pathogenesis and control of viral infections chapter 30
TRANSCRIPT
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
AZT
T
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