Viral Pathogenesis: Host Defense, Susceptibility, and Immune Response

Question 1

define window of susceptibility

Answer 1

the time at which antibody level is no longer sufficient to protect from infection, yet high enough to prevent vaccination = most at risk for infection/developing disease

Question 2

define innate immune response

Answer 2

cells: infected targets, NK cells, macrophages, dendritic cells, and granulocytes

soluble mediators: cytokines, chemokines, defensins, pentraxins, complement, etc.

Question 3

define adaptive immune response

Answer 3

cells: T and B lymphocytes

CD4+ (helper) T cells: produce cytokines to help differentiate B cells into plasma cells and undergo isotype switching and also produce IL-2 to help activate CD8+ T cells to kill virally infected cells

CD8+ (cytotoxic) T cells: when recognize a viral peptide presented on MHC I of infected host cell, these guys use perforin/granzyme killing or Fas/FasL killing; but DO NOT kill extracellular virions

B cells: produce antibodies (see antibody functions)

soluble products: cytokines, chemokines, antibodies

Question 4

define interferon

Answer 4

produced by virally infected cells; released in a paracrine manner to induce antiviral state in uninfected neighboring cells; interferes with viral replication to prevent uninfected cells from allowing viral genome replication

Question 5

compare and contrast the innate and adaptive immune response

Answer 5

both have self vs. nonself discrimination

innate: no lag phase (immediate response), limitied specificity, limited diversity, and no memory (subsequent exposures to the same agent produce the same response)

acquired: response takes at least a few days (requires antigenic proming), high specificity, extensive diversity, have memory (subsequent exposures to the same agent produce amplified responses)

Question 6

list viral products that trigger the innate immune system and what that trigger induces

Answer 6

many products trigger: dsRNA, viral glycoproteins, ssRNA or dsRNA intermediates, etc.

trigger induces some fever if viremia but MAINLY INTERFERON PRODUCTION

Question 7

describe how NK cells interact with other cells and decide when to release toxic granules to kill virally infected cells (3)

Answer 7

1. NK cells release large amount of IFN-gamma which activates macrophages to more efficiently kill intracellular pathogens
2. NK cells have activating and inhibitory receptors; if inhibitory receptors are not activated (would be activated by MHC I on a host/self cell), activating receptors lead to NK cell degranulation and killing of virally infected cells
3. some viruses can encode MHC I homologues that look like host MHC but have no function to avoid NK cell-mediated killing

Question 8

describe the concept of memory as it relates to adaptive immunity

Answer 8

once lymphocytes differentiate, some stick around and are ready for second exposure (memory), meaning that second response is much quicker and also likely more robust than first

Question 9

describe how antibodies can target free virus and virus-infected cells (7)

Answer 9

1. interfere with virion binding to receptors (block from approaching the door)
2. block uptake into cells (block from getting inside)
3. prevent uncoating of the genome in endosomes (stop from taking of shoes and getting comfy)
4. cause aggregation of virus particles (gather them all in one place)
5. many enveloped viruses are lysed when antiviral antibodies and serum complement disrupt membranes (disable or shoot them if we can)
6. opsonization: providing specificity to phagocytosis and enhanced signaling (call the cops and tell them who they are)
7. antibody-dependent cellular cytotoxicity: killing of antibody-coated (IgG)cell via NK cells (NK cells will NOT bind free IgG) (have the cops kill them)

Question 10

how have viruses evolved to evade antibodies (4 for enveloped viruses, and 1 for latent viruses)

Answer 10

enveloped viruses:
1. bud from internal membrane (aka there are no viral proteins on the plasma membrane of the cell they have infected)
2. cell-cell spread (syncytia formation)
3. heavily glycosylated receptors evade immunity
4. rapidly mutating receptors

persistent viruses: latent viruses do not express viral proteins on infected host cells, so can hide from immune system

Question 11

how have viruses evolved to evade T cells? both types

Answer 11

CD8+ evasion: mainly viruses escaping presentation of their antigens on MHC I (to avoid CD8+) detection; via preventing viral peptides loading onto MHC or downregulating the movement of MHC I to cell surface

longlasting: the antiviral function of both types of T cells may decline or become dysfunctional during some chronic viral diseases; CD8+ may lose cytotoxic activity, CD8+ may lessen cytokine production, and the memory CD8+ cells may be lost from the host, leading to slow or no recall to the antigen

Question 12

explain how maternal antibodies, young immune systems, and the window of susceptibility interact to produce current vaccine schedules that suggest several vaccinations

Answer 12

you want to help out an infant, since when they are born their immune system is not fully developed enough to protect them, so ideally you will vaccinate the mother because placental transfer or ingestion of antibodies via colostrum protects the young while they build their own active immunity

BUT

maternal antibodies can interfere with vaccination protocols and reduce vaccine efficacy (if high enough maternal antibody levels in baby at time of vaccination = baby no mount robust enough response to develop own active immunity); so want to vaccinate in window of susceptibility if possible!

how this looks:
initial vaccine series: increases coverage but may not necessarily boost the response, so will vaccinate again to ensure that if previous vx was blocked, will now work (don’t know which pups were actually protected from the first vx so just re-vx all to be safe); not necessarily boosting response each time, but just trying to catch at the right time (window of susceptibility)

Question 13

describe host factors that could alter the course of disease (6)

Answer 13

1. genetics of animal host: donkeys may be more resistant to a virus that is fatal in horses
2. age: young and elderly animals are more susceptible to most viruses and will experience more severe disease due to a waining immune system in elderly or an immature immune system in young animals (B and T cells not optimally functioning or failure of passive transfer, some cells actually lose susceptibility to some viruses with age)
3. endocrine factors:
   3a. corticosteroids are immune suppressive (impair function of T and B cells and neutrophil migration to tissues; can be endogenous or exogenous
   3b. periparturient or pregnant animals may be immunosuppressed due to pregnancy hormones
4. nutrition: effect on the integrity of the mucous membranes, skin, phagocytes, and the immune response
5. obesity: can have pro-inflammatory or suppressive effects
6. polymicrobial infection: depletion of immune resources, complimentary pathology, skewing of immune response to non-protective outcome (co-infection)