Pathogenesis and Control of Viral Infections

Chapter 30

Principles of Viral Diseases

• Pathogenesis is disease progression

• A pathogenic virus is one that causes disease

• Virulence refers to the degree of pathogenicity

• Ebola Zaire virus is highly virulent

• Herpesviruses are not

• Clinical spectrum

• Subclinical

• Invisible or subtle infection

• May or may not progress further (80% of WNV infections are subclinical)

• Clinical

• Visible onset of disease

Pathogenesis of Viral Diseases

• Steps of pathogenesis

• Entry and primary replication (acute infection)• Portals of entry where first localized infections

occur

• Varies with virus

• Viral spread and cell tropism• Sites distant from entry where virus can replicate

• Viremia - the spread of virus through the blood

• Nervous system spread - rabies, herpesviruses

• Infections are usually organ or tissue specific

• Usually controlled by viral proteins that mediate attachment to cells

• Viruses encode proteins, including enzymes, that seize control of susceptible cells

• Cellular transcription factors often dictate susceptibility

Measles - a respiratory disease

Pathogenesis of Viral Diseases• Steps of pathogenesis (cont.)

• Cell injury and clinical illness• Cellular pathology and death (e.g., exiting virus)

• Immune response to tissue injury (inflammation and cytotoxicity) exacerbates clinical manifestations

• Recovery from Infection (convalescence)• For most viral diseases, virus is eliminated by the immune response

and complete recovery occurs

• Others have persistent infections

• Chronic - virus is always detectable

• Latent - virus sequesters in a tissue with recrudescence (recurrent outbreaks)

• In some cases, long-term or permanent disabilities occur• Muscle weakness from West Nile virus infection

• Neurological manifestations; Polio, measles, mumps

• Virus Shedding• Shedding is the release of virus from either cells or the animal

• It is required for virus transmission

• Coughing, sneezing, diarrhea, hemorrhage, etc.

Prevention and Treatment of Viral Infections

• Antiviral chemotherapy

• Nucleoside analogs - interfere with polymerases

• Nucleotide analogs - interfere with polymerases

• Non-nucleotide inhibitors - bind to polymerase such that it is inactivated

• Protease inhibitors - bind to and inactivate viral proteases that are required for polypeptide cleavage into mature viral subunit proteins

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Prevention and Treatment of Viral Infections

• Interferons (Table 30-7)

• Type I• IFNα, IFNβ

• Likely derived from ancestral gene duplication event

• Synthesized and secreted by all virally-infected cells

• Bind to Type I IFN receptors on adjacent cells, alerting them to the infection

• Induces the expression of dozens of antiviral genes

• Type II• IFNγ

• AKA - immune interferon

• No sequence similarity to type I IFNs

• Synthesized by T cells and natural killer (NK) cells

• Binds to Type II IFN receptors and induces expression of antiviral genes

Prevention and Treatment of Viral Infections

• Interferons (cont.)

• Virus mechanisms to counteract IFNs

• Disabling PKR• When IFN binds to its receptor, several signal transduction events

occur, including the expression of PKR protein kinase gene

• PKR protein is activated by double-stranded RNA (autophosphorylated)

• Phosphorylated PKR binds to and inactivates eukaryotic protein synthesis initiation factor-2 (EIF-2), thus inhibiting protein synthesis

• Some viruses have proteins that disable PKR, thus protein synthesis continues

• Many other viral proteins target this pathway

• Clinical Studies

• Interferons have been used to treat some viral diseases

• Most notable - hepatitis C infection

Prevention and Treatment of Viral Infections

• Viral Vaccines

• General principles• Vaccines work by stimulating an adaptive immune response (e.g.

antibodies, T cells) without causing disease

• In the event the virus is subsequently encountered, antibodies and cells are poised to engage it before clinical manifestations arise

• Should provide durable immunity (decades)

• Inactivated Vaccines• Inactivated vaccines usually stimulate a strong antibody

response, but a weaker T cell response

• They usually require several boosters for strong immunity

• For many viruses, inactivation is ineffectual for vaccination

• Live, attenuated vaccines• Infectious virus with very low or no pathogenic properties

• More closely resembles real infection, thus promotes both strong antibody and T cell responses

• Requires fewer or no boosters compared to inactivated vaccines

Prevention and Treatment of Viral Infections

• Viral Vaccines (cont.)

• Proper use of vaccines• Vaccinations are public health programs

• Each vaccination has a target coverage rate

• This rate varies with each vaccine, usually 80%-90%

• If the target is reached, the disease is usually sporadic or nonexistent

• Just under the target and small outbreaks occur

• Substantially under the target leads to epidemics

• Future of Vaccines• Genetically-modified hybrid vaccines

• Protein subunit vaccines

• Recombinant DNA

• Synthetic viral peptides

• Edible vaccines

• DNA vaccines

• Portal vaccines