Basis Of Viral Disease

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Viral infection can be...

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Acute
Chronic
Latent

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Viral infection pattern influenced by

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Size of inoculum
Genetic make up of the virus
Route of infection
Age (0-3, 65+)
Immune status
Transmissibility
Virulence

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Susceptibility to infection depends on...

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Presence of host receptors for attachment and entry
HIV uses CD4 as a receptor on T cells
Influenza uses sialic acid (on most cells)
Others: ICAM, CD46 (measles)

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General patterns of infection

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Acute infections: viral load corresponds to severity of symptoms
Persistent infection: high viral load asymptomatic; at some point become severely symptomatic
Latent infections: reactivation and decline of viral load over and over, sometimes with symptoms, sometimes without (e.g. herpes)
Slow virus infection: acute infection followed by low viral load; much later very high viral load and death

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Acute viral infections

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Typically produce large amounts of progeny virus
Usually correlate to clinical symptoms

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Acute infection course

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Entry of virus; innate defenses; usually a few days of shedding virus without symptoms
Threshold of virus to activate adaptive immune response
Reaches a peak before adaptive immune response can take out infection
Memory

At some point when virus begins to wane, can get enhanced symptoms via secondary infections

Serum antibody slow to produce protective immunity --> need 3-4 weeks for vaccine to be effective

Time to onset of symptoms (incubation period) varies a lot

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Acute infections and public health

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Acute viruses commonly associated with epidemics (flu, measles, colds)
By the time symptoms emerge, patient likely to have transmitted infection
Difficult to control in large pops and crowded environments
Effective antiviral drug therapy requires early intervention -- not practical for acute infections

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Non-acute virus infections

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Persistent- chronic or latent

Lytic

Growth transforming

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Chronic infection

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Cells maintain normal fxn but generate low level virus production; little or no cell death

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Latent infection

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Virus infects and ALL replication ceases; genome maintained and can be reactivated later (herpes)

Don't always produce titer - ex. CMV

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Lytic infection

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Inhibition of macromolecular synthesis and other cell processes; high level virus replication and necrotic cell death

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Growth transforming infections

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Expression of viral proteins during productive infection resulting in disruption of normal cell cycle/growth control --> can be cancer causing

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NK cells

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Monitor and recognize virally-infected cells by MHC I
Some viruses suppress MHCI to avoid immune recognition

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Interferons

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Very important
Promote the establishment of the anti-viral state in non-infected cels and induce death in infected cells

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TLRs

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Usually recognize nucleic acid component of viruses most

When TLRs receive signal from some kind of viral PAMP --> IFN released

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Interferon types

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Type I - IFNa IFNb - many cell types
Type II - IFNgamma - macrophages, NK cells, activated T cells
Type III - IFNlambda - still being defined

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Interferon mech

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Some kind of receptor, could be TLR on endosome
IFN produced by infected cell
Neighboring cell bathed in IFN
Upregulates 300+ genes to stop any virus from coming in, replicating, assembling, releasing, etc.

IFN feeds back on infected cell, usually killing it

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TLR4

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Appears to be important in recognizing RSV (respiratory syncytial virus

Mice with deleted TLR4 - infected with RSV, but could not clear as quickly as TLR4 positive

Influenza does not appear to use TLR4

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IFITM

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Interferon-inducible transmembrane proteins

Involved in stopping viruses from escaping from endosomes

Folks with attenuating polymorphisms in these genes are more infected and for longer -- H1N1, west nile, dengue virus

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IFN evasion

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Most viruses encode IFN antagonist genes

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Fate of infected cells

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Damage/kill outright: ex. polio - cytolitic of motor neurons in spinal cord, leading to paralysis

Induction of immunopathology - RSV, H5N1 influenza virus

Transformation --> cancer - cervical cancers, lymphomas, leukemias, Kaposi's sarcoma

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Cell death outcomes

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Necrosis: cell gives up, breaks apart, dissolves--> inflammatory response that is pathological

Apoptosis: cell commits suicide, undergoes morphological changes, blebs off; non-inflammatory -- virus attempts to evade death receptors and caspase cascade with viral genes (some suppress IFN); ex. RSV

Autophagy: self-digests; may die or survive; exploited by some viruses to maintain life cycle

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Evasion of adaptive response

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1. infection of immune effector cells: HIV, CMV, measles
2. Inhibition of antigen presentation: inhibit peptide loading of MHCI (all herpes, adenovirus, HIV) or inhibit surface expression of MHCI (adenoviruses, HIV, HSV)
3. Antigenic variation

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Antigenic drift

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Requirements: must be PRONE to mutation; must have some kind of CHALLENGE -- ex. existing antibody