Host Response to Viral Infection Flashcards
General outcomes of viral infection of cell
- abortive infection (failed infection)
- lytic infection: production of virus and death of cell
- persistent infection:
a. chronic=production of virus
b. latent=no virus produced
c. transforming=may produce virus
Cytopathic effects definition
any detectable morphologic changes in the host cell
Causes of direct cell damage from viral infection
- diversion of cell energy
- shutdown of macromolecular synthesis
- occupation of ribosomes by viral mRNA
- viral promoters and enhancers competing for cellular factors
- inhibition of interferon defense mechanism
Types of morphological cytopathic effects and viral causes
- nuclear shrinkage and membrane proliferation (picornavirus)
- nuclear membrane proliferation (alphavirus, herpesvirus)
- cytoplasmic vacuolization (papovavirus)
- cell fusion (“syncytia”) (paramyxo, coronavirus)
- chromosomal margination/breakage (herpesvirus)
- round and detachment of tissue culture cells (herpesvirus)
Types of inclusion bodies and viral causes
- virions and proteins in nucleus (adenovirus)
- protein and RNA and cytoplasm=”negri bodies” (rabies virus
- virus protein complexes and nascent virus in cytoplasm (poxvirus)
- chromatin clumps in nucleus (herpesvirus)
Causes of indirect cell damage from viral infection
- integration of viral genome
- induction of mutations in host genome
- inflammation
- host immune response
Permissive vs. Nonpermissive cell definition
- contains the machinery and components required for completion of viral replication
- non-permissive does not
- range of permissibilities between the two
Innate defenses against viral infection
- natural barriers: skin, mucus, ciliated epithelium, gastric acid, tears, bile
- cells: macrophages, neutrophils, dendritic cells, NK cells
- soluble factors, interferons, cytokines, complement, chemokines
- intracellular restriction factors
Innate vs. Adaptive immunity against viral infection (generally)
- innate is non-specific and immediate
- innate primes and initiates adaptive immune response
- adaptive generally responsible for immunologic memory
Intracellular restriction factors and examples
- cellular proteins that block post-entry steps of viral infections
- not adaptive immune response, but specific for viruses
- viruses have evolved mechanisms to avoid restriction factors
- e.g. Trim5 blocks retroviruses, APOBEC blocks HIV and HCV
Important TLRs in viral infection
-TLR3 –< dsRNA (viruses)
-TLR4 –< fusion/envelope protein (respiratory syncytial virus)
TLR7/8 –> Imidazoquinolone (synthetic) & ssRNA (viruses)
-TLR9 –< CpG-containing DNA (bacteria and viruses)
Class of proteins (other than TLR) that recognize viruses
- Retinoic acid-inducible gene I-like helicases (RLHs)
- coordinate similar pathways to TLR
Type I IFNs
- alphaIFN and betaIFN
- secreted by most infected cells w/in hours of infection
- antiviral cytokines produced transiently
Type II IFNs
- gammaIFN
- produced only by T cells and NK cells
Cell response of IFN
- IFN receptors –> Jak/Stat pathways
- control trxn of genes via:
- ISREs (Interferon-stimulated response elements) <– Type II IFN
Characteristics of the anti-viral state
- induced by IFN binding to receptor
- optimal state to block viral replication
- alter trxn of 100+ genes
- facilitated by dsRNA (intermediate in replication of some viruses)
- blocks cell proliferation, decreases cell metabolism
- increases antigen presentation, potentiates NK cell activity –> apoptosis
- IFN production –> “flu-like” syndrome
Major mediators of IFN-induced anti-viral state
- PKR=protein kinase that phosphorylates (inactivates) translation initiation factor –> decreased protein synthesis
- OAS=activates ribonuclease that degrades mRNA
Cytokines of the innate immune system
- small proteins that help body respond to infection
- IFN, IL-1, TNFalpha, IL-6, IL-12, IL-18
Chemokines of innate immune system
- chemoattractant cytokines for leukocytesm monocytes, neutrophils, and other effectors to site of infection
- IL-8, IP10, M1P1alpha
Role of NK cells in viral infection
- activated in response to interferons or macrophage-derived cytokines
- contain virus while the adaptive immune response generates CTL to clear infection
Humoral response to viral infection
- B cells bind viral antigen and are stimulated to divide –> plasma cells secrete Ab
- Abs produced during primary viral infection are usually lower affinity than those produced later, and are often IgM
- IgA: inhibits virion attachment, neutralizes toxins
- IgG: inhibits fusion of enveloped viruses
- IgG/IgM: opsonize or complement lysis virions
- IgM: agglutinate virions
Group specific vs. type specific Abs
- group=see epitopes shared by all of a virus group
- type=see epitopes defining a virus group subset
Cell-mediated response to viral infection
- used to target virus by killing infected cells
- T cells bind viral epitopes presented on MHC class I (CTL) or MHC class II (Th)
- T cells/NK cells secrete gammaIFN
- CTLs lyse virus-infected cells
Viral strategies to evade host defense (7)
- antigenic variation
- immune tolerance=molecular mimicry
- restricted expression of viral genes=”going invisible” i.e. latent infections
- viral mlx act as inhibitors or decoys=blind or block cellular mediators or mimic
- down-regulation of host proteins=e.g. MHC class I or adhesion mlx
- infection of immunoprivileged sites
- direct infection of immune system
- inhibition of apoptosis and cell cycle control
Example of viruses that produce proteins to inhibit host defense
- Pox
- Herpesviruses
Examples of antigenic variation
- antigenic drift (point mutations)=HIV, influenza A
- antigenic shuffling=influenza A
Example of down-regulation of host proteins
- Pox
- Herpesviruses
Example of infection of immunoprivileged sites
- e.g. brain
- HSV
Examples of direct infection of the immune system
- HIV
- EBV
Examples of inhibition of apoptosis/cell cycle control
- SV40 large T antigen
- Adenovirus E1A
- pathway is also involved in tumorigenesis
