12.2 Mechanisms of virus-induced cellular damage

Viruses wreak havoc on our cells in sneaky ways. They can directly bust open cells, hijack cellular machinery, or trigger our immune system to go haywire. Understanding these tricks helps us grasp how viruses cause diseases and why some infections are worse than others.

Viral damage isn't always straightforward. Some viruses cause visible changes in cells, while others fly under the radar. The balance between cell death types (apoptosis vs. necrosis) and how different organs respond to infection shapes the course of viral diseases.

Viral Mechanisms of Cellular Damage

Direct Cytopathic Effects

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• Viruses cause lysis of host cells through membrane disruption and osmotic imbalance
• Viral hijacking of cellular machinery redirects resources to viral replication (ribosomes, nucleotides)
• Disruption of cellular metabolism alters energy production and biosynthetic pathways
• Viral interference with cell cycle regulation leads to uncontrolled growth or division inhibition
  • Uncontrolled growth contributes to tumor formation (human papillomavirus)
  • Division inhibition results in tissue degeneration (measles virus in neurons)

Indirect and Immune-Mediated Damage

• Immune-mediated mechanisms trigger excessive inflammatory responses
• Cytokine storms cause widespread tissue damage (influenza, SARS-CoV-2)
• Persistent infections induce chronic cellular stress altering long-term function
• Manipulation of host gene expression leads to aberrant protein production
• Viral genome integration causes insertional mutagenesis (HIV, HPV)
  • Can activate oncogenes or disrupt tumor suppressor genes

Programmed Cell Death and Necrosis

• Viruses induce apoptosis (programmed cell death) through various pathways
  • Activation of death receptors (Fas ligand)
  • Mitochondrial damage leading to cytochrome c release
• Necrosis results in cellular swelling, membrane rupture, and content release
• Balance between apoptosis and necrosis influences disease severity
• Some viruses inhibit apoptosis to prolong host cell survival (herpesviruses)
• Others induce apoptosis to facilitate viral spread (influenza virus)

Cytopathic Effects in Viral Damage

Observable Morphological Changes

• Cell rounding alters normal cell shape and adherence properties
• Syncytia formation fuses infected cells creating multinucleated giant cells (measles virus)
• Inclusion bodies appear within infected cells (rabies virus Negri bodies)
• Changes in cell membrane permeability lead to osmotic imbalances
• Extent and type of CPE varies by virus species and host cell type
  • Rapid lysis in picornavirus infections
  • Slow, progressive changes in herpesvirus infections

Diagnostic and Research Applications

• CPEs used to identify and characterize viral infections in cell culture
• Plaque assays utilize CPE to quantify infectious virus particles
• Time to CPE onset helps determine viral replication kinetics
• Some viruses cause minimal observable CPE (hepatitis C virus)
  • Makes detection and study more challenging
  • Requires alternative methods like immunofluorescence or PCR

Cellular Content Release and Inflammation

• Cell lysis releases damage-associated molecular patterns (DAMPs)
• DAMPs trigger inflammatory responses through pattern recognition receptors
• Released viral particles and antigens stimulate adaptive immune responses
• Cellular enzymes from lysed cells can damage surrounding tissue
• Disruption of tissue architecture impairs organ function

Apoptosis vs Necrosis in Viral Pathogenesis

Apoptosis Mechanisms and Viral Manipulation

• Intrinsic pathway activated by intracellular stress signals
  • Mitochondrial outer membrane permeabilization
  • Release of cytochrome c and other pro-apoptotic factors
• Extrinsic pathway triggered by death receptor activation (Fas, TNFR)
• Caspase cascades execute cellular demolition
• Viruses encode proteins to modulate apoptotic pathways
  • Bcl-2 homologs inhibit mitochondrial pathway (Epstein-Barr virus BHRF1)
  • Caspase inhibitors block execution phase (cowpox virus CrmA)
• Some viruses induce apoptosis to facilitate spread
  • HIV-induced T cell apoptosis contributes to immunodeficiency

Necrosis and Inflammatory Consequences

• Characterized by cellular swelling, membrane rupture, and content release
• Often triggered by severe cellular stress or damage
• Release of cellular contents promotes inflammation
  • Activation of innate immune cells (neutrophils, macrophages)
  • Production of pro-inflammatory cytokines (IL-1β, TNF-α)
• Necrosis can lead to more extensive tissue damage than apoptosis
• Some viruses actively induce necrosis (parvovirus B19 in erythroid progenitors)

Impact on Disease Progression and Immunity

• Balance between apoptosis and necrosis influences disease severity
• Excessive apoptosis can lead to immunosuppression (HIV infection)
• Necrosis-induced inflammation can cause collateral tissue damage
• Timing of cell death affects viral clearance and persistence
  • Early apoptosis can limit viral replication
  • Delayed cell death allows for increased viral production
• Apoptotic bodies containing viral antigens stimulate adaptive immunity
• Necrosis releases viral particles, promoting spread to neighboring cells

Consequences of Viral Damage on Organs

Organ-Specific Dysfunction

• Respiratory failure in severe viral pneumonia (influenza, SARS-CoV-2)
  • Alveolar damage impairs gas exchange
  • Inflammatory exudates obstruct airways
• Liver failure in viral hepatitis (hepatitis B and C viruses)
  • Hepatocyte death reduces metabolic and synthetic functions
  • Impaired toxin clearance leads to encephalopathy
• Cardiomyopathy in viral myocarditis (coxsackievirus B)
  • Myocyte damage reduces contractility
  • Arrhythmias from disrupted electrical conduction
• Encephalitis in neurotropic viral infections (rabies virus, West Nile virus)
  • Neuronal death causes cognitive impairment and seizures
  • Inflammation leads to cerebral edema and increased intracranial pressure

Systemic Effects and Multi-Organ Dysfunction

• Multi-organ dysfunction syndrome (MODS) from widespread cellular damage
• Systemic inflammatory response syndrome (SIRS) triggered by viral infection
• Disruption of tissue barriers increases susceptibility to secondary infections
• Chronic viral infections lead to progressive organ damage and fibrosis
  • Cirrhosis in chronic hepatitis B and C infections
  • Pulmonary fibrosis in some coronavirus infections
• Virus-induced cellular damage triggers regenerative responses
  • Tissue remodeling and scarring alter organ structure and function
  • Oncogenic transformation in some cases (HPV in cervical cancer)

Host Factors Influencing Organ Dysfunction

• Age affects susceptibility and severity of viral-induced organ damage
  • Immature immune systems in neonates increase vulnerability
  • Age-related decline in organ reserve reduces ability to compensate
• Comorbidities exacerbate viral-induced organ dysfunction
  • Diabetes increases risk of severe outcomes in respiratory viral infections
  • Chronic liver disease worsens prognosis in hepatitis virus infections
• Genetic susceptibility influences individual responses to viral infections
  • HLA types affect immune recognition of viral antigens
  • Polymorphisms in innate immune genes alter inflammatory responses