Viral Pathogenesis: Host Responses to Viral Infections

Question 1

3 general outcomes of viral infections:

Answer 1

1. Abortive infection/failed infection
2. Lytic infection -> production of virus and death of host
3. Persistent infection -> chronic (makes virus), latent (no virus made) or transforming (may make virus)

Question 2

Cytopathic effect (CPE):

Answer 2

morphological changes in the host cell

1. Indirect cell damage
2. Direct cell damage

Question 3

Indirect cell damage can result from

Answer 3

• integration of the viral genome
• induction of mutations in the host genome
• inflammation

Question 4

Direct cell damage ->

Answer 4

due to cell’s energy, shutoff of cell macromolecular synthesis, competition of viral mRNA for cellular ribosomes, competition of viral promoters and enhancers for cellular factors and inhibition of the interferon defense mechanisms

Question 5

Morphological changes:

Answer 5

nuclear shrinking (pyknosis) and membrane proliferation, nuclear membrane proliferation, cytoplasmic vacuolization, cell fusion (syncytia), chromosomal margination and breakage, rounding and detachment of tissue culture cells

Question 6

Inclusion bodies:

Answer 6

virions and proteins in nucleus, protein and RNA in cytoplasm, virus protein complexes and nascent virus in cytoplasm, chromatin clumps in nucleus.

Question 7

Syncytia

Answer 7

cell fusion of uninuclear cell to form multinuclear cell

Question 8

Permissive vs. nonpermissive

Answer 8

Permissive: provides machinery and components for viral rep -> virus can be efficiently produced
Non-permissive: does not have machinery for viral rep -> inefficient production of the virus to lead to cell death, but can lead to latent or transforming infections
***there is a spectrum

Question 9

Interferon response:

Answer 9

interfere with viral infection of neighboring cells
-Stat/Jak pathways signal IFN receptors to control genes. ISREs (interferon-stimulated response elements) regulate Type I and GAS (gamma activated state) regulate Type II

Question 10

Type I IFNs: (alpha and beta-IFN) =

Answer 10

antiviral cytokines transiently produced and secreted by -most infected cells within hours of infection

Question 11

Type II IFN (gamma IFN) =

Answer 11

produced by T cell and NK cells, some others, but more restricted than Type I

Question 12

Antiviral state:

Answer 12

cell (not necessarily one that has been infected) has been bound and responds to IFN -> blocks viral rep by altering transcription of more than 100 cellular genes and results in temporary blockade of cell proliferation, reduces cellular metabolism, potentiates NK cell activity including gamma-IFN production, increases expression of antigen presentation molecules, may lead to apoptosis, and more It is facilitated by dsRNA, which in turn activates IFN responsive genes. It can be produced by some viruses or produced as a replication intermediate.

Question 13

Innate anti-viral response

Answer 13

cells include the mononuclear phagocytes that phagocytize, release inflammatory mediators and do antigen presentation, dendritic cells that are found in every tissue (except brain) and present antigens to T cells, stimulate B cell differentiation and proliferation, modulate development of adaptive immune response and secrete antiviral and immunoregulatory cytokines, Natural Killer cells that are activated in response to interferons or macrophage derived cytokines, contain virus infection but adaptive immune response generates antigen specific cytotoxic T cells that can CLEAR the infection, granulocytes (inflammatory cells like PMNs, basophils and eosinophils)

Question 14

Cytokines of innate defense:

Answer 14

small proteins released by cell in body in response to activating stimulus, such as infection or ligand binding of a receptor, bind to specific receptors, act in an autocrine or paracrine manner (some in endocrine), IFNs, IL-1, TNF-alpha, IL-6, IL-12 and IL-18

Question 15

Chemokines of innate defense:

Answer 15

chemo attractant cytokines for leukocytes, monocytes, neutrophils from the blood to sites of infection, receptors are all integral membrane proteins containing 7 membrane-spanning helices. IL-8, IP10, MIP1alpha

Question 16

Adaptive anti-viral response

Answer 16

humoral response and cell-mediated response

Question 17

anti-viral humoral response

Answer 17

B-lymphocytes are the effectors in the humoral response, they produce immunoglobulin (B cell receptors) specific to structural epitopes that serve two purposes:

1. Surface bound is critical for B cell presentation to T cells.
2. Secreted antibody.

When B cell binds antigen, they are stimulated to divide, this promotes antibody affinity maturation or selection of those B cells producing the highest affinity Ab, and differentiation of those B cells to become plasma cells and secrete Ab. Stimulation of B cells through B cell receptor also leads to isotype switching (from IgM to IgG, E or A). Antibodies produced during primary infection are usually lower affinity than those produced later, because they are often IgM. IgG: inhibits fusion of enveloped viruses with host membrane, IgA (Secretory): inhibits virion/host attachement, neutralizes toxins/enzymes. IgG and IgM opsonize virions to enhance phagocytosis. IgM can coat and agglutinate some virions. IgG and IgM can facilitate complement lysis of enveloped viruses. Humoral response is critically for recognition of virions because once inside the cell, viruses are not accessible to antibodies and be eliminated ONLY by the destruction of the infected cells on which they depend.

Question 18

Cell-mediated anti-viral response

Answer 18

Critical for recognizing and eliminating viral INFECTED cells. T lymphocytes are the effectors of cell-mediated immune response. T cell receptors also bind specific structural epitopes but there epitopes are made up of host MHC Class I or II together with the viral peptide on surface of APC. T helper cells bind peptide bound to Class II. Cytotoxic T cells bind to Class I and can bind to virally infected cells and help kill them. IFNgamma secreted by helper and cytotoxic T cells, CTLs destroy infected cells, NK cells and macrophages kill infected cells directly or by antibody-dependent cell mediated cytotoxicity