Pathogenesis and Control of Viral Diseases

General Concepts

  • Pathogenesis

    • Defined as the process by which viruses cause disease in a host and the resulting injury to discrete cell populations.
    • Directly linked to the appearance of disease—a detectable departure from normal physiology manifested as signs and symptoms at one or more target organs.

  • Why study viral pathogenesis?

    • Provides the intellectual framework for developing effective control strategies (vaccines, antivirals, public-health measures).
    • Clarifies how host, virus, environment and time interact to produce illness, recovery or death.

Five Canonical Steps in Viral Pathogenesis

  1. Entry & Primary Replication
  2. Viral Spread & Tropism
  3. Cell Injury → Clinical Illness
  4. Recovery (or death)
  5. Virus Shedding

1. Entry & Primary Replication

  • Viruses must breach or bypass physical, chemical and immunological barriers at body surfaces.

  • Principal portals of entry:

    • Skin
    • Direct mechanical trauma (HPV, HSV, HIV, HBV, poxvirus).
    • Injection (needles → HBV, HIV).
    • Arthropod bite (arboviruses).
    • Animal bite (rabies).
    • Respiratory Tract
    • Local infection: influenza, respiratory syncytial virus (RSV), rhinoviruses.
    • Entry followed by systemic spread: measles, mumps, VZV, enteroviruses.
    • Transmission predominantly via aerosolized droplets.
    • Gastro-intestinal Tract
    • Local replication: rotavirus, coronavirus, adenovirus.
    • Systemic disease: enteroviruses, hepatitis A.
    • Critical survival traits: acid stability, bile resistance, resistance (or in some cases activation) by proteases; typically non-enveloped.
    • Genitourinary Tract
    • Entry facilitated by micro-abrasions.
    • Sexually transmitted viruses: HIV, HSV-2, genital HPV, HBV.
    • Local defence = cervical mucus, vaginal pH, urine chemistry.
    • Conjunctiva (less emphasized but still possible).

  • Viruses restricted to the entry site

    • Influenza (respiratory), norovirus (intestinal).

  • Viruses that disseminate

    • HBV, arboviruses (blood); rabies (peripheral nerves).

2. Viral Spread & Tropism

  • Viremia = presence of virus in blood; may be primary (early) or secondary (after replication in reticulo-endothelial organs).

  • Common routes of dissemination: bloodstream, lymphatics, peripheral nerves.

  • Tropism = host, organ and cell specificity. Determinants:

    • Availability of appropriate cell receptors.
    • Presence of cellular transcription factors enabling viral gene expression.
    • Ability of cellular physiology to support replication.
    • Physical barriers (tight junctions, myelin, etc.).
    • Local micro-environment (temperature, pH, O2\text{O}_2 tension).
    • Host enzymes (digestive enzymes, bile) – can impede or sometimes activate.

  • Examples

    • HBV → hepatocytes.
    • Enteroviruses → enter via gut yet cause CNS disease.
    • Rabies travels retrogradely along peripheral nerves.

  • CNS Invasion Pathways

    1. Hematogenous (blood–brain barrier crossing).
    2. Neuronal (axonal transport).
    • Major neurotropic families: herpes (HSV, VZV, EBV, CMV, HHV-6), toga, flavi, entero, rhabdo, paramyxo, bunya.

3. Cell Injury → Clinical Illness

  • Mechanisms
    • Direct cytocidal effect (cell lysis).
    • Functional physiological alteration without lysis (e.g., endocrine hormone loss).
    • Cytopathic effects (CPE) used diagnostically:
    • Cell rounding/detachment.
    • Senescence – enlarged, vacuolated cells.
    • Syncytia – fusion of infected cells into multinucleated giant cells (RSV, measles, HIV).
    • Inclusion bodies – aggregations of viral proteins/genome (Negri bodies in rabies, “owl’s eyes” in CMV, Cowdry A in HSV/VZV, poxvirus inclusions).
  • Persistent Infections
    • Latent: genome present, no replication until reactivation (VZV → chickenpox then shingles).
    • Chronic: continuous low-level replication (HBV → chronic hepatitis, cirrhosis, HCC).
  • Host reaction – cytokine-mediated malaise, fatigue, anorexia.

4. Recovery from Infection

  • Innate immunity: interferons, NK cells – rapid, non-specific.
  • Adaptive immunity:
    • B cells → neutralizing antibodies (block entry, opsonize).
    • T cells → CD8+^+ cytotoxic responses, CD4+^+ help.
  • Genetic polymorphisms influence susceptibility or resistance (e.g., CCR5-Δ32\Delta32 and HIV).

5. Virus Shedding & Transmission

  • Shedding often occurs from the same surface that served as entry, defining the period of infectiousness.
  • Horizontal transmission
    1. Direct contact:
    • Skin lesions (HPV), saliva (rabies, mumps, CMV, EBV, HIV), aerosols (influenza, measles, rhinovirus), sexual contact, trauma.
    1. Indirect via fomites, food/water, needles, vectors (HAV, polio, HBV, yellow fever).
  • Vertical transmission
    • Congenital (transplacental): CMV, parvovirus B19, rubella.
    • Perinatal (during birth): HIV, HSV.
    • Breast milk: HIV-1, HTLV-1.
  • Dead-end infections: rabies in humans—virus does not normally shed.

Congenital & Perinatal Viral Infections

  • Transplacental viruses can cause miscarriage, malformations, growth retardation (rubella syndrome, CMV).
  • Perinatal acquisition from genital secretions, stool, blood; e.g., HSV, VZV, HBV, enteroviruses.

Respiratory Viral Syndromes by Age (Overview)

  • Common cold: rhinovirus predominant across all ages; adeno in infants/children; coronaviruses in adults.
  • Pharyngitis: adenovirus most common.
  • Croup/Laryngitis: parainfluenza major agent; influenza also.
  • Bronchiolitis: RSV in infants; rare in adults.
  • Pneumonia: RSV (infants), influenza (children & adults), adenovirus.

Acute Viral Respiratory Infections

  • Common cold virology
    • Rhinoviruses: non-enveloped, positive-sense ssRNA; >115 serotypes.
    • ≈15%\approx15\% of colds: coronaviruses.
    • ≈10%\approx10\%: assorted others (adenovirus, RSV, etc.).
  • Cold vs. Flu comparison
    • Flu shows abrupt onset, fever, marked aches, chills, severe cough; cold is gradual, afebrile, prominent sneezing/stuffy nose.

Prevention & Treatment Strategies

Vaccines – Harness Adaptive Immunity

  • Live-attenuated
    • Reduced pathogenicity by passage/adaptation; replicate in host → robust, long-lived immunity; small risk of reversion.
  • Killed (inactivated)
    • Virus chemically/physically inactivated (formalin, detergent); structure preserved; safer, but lower immunogenicity; multiple doses/boosters required.
  • Viral-vector
    • Non-pathogenic carrier virus delivers antigen gene (e.g., ChAdOx1-nCoV-19, Ad26 for COVID-19).
  • mRNA
    • Synthetic mRNA encodes viral antigen; translated in host cytoplasm → antigen presentation → antibody + T-cell responses.
  • Examples in Malaysian National Immunisation Programme (public sector)
    • BCG, DTaP, DT, Hib, MMR, MR booster, JE (Sarawak), HPV for girls (2-dose schedule 0,6 months0,6\text{ months}).

Antiviral Chemotherapy – Block Virus without Harming Host

  1. Uncoating inhibitors
    • Amantadine, rimantadine: block M2 proton channel of influenza A; used prophylactically.
  2. Fusion inhibitors
    • Enfuvirtide (Fuzeon): a peptide that prevents HIV-1 gp41 mediated fusion.
  3. Nucleoside & Nucleotide Analogs
    • Mimic normal bases → chain termination or enzyme inhibition.
    • Nucleosides: acyclovir, ribavirin, lamivudine (3TC), zidovudine (AZT), vidarabine.
    • Nucleotides (already phosphorylated): cidofovir.
    • High mutation rates → resistance; combination therapy (e.g., “triple therapy” for HIV) delays resistance.
    • Acyclovir: HSV genital & encephalitis; VZV in immunocompromised; prophylaxis in transplant/RTx patients.
  4. Reverse Transcriptase Inhibitors
    • NRTIs & NNRTIs; AZT is classic—phosphorylated intracellularly → inhibits RT, terminates DNA chain; cornerstone of HIV therapy.
  5. Protease Inhibitors
    • Saquinavir (first‐in-class), indinavir, ritonavir: bind active site of HIV protease → non-infectious virions.
  6. Late-stage Assembly Inhibitors
    • Methisazone: inhibits poxvirus structural protein synthesis → immature particles.
  • Rationale for Antivirals
    • Incubation periods permit many replication cycles before symptoms; drug must act early or prophylactically.
    • Needed where no vaccine exists, or in immunosuppressed populations, to reduce morbidity, mortality, and economic burden.

Integrated View / Ethical & Practical Implications

  • Vaccination remains the most cost-effective public-health tool; herd immunity protects vulnerable groups (newborns, immunocompromised).
  • Antivirals provide critical back-up where vaccines are absent or ineffective (HIV, HSV). Stewardship is required to slow resistance.
  • Vertical transmission raises ethical issues for prenatal screening and maternal therapy; prevention averts lifelong disability.
  • Understanding pathogenesis guides everything—from designing mucosal vaccines (stop entry) to choosing drug targets (e.g., polymerase vs. protease) and predicting complications (e.g., VZV latency → shingles policy for elderly vaccination).

Key Equations / Numbers to Remember

  • Percentage etiology of common cold: Rhinovirus≈75%\text{Rhinovirus}\approx75\%, Coronavirus≈15%\text{Coronavirus}\approx15\%, Others≈10%\text{Others}\approx10\%.
  • Vaccine schedules: HPV 2-dose 0,60,6 months (girls 13 yrs), MR second dose at 7 yrs (until 2022).
  • HIV combination therapy often uses 2 NRTIs + 1 NNRTI/PI to maintain viral load <50\,\text{copies mL}^{-1} and delay resistance.

Rapid Review Checklist

  • Can I list and explain the five steps of viral pathogenesis?
  • Do I know key entry routes and exemplar viruses?
  • Can I describe mechanisms of CPE and give inclusion-body examples?
  • What determines tropism?
  • How do innate vs. adaptive responses control infection?
  • Distinguish live-attenuated vs. inactivated vs. mRNA vaccines.
  • Match antiviral class → mechanism → example drug.