How do viruses replicate and cause tissue damage?

How Viruses Survive, Propagate, and Cause Tissue Damage

Viruses survive by hijacking host cellular machinery to replicate, propagate through cell-to-cell spread and immune evasion, and cause tissue damage through both direct cytolytic effects and immune-mediated inflammation.

Viral Survival and Entry Mechanisms

Viruses are obligate intracellular parasites that cannot replicate independently and must exploit host cells for their essential replication machinery 1. The survival strategy begins with cell entry through specific receptor recognition, such as SARS-CoV-2 binding to ACE2 receptors, followed by activation of viral proteins by host cellular proteases like TMPRSS2 1.

• After receptor binding, the viral envelope fuses with the cellular membrane, allowing the virus to enter the cell 1
• Viruses are composed of either DNA or RNA surrounded by a protective capsid structure 1
• The viral genetic material must evade the immune system and be transported to the appropriate cellular compartment for replication 1

Viral Replication and Propagation

Once inside the host cell, viruses commandeer cellular processes to mass-produce viral components and assemble new infectious particles. The replication cycle follows a systematic process 1:

• The viral genetic material is uncoated and translated into polyproteins, which are cleaved by viral proteases 1
• These processed proteins form replicase-transcriptase complexes that remodel cellular membranes to create dedicated organelles (double-membrane vesicles) for viral RNA synthesis 1
• The virus produces multiple copies of its genetic material and structural proteins (spike, envelope, membrane, and nucleocapsid proteins) 1
• New viral particles assemble in the endoplasmic reticulum-Golgi intermediate compartment and are released by exocytosis 1

Cell Division Requirements

Different viruses have varying requirements for successful infection 1:

• Some viruses can infect both dividing and non-dividing cells (such as neurons) 1
• Others are effective only in actively dividing cells 1
• Some viruses integrate their DNA into the host chromosome, providing permanent genetic presence 1

Viral Persistence Strategies

Viruses employ multiple strategies to establish long-term survival in the host 1:

• Viral proteins and RNA can persist in multiple organ systems including the reproductive system, cardiovascular system, brain, muscles, lymph nodes, gastrointestinal tract, and other tissues 1
• Circulating viral spike antigen has been detected in patients up to 12 months after initial infection, suggesting active viral reservoirs 1
• Integration of viral DNA into hepatocyte chromosomes can occur early and throughout infection, creating permanent cellular changes 1

Mechanisms of Tissue Damage

Direct Cytolytic Effects

Acute viral infections cause immediate tissue damage through direct destruction of infected cells 2:

• Acute cellular swelling occurs with eventual cytolysis (cell rupture) 2
• Syncytial giant cell formation may occur when infected cells fuse together 2
• Viral inclusion bodies can form within infected cells 2
• Lesions in acute infections are largely attributable to the cytolytic effects of the virus on host cells 2

Immune-Mediated Damage

Paradoxically, the host immune response necessary for viral clearance often contributes significantly to tissue damage 3, 2:

• The initial neutrophilic inflammatory response to virus-induced cellular necrosis is rapidly superseded by virus-specific inflammation mediated by both humoral and cellular factors 2
• Pattern recognition receptors detect viral components and induce type I interferons and pro-inflammatory cytokines 4
• Recruitment of inflammatory monocytes, T cells, and NK cells into tissues leads to non-specific hepatocyte and tissue killing 1
• Vasculitis produces nonspecific tissue damage via hemorrhage and ischemia 2

Multi-Organ System Effects

Modern understanding reveals that viruses cause system-wide damage beyond their primary target organs 1:

• SARS-CoV-2 affects the heart, central nervous system, lungs, vasculature, kidneys, and gastrointestinal tract 1
• Endothelial dysfunction leads to circulatory system disruption, including deep vein thrombosis, pulmonary embolism, and microclot formation 1
• Multi-organ damage occurs in a significant proportion of infected individuals, with 70% showing damage to at least one organ and 29% showing multi-organ damage 1
• Cardiac impairment has been documented in 78% of individuals after COVID-19 infection 1

Chronic and Persistent Infection Patterns

Chronic viral diseases display distinct pathological patterns compared to acute infections 2:

• Low or difficult-to-detect levels of infectious virus in tissues 2
• Lesions dominated by inflammation, antiviral immune responses, and host tissue proliferation rather than direct viral cytolysis 2
• Persistently infected cells may appear morphologically normal but are functionally deficient and may eventually display degenerative changes 2

Viral Immune Evasion and Manipulation

Viruses have evolved sophisticated mechanisms to actively manipulate host immune responses 5:

• Viruses modulate cytokine and chemokine signaling networks to create environments more favorable for infection 5
• Interference with antigen presentation prevents effective T cell responses 5
• Prevention of antibody production allows continued viral replication 5
• Viral factors can inhibit innate immune receptor pathways 4

Regulatory T Cell Interactions

An important caveat exists regarding immune suppression 6:

• Regulatory T cells (Tregs) facilitate early protective responses to viral infection by allowing timely entry of immune cells into infected tissue 6
• Ablation of Tregs during herpes simplex virus infection resulted in accelerated fatal infection with increased viral loads, despite augmented interferon production 6
• This demonstrates that some immune regulation is protective rather than detrimental 6

Clinical Implications in Immunocompromised Hosts

Immunocompromised patients experience more severe and prolonged viral infections 7, 8:

• Extensive, deep, nonhealing ulcerations develop in patients with weakened immune systems 7
• Chronic ulcerations with persistent viral replication become complicated by secondary bacterial and fungal superinfections 7
• Skin lesions develop over longer periods and heal more slowly without effective antiviral therapy 7, 8
• High-dose IV acyclovir remains the treatment of choice for severe viral infections in immunocompromised hosts 8