Viral Pathogenesis

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Symptoms of Virus Infection Result When Cell Death and Cytokine Production Reach A Threshold Level

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Inapparent infection
-never reaches thresholds for symptoms
-most viral infections are inapparent
Acute infection
-reaches threshold for symptoms and then declines
Chronic infection
-Remains above threshold for symptoms
Latent infection
-Initial acute infection followed by reactivation and subsequent acute infections after time

Front 2

Viruses Often Kill Infected Cells By Inducing Host Antiviral Responses

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Induction of “cytopathic effect” (“CPE”):
-Programmed cell death (apoptosis) is a common response to virus infection
-Host cells try to enter apoptosis, but viral proteins inhibit cell death pathways. Result is not exactly apoptosis, not exactly necrosis

Death inducing cytokines + NK cells and Tc cells + cytotoxic antibodies = immunopathology

Front 3

Localized versus Systemic Infections

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Localized infection:
-Virus replicates only at site of entry

Systemic infection:
-Virus spreads from site of entry to other organs

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Routes of Virus Entry

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Respiratory (influenza virus)
-most common
Gastrointestinal (rotavirus)
Breaks in the skin or mucosal surface:
-arthropod-borne (West Nile virus). Requires virus replication in arthropod vector.
-animal bite (rabies virus)
-i.v. inoculation (HIV, HCV)
-sexually transmitted disease (HIV, herpes simplex virus)

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Steps in Systemic Virus Infections

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Virus Entry
Virus replication at site of entry
-Asymptomatic = “incubation period”
-Nonspecific symptoms = “prodrome”
Virus spread
-Viremia: usually involves spread of virus to draining lymph nodes (primary viremia) and replication in immune cells, that then traffic to other sites (secondary) – spleen, liver, etc.
-Neural spread: virus enters neurons at one synaptic junction, replicates in cell body, and is released at the next synaptic junction
Virus replication in target organs
Recovery

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Virus replication in “target” organs leads to “specific” symptoms of disease:

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a. Liver - hepatitis
b. Capillary endothelium and skin – rash (exanthem)
c. Capillary endothelium and many organs – hemorrhagic fever
d. Heart – myocarditis
e. Lymphoid organs - immunodeficiency
f. CNS – encephalitis and/or meningitis

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Points of Entry of Viruses into the CNS

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Infection of peripheral nervous system:
- Motor neurons (rabies)
- Sensory neurons (herpes simplex)
Compromised blood-brain barrier (polio?, West Nile?):
- Inflammation ?
- Trauma ?

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Recovery from Virus Infections

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Innate Immune Responses (not virus-specific):
- Type 1 IFN: IFN a and b, other cytokines from epithelial cells, macrophages, dendritic cells.
- NK cells induced by IFNs, preferentially lyse cells with low levels of class I MHC molecules (most virus-infected cells)
Adaptive Immune Responses (virus-specific):
- T lymphocytes:
--Tc (CTL)– lysis of infected cells, IFN g
--Th1 (helper)– activate B lymphocytes, IFN g
- B lymphocytes: Neutralizing antibodies (prevent reinfection)

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Timing of Host Responses
to Virus Infection

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1. IFN a and b
2. NK cell activation
3. CTL activation, IFN g, IL2
4. B cell activation (after 1 week)

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Interferons and Other Antiviral Cytokines

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Type I interferons - all bind to a common receptor:
-IFN a: 14 different genes in humans
-IFN b: 1 gene
-IFN w: 1 gene
Type II interferon - binds to a separate receptor:
-IFN g: 1 gene, produced by activated lymphocytes
Other antiviral cytokines produced by innate immune response:
-IL1: fever, inflammation
-TGFb and TNFa : apoptosis of infected cells, inflammation
-Chemokines: chemotaxis of inflammatory cells
-IL12: Activate adaptive immune response, esp. Th1 cells

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Induction and response to type I IFNs

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Two separate phases, induction usually in infected cells, response usually in neighboring uninfected cells

Induction:
1. Many viral components induce IFN production, but dsRNA (usually a by-product of virus infection) is among the most potent.

2. Signaling pathways phosphorylate transcription factors such as IRF-3 (interferon regulatory factor), which activate transcription of IFN genes

3. IRF-3 also activates transcription of other antiviral genes normally activated by IFNs (ISGs = “interferon-stimulated genes”)

Response:
1. Binding of IFNs to their receptor activates JAK protein kinases, which phosphorylate STAT transcription factors

2. STAT transcription factors activate transcription of many (>100) interferon-stimulated genes (ISGs). Example: Protein kinase R (PKR) – activated by dsRNA, inhibits protein synthesis

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Viruses Produce Interferon Antagonists

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Influenza virus : NS1 protein binds ds RNA, inhibits host RNA processing, inhibits IFN synthesis

Measles virus: V protein inhibits STAT signaling, inhibits response to IFN

Herpesvirus: g34.5 protein counteracts effects of PKR

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Viruses Inhibit or Evade
Adaptive Immune Responses

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Herpesvirus: ICP47 inhibits antigen presentation by class I MHC
Influenza virus and HIV: Antigenic drift to escape neutralizing antibody.

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Viral Suppression of Host Response is a Major Determinant of Cell-Type Specificity

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Must be able to suppress anti-virus response to spread.