94
microbiome of the mouth
- infants mouth is colonized by non-pathogenic Neisseria (gram-negative) + Streptococcus and Lactobacillus (gram-positive)
- as teeth emerge other bacteria start growing between gums and teeth and on tooth enamel
- oral respiratory tract = most common site of infection
95
microbiome of the nose and oropharynx
- nostrils and nasopharynx are dominated by bacillota and actinomycetota (one dominates over other)
- Nasopharynx dominated by S. aureus and S. epidermidis
- oropharynx has similar composition to saliva
96
microbiome of the lungs
- not sterile, microbes are present here as biofilms
- many are anaerobes
- microbiota in diseases such as COPD, cystic fibrosis and asthma are distinct for each condition and different to that of a healthy lung
- the mucocilliatory escalator constantly sweeps inhaled particles up toward the throat
97
microbiome of the urogenital tract
- the kidneys and urinary bladder ate STERILE
- the urethra contains S. epidermidis which can cause UTIs
- composition of vaginal microbiota changes with the menstrual cycle - acidic secretions favour Lactobacillus (low pH in vagina) which is protective from STIs and improve reproduction
98
microbiome of the stomach
- stomach has very low pH
- helicobacter pylori survives at pH , burrows into mucus and causes gastric ulcers
- hypochlorydia can be caused by malnourishment or PPI use
- stomach acid is a key defensive barrier
99
microbiome of the intestine
- ratio of 1000 anaerobes to 1 facultative aerobe in feces
- the most important microbial ecosystem in the human body lives in the colon
- does as much metabolic work as the liver, regarded to as the forgotten organ
100
true or false : it is the metabolic potential of the gut microbiome that is important, not its specific species
true
101
what do our gut microbes do for us?
- regulate the immune system
- extract energy from food
- control potential pathogens
- make some essential metabolites, including vitamins and cofactors
- improve intestine function
- remove toxins and carcinogens
102
what is considered a "virtual organ" that is as important to us as our liver
the gut microbiome
103
how do we acquire our microbes
- vaginal delivery
- breast feeding
- interaction with the environment
104
how do we lose our microbes
- C-section delivery
- maternal antibiotics
- formula feeding
- indoor living
- excessive sanitation
- chemical preservation of food
105
a high diversity of species in our gut microbiome leads to...
- healthy ecosystem
- balance
- functional redundancy (high gene count)
- resistance to damage
106
a low diversity of species in out gut microbiome leads to...
- sick ecosystem
- imbalance
- functional disability (low gene count)
- susceptibility to damage
107
what does the AV lab research on "missing microbes" focus on
- studying the gut microbiome of remote hunter-gatherer people
- they have a far more diverse microbiome than we do
108
what is a robogut
- a bioreactor model used to emulate the gut environment
- bioreactors model of the human colic environment evaluates the gut microbial community ecology and functions
- a "host free" system used to culture the unculturable
- can support whole gut microbial ecosystems for several weeks
109
what happens when we have accidental penetration of physical barriers or damage in the immune system
- the microbiota behaves badly
- microbes that breach barriers are opportunistic pathogens
- the patient may be infected by the normal microbiota (e.g. inflammatory bowel disease)
110
how is the microbiota protective
- competitive exclusion: prevents pathogen from growing there
- environment modification: makes it hostile for the pathogen
- host stimulation: e.g. host cytokines regulate the immune system
- direct pacification: secreted factors from microbiome members can prevent expression of virulence genes
111
the microbiome-gut-brain axis
- the brain and gut microbiota signal to each other
- the metabolites made by gut microbes can affect your moos and behaviour
- signalling pathway = vagus nerve
112
what happens when microbial balance is compromised
- containment breaches
- niche disturbance
- extinction events
113
Obesity and dysbiosis - microbiome imbalance example
- gut microbiome influences nutrient acquisition and regulation of energy metabolism and fat storage
- obesity is associated with a less diverse microbiome
- obesity is also associated with low-grade intestinal inflammation
- loss of microbes that increase tight junctions
- increase of microbes that make pro-inflammatory molecules such as LPS
114
abnormal physiology of germ-free animals
- poorly developed immune system
- lower cardiac output
- require more calories
- thin, poorly developed intestinal walls with stunted villi
- enlarged ceca
- odd behaviour
- misshapen mitochondria
115
what is the innate immune system
- "non-specific"
- a rapid response system
- includes physical barriers + cellular and chemical responses (if physical barriers are breached)
- present since birth
116
for an infectious agent to cause disease, the pathogen needs to...
1. breach host defenses
2. survive innate defence mechanisms
3. begin to multiply
117
physical barriers to infection
Skin: difficult to penetrate when intact
Mucous membranes: selective permeability allows absorption of nutrients
Lungs: have a mucociliatory escalator to remove small particles, larger molecules are trapped by hair in the nose and cilia lining of upper airway
118
primary vs secondary lymphoid organs
primary: factory for lymphoid cells, include thymus and bone marrow
secondary: stations for antigen encounters, include lymph nodes, appendix, spleen, peyer's patches, tonsils
119
what is the complement system
- a surveillance system of proteins that circulate the blood in their inactive forms and are cleaved to become activated
- they compliment antibodies in the killing of bacteria by forming a MAC complex
120
Important components of the alternative complement pathway
- C3b acts as an opsonin
- C3a and C5a act as anaphylotoxins, directing immune cell traffic
- membrane attack complex (MAC) punches holes in target bacterial cells, killing them
121
what are cytokines
molecules secreted by cells which have an effect on other cells
- e.g. interferon: when a cell is infected by a virus the cell secretes interferons to call nearby cells to fend off the virus and limit spread of infection
122
what are defensins
small molecules able to lyse most microbial cells and some enveloped viruses
- in the gut, there is a concentration gradient of defensins - higher near the crypts of the epithelium
123
what are types of white blood cells
- leukocytes (PMNs)
- monocytes and macrophages
- dendritic cells (minor in innate)
- mast cells (minor in innate)
124
MYELOID bone marrow stem cells differentiate into...
phagocyte cells
125
why are bacterial cells difficult to catch by phagocytes? how does this get resolved?
- bacteria and phagocytes both carry a negative charge
- C3b binds non-specifically to the surface of bacterial cells and makes it easier for phagocytes to ingest them
126
NETs: neutrophil extracellular traps
- an unusual form of cell death by neutrophils called NETosis
- neutrophil senses invader and spews a latticework of chromatin and antimicrobial compounds to allow rapid phagocytosis of pathogen
- inappropriate netosis is thought to underlie an autoimmune disease called lupus
127
what bacterial structure might interfere with the process of NETosis?
capsule - forms a slimy layer for the bacteria to "slip" through
128
Why do monocytes differentiate into macrophages
- monocytes circulate the bloodstream
- as they are attracted to sites by cytokines they differentiate into macrophages while travelling though blood vessels
- macrophages will secrete more cytokines to attract other phagocytes
- they must differentiate because secreting cytokines while traveling through the blood is dangerous
129
what are monocytes
large structures that can ingest many microbes at one time
- usually found circulating but some organs contain patrolling resident macrophagese
130
examples of patrolling resident macrophages
1. Kuppfer cells in liver
2. Langerhans cells in the skin
3. microglia in the brain
4. alveolar macrophages in the lungs
131
dendrocytes possess...
long protrusions that can squeeze through tight spaced to sample microbes
132
what is the "language of our immune system"
- cytokines, chemokines and interferons
- close-range actin "hormone" system that allow cells of the body to communicate
- effective in signalling danger and anti-inflammatory signals after danger has passed
133
cardinal signs acute inflammation
heat, swelling (edema), redness, pain, altered function
134
basic inflammatory response
1. infection occurs
2. resident macrophages engulf pathogens
3. vasoactive factors and cytokines help deliver additional phagocytes
4. healing proceeds as pathogens are destroyed
135
Fever...
can be part of an inflammatory response, and heightens activity of components of the innate immune system (complement works better when the body is warmer)
136
macrophages and dendrocytes are...
antigen-presenting cells
137
what are antigen-presenting cells
- cells (macrophages and dendrocytes) that process antigens and display them on their surfaces for T cells
- form a link between the innate and adaptive immune system
138
role of antigen presenting cells
- phagocytosis of antigens
- fusion of lysosome and phagosome
- enzymes start to degrade enemy cell
- enemy cell broken into small fragments
- fragments of antigen presented on APC surface
- leftover fragments released by exocytosis
139
what are Peyer's patches
- specialist sites within the small intestine that take up antigens in the gut for presentation to macrophages
- rich in M cells (what takes up the bacteria)
- helps the body differentiate between self and non-self when faced with a complex microbiome
140
what component of the cell allows some pathogens to evade the innate immune system
capsule
141
how do receptors of the immune system recognize pathogens
- Pattern recognition receptors (PRRs) recognize invariant and essential microbial factors unique to the microbiome
- they do this by recognizing MAMPs (microbe-associated molecular patterns)
142
what are the 2 types of pattern recognition receptors (PRRs)
1. Toll-like receptors (TLR) - outside the cell
2. NOD-like receptors (NLR) - onside the cell
143
Toll-like receptor (TLR) and their mode of action
- transmembrane receptors that recognize pathogen products
- on binding to ligand they stimulate cytokines to signal inflammatory response
- induce macrophages to produce antimicrobial proteins and peptides
144
NOD-like receptor (NLR) and their mode of action
- internal (cytoplasmic) NOD like receptors bind MAMPs inside host cells
- they activate cytokine production and form an inflammasome that activates the adaptive immune response and triggers apoptosis (GOOD)
145
what is an inflammasome
a protein complex that allows rapid secretion of certain cytokines
146
what are natural killer cells
- lymphocytic cells distinct from T and B cells
- NON-phagocytic
- large and granular
- don't attack the pathogens themselves, instead attack host cells that have become overwhelmed by pathogens
- have pseudopod extensions
147
NK cells mechanism of action
1. NK cell alerted by interferons or macrophage-generated cytokines
2. infected host cell signals an "altered self" response (through changes on MHC class I molecules)
3. NK cell binds to infected cell, perforin punches holes in the cell membrane
4. "granzyme" moves through the pores and induces infected cell to undergo apoptosis
148
what is efferocytosis
- a process where neutrophils consume apoptotic bodies
- neutrophils dispose of apoptotic cell bodies along with the intruder microbes
- inflammation is kept to a minimum
149
what is the adaptive immune response
- branch of the immune system that has memory, develops as the need arises
- includes cell-mediated and humoral-mediated immunity (intertwined)
-
150
cell-mediated vs humoral immunity
Cell-mediated = teams of T-cells work together to recognize antigens displayed on infected cells - target infections in the body CELLS
Humoral = antibodies (from B cells) directly target microbial invaders - target infections if the body's HUMORS (fluid's)
151
how does adaptive immunity develop
- immune system recognizes small pieces of a given antigen - EPITOPES
- over a 3-4 day period following exposure to the invader the immune response develops
152
how do epitopes develop
1. phagocytosis of the bacteria/pathogen
2. antigen is broken up into many epitopes (can have one or more epitopes)
3. epitopes released from a cells as immunogenicity or haptens
4. immunogenicity can generate an immune response
153
what are haptens
small molecules that are too small to elect an immune response on its own, but when bound to a larger molecule can act as an antigen
154
what is immunogenicity
- the effectiveness by which an antigen elects an immune response
- increasing immunogenicity = lipids, carbs, proteins
- proteins are more 3D
155
T cell development
- education begins before birth
- T cells are born from hematopoietic stem cells found in bone marrow
- as they mature each will develop a unique T cell receptor which reacts to a different random epitope
- the thymus gland is where T cells develop
156
T cell education
T cells mature in the thymus gland before they can be released into the body, they are tested on...
- ability identify self-MHC peptides (positive selection)
- reactivity against self antigens in the thymus (negative selection)
If they fail these tests they are instantly killed so they don't attack healthy cells in the body
157
how do T cells of older adults get education?
- most T cell education occurs just before or at the time of birth
- reserves of educated T cells are maintained by the body and reproduce at a balanced rate
158
2 types of "effector" T cells
1. Cytotoxic T cells (CD8+)
- seek and destroy cells presenting antigens
2. Helper T cells (CD4+)
- memorize databanks of antigens an alert B-cells if circulating antigen is detected
159
memory and regulatory T cells
1. memory TH cells
- retain antigen affinity of the originally activated T cell
- act as later effector cells during reinfection
- overtime memory can get hazy, but can pass traits onto next generation
2. T-reg cells
- do not promote an immune response but help restore homeostasis after infection
- lack of these is associated with chronic inflammation
160
what are MHC proteins
- proteins onto which infected cells or APCs place antigens for display to the immune system
2 types...
MHCI: display antigens on the surface of an infected cell, cytotoxic T cells come to kill the CELL
MHCII: display antigens on the surface of APCs, helper T cells take further steps to neutralize infection. want ANTIGEN killed, not the cell
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initiation of cell-mediated (T cell) response to an antigen
- APCs that have phagocytosed a pathogen travel to lymph nodes (secondary lymphoid organ) to display their captured antigens to T cells
- the binding of antigen-loaded MHCI or MHCII to TCRs activated T cells and the response begins
- T cells directly kill the infected host and may also produce cytokines that initiate macrophages to migrate
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how do helper T cells activate humoral immunity
- helper T cells are the conduit between APCs and B cells
- free floating antigens from the microbe bind to B cell receptors specific for an epitope
- if a helper T cell presents the same antigen to a B cell as the one already on its B cell receptor the B cell becomes activated- then differentiated into a plasma cell to make antibodies
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B-cells can differentiate into...
1. Plasma cells: make antibodies, short-lived
2. memory B cells: speed up a subsequent immune response to the same invader, survive a decade or more
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RECAP: stages of the immune response
- APCs engulf a pathogen and travel to the nearest lymph node - as they move they digest the pathogen and display its antigens on their surface
- At the lymph node garrison the APCs activate T cells and free antigens activate B cells
- plasma cells, memory cells and cytotoxic T cells leave the garrison and enter the circulation
- cytotoxic T cells travel directly to the site of infection
- plasma cells and memory cells travel to the bone marrow
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how does antigen dose effect T and B cells
- if the antigen is over a threshold value then B and T cells become over-stimulated
- T cells become non-functional
- B cells do not respond to subsequent antigen exposures to make antibodies (anergy)
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"anatomy" of antibodies
- has 4 polypeptide chains: 2 large heavy chains and 2 smaller light chains
- small and large chain are bound by disulfide bonds
- constant region (body) and variable region (head)
- Fc region of the body reacts with complement or binds the surface of cells`
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what is the Fc region of an antibody
- bottom of the antibody
- reacts with complement OR binds to the surface of cells
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constant and variable regions of antibodies
- constant regions are conserved aa sequences - 5 heavy chain and 2 light chain types
- heavy chain defines the class: IgA, IgM, IgG, IgD, IgE
- each class is common to a species (isotope)
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isotype vs allotype vs idiotype
isotype: defines the various heavy chains of a SPECIES
allotype: differences in the constant region shared by some but not all members of a species
idiotype: differences in the hypervariable region within an individual
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IgG antibody
- simplest, smallest, most abundant antibody
- monomer with 4 classes (IgG1-4)
- binds and opsonizes microbes
- binds and neutralizes viruses
- activates the classical complement pathway
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IgA antibody
- major secreted antibody of mucosal surfaces (sIgA found in tears, breast milk and on mucosal surfaces)
- found as a dimer, linked by disulfide bonds to the J-chain protein
- secretory piece is wrapped around both molecules during secretion
- can bind 4 antigens
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IgM antibody
- can be found as monomers on the surface of B cells (part of receptor)
- most commonly found asthma pentamer held together by J-proteins - one IgM can bind 10 antigens
- first antibody isotype detected during the course of infection
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IgD antibody
- trace amounts in the blood
- exists in monomeric form of the surface of B cells
- does NOT bind complement
- plays role in B cell activation but function not well understood
- possible enhances mucosal homeostasis and immune surveillance by basophils and mast cells
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IgE antibody
- trace amounts in blood
- mostly found on the surfaces od mast cells and basophils which are loaded with inflammatory mediators
- when 2 molecules of IgE on mast cells or basophils are cross-linked by antigen, cells degranulate and act quickly to amplify the immune response
- primary role = amplify the body's response to invaders
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what is an allergy
- antigens which are harmless to most people are threats to some
- anti-allergen IgE triggers release to chemicals such as histamine form mast cells, or leukotrienes from eosinophils
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the allergy response
1. allergy-prone person first encounters the allergen (e.g. ragweed)
2. large amounts of ragweed IgE is made
3. anti-ragweed IgE attaches to mast cells
4. on second encounter cross-linking of IgEof mast cells triggers a signal cascade causing release of chemicals such as histamine
5. person suffers from sneezing, runny nose, watery eyes and itching
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what is anaphylaxis
- very severe form of an allergy
- excess histamine triggers smooth muscle contraction (e.g. contraction of lung smooth muscles interferes with breathing)
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excess histamine in allergies
- weakens junctions between cells lining blood vessels
- fluid is forced from the circulation into the tissues
- the fluid contains histamine and the reaction spreads rapidly
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why does an epipen help neutralize allergies
- epipen releases epinephrine to increase cAMP from cells
- cAMP decreases degranulation of cells and strops histamine production immediately
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which antibody classes bind complement
IgG and IgM
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which antibody class is transmitted across the placenta
IgG
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the classical complement pathway and adaptive immunity
- antibodies made as part of the adaptive immune response activate the classical pathway
- C3 is the major player
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the lectin-mediated complement pathway
- lectins are made in the liver and bind sugars in bacterial cells
- allow complement proteins to bind and trigger the formation of C3 convertase, then the pathway is the same as the classical pathway
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why do we need 3 different complement pathways
3 pathways = 3 ways to recognize pathogens = minimized virulence of pathogen phase variation
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what are "shapeshifting" pathogens
- virulence strategy is to change their antigens regularly to elude the immune system
- new antigens are not recognized by antibodies and are thus invisible to cytotoxic T cells
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how does the gut microbiota fend off invaders while hosting a vast and complex ecosystem like the gut microbiota
1. epithelial barriers are studded with T cells that have encountered antigens (inter epithelial lymphocytes are sensitive of pathogens)
2. dendritic cells reach between epithelial cells to sample antigens from the microbiota
3. M cells in peyer's patches also sample antigens
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sIgA and the lumen of the gut
- sIgA coats microbiota components in the gut that are considered to be threats
- prevents bound microbes from penetrating the barrier
- may promote colonization of certain important beneficial microbes allowing them to stick around and colonize
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positioning of TLRs and their responses
- TLRs on epithelial side facing the gut lumen see many antigens
- TLRs on the basal side of the layer see fewer antigens only from invasive pathogens
- TLRs on basal side are much more reactive
- many beneficial microbes have evolved to dampen TLR signalling
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what is immunologic specificity
- the degree to which an antibody recognizes an antigen
- can distinguish between similar-looking antigens
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earliest clues about immunospecificity came from...
small pox
- survivors of the disease did not get it again
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cross-protection: small pox example
- inoculation of cowpox worked to protect against smallpox
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why is prevention of disease better than curing the disease
- suffering an infection with a pathogen results in an immune response with innate driven protection
- for nasty pathogens this comes with risk of high morbidity and sometimes mortality
- also comes with risk of infecting others nearby
- disease prevention comes without the risk of pathogen-mediated disease
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what is immunization
- tricking the body into seeing a pathogen and raising an immune response without the risk of pathogen-mediated disease
- vaccination is a type of immunization that works because of our adaptive immune response
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what are the 4 types of vaccination
1. killed whole organisms
2. live attenuated organisms
3. subunit vaccines
4. nucleic acid vaccines
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killed whole organisms - basic vaccination type
- benefits: easy to produce, many antigens presented for robust response
- drawbacks: complete inactivation is difficult
- e.g. Salk vaccine for polio, HepA
- the Cutter incident: some batches of the Salk vaccine were incorrectly tested and passed which contained live virus - caused many cases of paralysis
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live attenuated organisms - basic vaccination type
- organisms are weakened before administration to give the immune system the upper hand
- benefits: pathogen infection process is appropriate, many antigens presented to immune system
- drawbacks: difficult to produce, contraindicated for those immunosuppresed
- examples: BCG, sabin vaccine for polio
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subunit vaccines - basic vaccination type
- selected, purified antigenic components of pathogens
- benefits: easy to produce, no chance of infection
- drawbacks: hard to find a protective antigen
- come subunit vaccines contain subunits of antigens from multiple pathogens on the same backbone for efficiency
- e.g. S. pneumonia capsular antigen, viral capsids from papilloma virus, toxoid vaccines
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nucleic acid vaccines - basic vaccination type
- include mRNA vaccines and viral vector vaccines
- mRNA vaccine contains mRNA that codes for specific antigen that is wrapped in a lipid layer and injected - briefly makes the target antigen to stimulate an immune response
- benefits: easy to make, quick to get to market, no chance of infection
drawbacks: cold chain distribution, poor public understanding
- e.g. spikevax and cmirnaty (Covid)
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which vaccine type is good for variants
nucleic acid vaccines because can be developed fast
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why do we vaccinate early in childhood
- passive immunity from mother protects child for first couple months after birth
- after this period the child needs antibodies it can't make yet so they are vaccinated
- HepB is given right at birth because mother can easily pass it to child
- most other vaccines are given just past 2 months
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why might we need repeated doses of a vaccine?
1. boost response
2. overcome antigenic changes (mutations)
3. waning memory
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need for repeated vaccine dose - boost response
- the first dose of a vaccine leads to early synthesis of IgM (bigger Ab) followed by IgG (more specific Ab)
- the second "booster" dose results in a rapid response because memory B cells were formed during the response
- the boost ensures sufficient antibodies with reactivity toward the antigen are circulating the body, protecting against reinfection
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need for repeated vaccine dose - overcoming antigenic changes
- some pathogens change their antigens rapidly (variants)
- a vaccine primes the body against an antigen that may be lost or changed
- e.g. for covid and influenza we need s slightly different vaccine as soon as the virus mutates
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need for repeated vaccine dose - waning memory
memory T cells and memory B cells are not indefinite
- as they replicate over time they lose specificity and eventually become unprotective
- e.g. need a tetanus shot every 10 years
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which type of vaccination is usually superior to the others
live attenuated vaccine
- elects the proper response for the most protection
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Salk (dead) vs Sabin (live attenuated) polio vaccines
- Salk vaccine elects an antibody response that is protective against paralysis but it does not elect the mucosal response
- later a person can get mild form of disease through the fecal-oral route and pass on the infection to unvaccinated people
- Sabin vaccine is more protective
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how is the covid 19 mRNA vaccine only partially protective
- the vaccine is injected and the antibody response is protective against severe disease, but does not elect the typical mucosal response
- a person can get a mild form of disease through natural infection and pass it on to others
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what is herd immunity
vaccinating a large part of the community effectively interrupts the transmission of the disease
- it protects immunocompromised people who cannot get vaccinated as they rely on others
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why does the concept of herd immunity not work for tetanus
tetanus is not spread from person to person
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contributions to the discovery of antibiotics
Ernst Duchesne: originally discovered penicillium molds
Alexander flemming: rediscovered penicillin and is credited for it
Howard Florey and Enrst Chain: credited with purification of penecillin
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Gerhard Domagk's contribution to antibiotics
- after infection by a pinprick, he injected his daughter with a dye called Prontosil
- prontosil is not active on plates because it needs to be metabolized to sulfanilamide by the body
- too much prontosil is toxic
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Prontosil and the development of sulfa drugs
- prontosil is metabolized to sulfanilamide by the body
- sulfa looks similar to PABA which is the pre-cursor for folic acid
- humans cannot synthesize folic acid, but bacteria can
- sulfanilamide replaces PABA to inhibit the enzyme that makes folic acid
- this interrupts bacterial metabolism
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Selman Waksman's contribution to antibiotics
- screened 10000 strains of soil bacteria for antimicrobial activity
- lead to his discovery of streptomycin
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selective toxicity of antibiotics
- possible because let elements of microbial physiology are unique from eukaryotic cells
- e.g. can target peptidoglycan in bacterial cell walls and the different units in their ribosomes
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bactericidal vs bacteriostatic antibiotics
bactericidal: kill the bacterium itself
bacteriostatic: prevents growth of the bacterium but does not kill it
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why are bacteriostatic antibiotics effective if they don't kill the pathogen
- they buy time for the immune system to gain the upper hand
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the term antibiotic is reversed for compounds that...
affect bacteria
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what does antibiotic effectiveness depend on
- the organism being treated
- the attainable tissue levels of the srug
- the route of administration
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in vitro we can measure the _____ of an antibiotic against its target
minimum inhibitory concentration (MIC)
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what are common antibiotic targets in bacterial cells
- cell wall synthesis
- cell membrane integrity
- DNA synthesis
- RNA synthesis
- Protein synthesis
- metaboloism
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which antibiotics are cell wall inhibitors
- penicillins
- cephalosporins
- vancomycin
- bacitracin
- monobactams
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which antibiotics are cell membrane inhibitors
- polymyxins
- daptomycin
- gramicidin
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what is the specific component targeted by cell wall antibiotics
peptidoglycan
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how does Bacitracin work as a cell wall antibiotic
- prevents bactoprenol from accepting new units of UDP-NAM
- can't get NAM from the cytosol to the cell wall
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how does Cycloserine work as a cell wall antibiotic
- inhibits the 2 enzymes that form the precursor peptide of the NAM side-chain
- can't make the dipeptide
- useful for treating tuberculosis
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which cell wall antibiotics inhibit peptide cross-linking
vancomycin, penicillin and cephalosporins
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how does vancomycin work as a cell wall antibiotic
- binds to the D-Ala-D-Ala terminal end of the disaccharide and prevents binding of transglycosylases and transpeptidases
- inhibits crosslinking of NAM molecules
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what are beta-lactam antibiotics (target cell wall)
- derived from fungi
- consist of a beta-lactam ring structure to which R groups can be added to
- if a lactam ring is added to the cell wall, enzymes start to add R groups which do not work with the cell structure
- cell wall loses rigidity and the cell will swell and die
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what are penicillin binding proteins
transpeptidase and transglycosylase - enzymes involved in cell wall building
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bacteria's mechanism to beta-lactam antibiotic resistance
1. inheritance of a gene that codes for a beta lactamase gene
2. inheritance of a gene that codes for an altered penicillin-binding protein that does not bind the antibiotic (not as good as first mechanism)
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cephalosporin cell wall antibiotics - used in worst case scenarios
- beta-lactam antibiotic which has been synthetically altered to combat the development of resistance
- microbes adapt quick
- only used to slow down the development of reisstance
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gramicidin - cell membrane antibiotic
a cyclic peptidase that inserts into the bacterial genome
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polymyxin - cell membrane antibiotic
- binds to both the outer and inner membranes of G-bacteria
- disrupts the inner membrane like a detergent
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which cell membrane antibiotics can only be used topically
gramicidin and polymyxin - because they have activity towards mammalian cell membranes
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daptomycin - cell membrane antibiotic
- aggregates in G+ bacterial membranes to form channels
- effective against MRSA
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examples of drugs that affect DNA synthesis
1. sulfa drugs
2. quinolones
3. metronidazole
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Sulfa drugs - DNA synthesis antibiotics
- interfere with nucleic acid synthesis by preventing synthesis of THF
- selectively toxic to Bactria because they make their own folic acid and we do not
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quinolones - DNA synthesis antibiotics
- target microbial topoisomerase which catalyzes changes in DNA topology to allow replication and transcription
- not often used because they are toxic to mitochondria (because they used to be bacteria)
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metronidazole - DNA synthesis antibiotics
- example of a pro-drug (needs to be converted to active form)
- activated on reduction by microbial flavodoxin or ferrodoxin, found in ANAEROBIC bacteria
- nicks DNA at random once activated
- not effective against aerobic bacteria
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examples of RNA synthesis antibiotics
1. rifampicin
2. actinomycin D
- only rifampicin is used clinically
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rifampicin - RNA synthesis antibiotic
- binds to exit tunnel of bacterial RNA polymerase, blocking RNA from exiting
- halts transcription
- turns bodily secretions bright orange
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protein synthesis antibiotics overview
- bind and interfere with the function of bacterial rRNA
- bacterial ribosomes have unique properties
- can target either the 30S or 50S subunit of the ribosome
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30S subunit antibiotics examples
1. Aminoglycosides
2. Tetracyclines
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aminoglycosides - 30S ribosome antibiotic
binds 16S ribosomal RNA (part of 30S ribosome) and cause translation misreading of mRNA
- results in peptides being jumbled or truncated
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tetracyclines - 30S ribosome antibiotic
- bind to and distort the ribosomal A site
- can interfere with bone development in fetuses and young children
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examples of 50S ribosome antibiotics
1. Macrolides and lincosamides
2. chloramphenicol
3. Oxazolidinones
4. Streptogramins
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Macrolides and lincosamides - 50S ribosome antibiotics
inhibit translocation of the growing peptide chain
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chloramphenicol - 50S ribosome antibiotics
inhibits peptidyltransferase activity
- can depress production of blood cells in the bone marrow in some people
- not used for a long time
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oxazolidinone - 50S ribosome antibiotics
binds to 23S rRNA component and prevents formation of the protein synthesis 70S initiation complex
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streptogramins - 50S ribosome antibiotics
types A and B that are used together, both bind to the peptidyltransferase site
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mupirocin - targeting aminoacyl tRNA synthetases
- binds to bacterial enzymes that attach amino acids to the end of tRNA molecules, halting protein synthesis
- used topically in creams to treat infections by G+ bacteria
- cannot be used internally because it is rapidly degraded in the bloodstream
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when does antibiotic resistance become a problem
- when we use high concentrations of antibiotics for long periods of time
- this exerts selective pressure on bacteria to evolve
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what are the strategies bacteria uses for antibiotic resistance
1. keep antibiotics out of the cell
2. prevent antibiotics from binding their target
3. dislodge an antibiotic bound to its target
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ABR strategy 1: keep antibiotics out of the cell
- destroy the antibiotic before they can enter the cell (e.g. using beta-lactamases)
- decrease membrane permeability by expressing narrower pores (e.g. fluoroquinolone resistance)
- pump the antibiotic out of the cell using specific transporters (e.g. tetracycline resistance)
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ABR strategy 2: prevent antibiotics from binding their target
- bacteria modify the target so that it no longer binds the antibiotic (e.g. shape of PBP or ribosomal proteins)
- add modifying groups to the antibiotic so that the antibiotic is inactivated (e.g. amino glycoside resistance through production of enzymes that change antibiotic structure)
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ABR strategy 3: dislodge an antibiotic bound to its target
- ribosome protection or rescue - some G+ organisms make proteins that bind to ribosomes and dislodge or prevent the binding of antibiotics that bind near the peptidyltransferase site
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resistance may be acquired...
1. intrinsically: natural resistance (e.g. G-bacteria and vancomycin)
2. through genetic mutations: gene encoding the antibiotic target acquired a mutation making it drug resistant
3. through receipt of an antibiotic resistance gene: a resistant gene is carried on a mobile genetic element such as a plasmid, transposon or integron
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ways that we have adopted taking antibiotics inappropriately
- used in enormous quantities
- prescribed inappropriately
- not taken appropriatly
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antibiotic stewardship
- should never be used to that viral infections
- do not use if the patients microbiome includes strains that are already resistant
- know which resistant strains are prevalent
- consider how long they need to be taken for
- use narrow-spectrum
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what is SARS-CoV-2
- severe acute respiratory syndrome Coronavirus-2
- an enveloped, positive strand RNA virus in the family coronaviridae (Group IV)
- the 7th corona virus found to infect humans
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important proteins on SARS-CoV-2
envelope protein: interacts with M protein to form the viral envelope
nucleocapsid protein: binds to RNA genome to make helical ribonucleoprotein
membrane protein: determines shape of viral envelope
spike protein: binds to host cell receptors to facilitate viral entry
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How does SARS-CoV-2 replicate itself in the cells of those infected
1. spike protein on the virion binds to ACE2, TMPRSS2 helps the vision enter
2. the virion releases its RNA
3. some RNA is translated in to proteins by the cell's machinery
4. some of these proteins form a replication complex to make more RNA
5. proteins and RNA are assembled into a new virion in the golgi and released
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what are spike proteins
- proteins found on viruses that initiate infection by binding to ACE2 on the host membrane
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what are harmful effects of angiotensin II
- modulates blood pressure through contraction of vascular smooth muscle
- influences sodium resorption in the kidney
- involved in inflammation, blood clotting, mitochondrial function
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what happens when Spike protein of SARS-CoV-2 binds ACE2
- it disrupts the equilibrium between ACE2 and ANGII which causes increased damage to cells
- ACE2 cannot break ANGII so it exerts harmful effects such as out of control BP and causing organ damage
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ACE2 levels are higher in cells of those that...
have hypertension, cardio vascular disease, diabetes and are older
- renders then high risk of sever Covid-19
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a key factor in determining severity of damage in COVID-19 patients is...
the amount of angiotensin they are producing
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the INNATE immune response to SARS-CoV-2
- virus outside host is recognized by TLRs: TLR2 recognizes envelope protein, other TLRs activated by components of the virus
- internalized viruses are recognized by internal PRRs
- interferons are quickly released to warn cells
- antigens are displayed on MHCI for targeting g by cellular immune response
- more cytokines released in the process
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the ADAPTIVE immune response to SARS-CoV-2
- helper and cytotoxic T cells are the first APCs to get to the lymph node
- B cells get activated and IgM, IgA and IgG specific to viral epitopes are made after a lag period
- after covid infection B cells are activated but the selection process is not complete properly and protection does not last long
- after vaccination B cell activation is more robust and complete to antigen used in immunization
- after disease is cleared memory T cells are sent ot the lung
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disease outcomes depend on many factors...
1. immunosenescence
2. co-morbidities
3. viral exposure
4. extent of cytokine storm and collateral damage
5. presence of neutralizing antibodies specific to the infection strain
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serious disease and death from covid result when...
lungs become damaged by actions of the immune response and are unable to absorb oxygen
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antiviral treatment of covid-19
- Paxlovid is oral delivered, acts as a protease inhibitor
- Veklury is injected into the bloodstream and inhibits viral RNA polymerase
- both medications cause severe side effects
- must be administrated within a few days of symptoms
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why was ivermectin thought to have possible protection against covid
- it is an anti-parasitic drug known to inhale interferon expression and inhibit viral replication
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what is enterohemorrhagic E. coli (EHEC)
- causes serious diarrheic infection that can lead to kidney destruction (hemolytic ureic syndrome - HUS)
- E.coli O157 [NM], NM = non-motor (no flagella)
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EHEC is a zoonotic disease...
- associated with cattle and other ruminants
- lives as a commensal in the ruminant gut
- transmitted via contaminated meat or vegetables
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symptoms of EHEC
bloody diarrhea, weakness, HUS
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how does EHEC infect plants and animals - mechanism
- possess a type 3 secretion system, acts as an injectisome
- allows bacteria to directly inject its proteins into cells
- injects a number of effector proteins into host
- first protein = Tir - inserts itself into the host cell membrane and becomes the receptor for the bacterial adhesin
- bacteria can make tight conditions with host
- Tir recruits actin monomers to its cytosolic side, which form onto polymers and forces up the cell membrane
- bacteria sits on a "pedestal"
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EHEC and Shiga toxin
- shiga toxin is an exotoxin secreted by EHEC
- shiga toxin binds to 28S rRNA of 50S subunit
- this blocks protein production, initiates apoptosis and signals inflammation through cytokines
- toxin has tropism for endothelial cells of vascular system and kidneys
- causes small blood vessels to become damages, worst effects seen in kidneys
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treatment for EHEC and HUS
- supportive treatment includes hospitalization, dialysis and hydration
- antitoxins are in development
- kidney damage can be permanent
- antibiotics should not be used because it would kill E. coli and release shiga toxin into the environment (BAD)
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prevention of EHEC
- very acid tolerant but poorly heat tolerant
- et fully cooked meat and wash vegetables
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