Mechanisms of Viral Injury

Slide 1 · Mechanisms of Viral Injury

Pathogenesis • cellular tropism • tissue damage

Viral tropism

Direct cytopathic effects

Host immune injury

Cellular transformation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how viral receptors and cell-specific factors determine tissue tropism.

Trace the cellular pathways by which viral replication produces injury.

Distinguish direct cytopathic damage from immune-mediated tissue injury.

Explain viral transformation and its relationship to chronic inflammation.

Slide 3 · Three routes from infection to disease

Direct viral injury

Host synthesis shutoff; Toxic proteins; ER stress; Lysis or fusion

Immune-mediated injury

Host lymphocytes destroy infected cells; Inflammation can damage tissue

Altered growth and survival

Viral oncogenes or inactivation of tumor suppressor pathways

These pathways may coexist within an infected tissue.

Slide 4 · Viral injury begins with successful infection

Exposure

Susceptible cell

Entry and replication

Cell injury / altered growth

An encountered virus produces damage only if host and cellular conditions permit infection.

Slide 5 · Tropism: Preferential infection of particular cells

Tropism is the tendency of a virus to infect some cell types but not others.

Host-cell entry receptors are a major determinant of this selectivity.

Post-entry factors and local physical conditions also constrain tropism.

Slide 6 · Receptor availability is an entry gate

Virus

Host entry receptor

Host cell

Viral attachment factor

A cell lacking a required entry molecule is generally resistant at the entry step.

Slide 7 · Viral receptors have normal host functions

Normal host role

Cell signaling receptors

Adhesion-associated surface molecules

Other physiological membrane proteins

Viral exploitation

Binding to host-cell surface

Use of receptor for attachment/entry

New route for intracellular replication

Viral binding does not imply that a receptor exists solely for infection.

Slide 8 · An entry receptor does not explain every tropism

Receptor expression

Intracellular permissivity

Local environment

Productive infection

Tropism integrates access to the cell with the cell’s ability to support viral gene expression.

Slide 9 · HIV gp120 engages CD4 and a coreceptor

HIV gp120

CD4 receptor

CCR5 or CXCR4

Entry into susceptible cells

CD4 binding and chemokine coreceptors cooperate to determine cellular entry.

Slide 10 · HIV coreceptors and cellular targeting

Component

Cellular association

Mechanistic role

CD4

Host cell surface receptor

Binding partner for gp120

CXCR4

Mainly T cells

Chemokine coreceptor

CCR5

Mainly macrophages

Chemokine coreceptor

These are characteristic associations, not absolute cell-type restrictions.

Slide 11 · EBV uses CD21 on B cells

EBV attachment

CR2 / CD21

B-cell susceptibility

Complement receptor 2 (CR2), also designated CD21, is the cited receptor.

Slide 12 · SARS-CoV-2 spike binds ACE2

Spike protein

Host ACE2 receptor

Viral attachment / entry

The receptor interaction is an example of molecular tropism; Injury mechanisms follow after infection.

Slide 13 · Viral receptor examples: Compare the gate

Virus

Viral attachment factor

Host molecule

HIV

gp120

CD4 plus CCR5/CXCR4

Epstein–Barr virus

Viral attachment machinery

CR2 (CD21)

SARS-CoV-2

Spike protein

ACE2

The attachment molecule determines only one component of viral tropism.

Slide 14 · JC virus: A post-entry tropism example

JC virus infection

Glial-specific host transcription factors

Viral gene expression

Oligodendroglial tropism

JC viral gene expression is restricted by host factors within oligodendroglial cells.

Slide 15 · Cell lineage can control viral gene expression

Surface-level selectivity

Receptor–ligand compatibility

Access and entry

Intracellular selectivity

Lineage-specific transcription factors

Support for viral gene expression

Receptor binding and gene expression are distinct restrictions on infection.

Slide 16 · Enteroviruses withstand the intestinal milieu

Exposure to intestinal contents

Resistance to acid, bile and digestive enzymes

Replication in intestine

Physical and chemical survival can determine which sites support infection.

Slide 17 · Rhinoviruses favor cooler respiratory sites

Upper respiratory tract

Relatively lower local temperature

Favorable viral replication

Temperature sensitivity helps explain preferential upper respiratory replication.

Slide 18 · Physical environment modifies tropism

Host-site factor

Source example

Why it matters

Luminal chemistry

Enteroviruses

Survival despite acid, bile, enzymes

Local temperature

Rhinoviruses

Replication favored at cooler sites

Lineage-specific factors

JC virus

Viral transcription permitted in glia

A receptor-centric account alone misses the conditions after exposure.

Slide 19 · Tropism is a sequence of restrictions

1. Access

Virus reaches a tissue

2. Attachment

Appropriate entry factor is present

3. Permissivity

Cell supports viral gene expression

4. Replication

Local environment permits growth

Failure at any stage may prevent productive infection.

Slide 20 · Apply tropism: Why are all cells not infected?

Observation: Two cell populations encounter the same virus; Infection develops in only one.

1

First ask whether both populations express the entry receptor.

2

Then test whether their intracellular factors and local environments permit replication.

Slide 21 · A simplified intracellular viral sequence

Attachment/entry

Contact with a compatible receptor

Uncoating

Genome released into cell

Replication

Viral genome and mRNA production

Translation

Viral proteins synthesized

Assembly

Viral components accumulate

These replication stages can each be linked to distinct routes of cell injury.

Slide 22 · Entry and uncoating give viral genes access

Viral receptor engagement

Entry into the cell

Uncoating

Intracellular viral genome

After uncoating, the viral genome becomes available for intracellular processes.

Slide 23 · Viral genome replication redirects resources

Viral requirements

Genome replication

Viral mRNA synthesis

Host metabolic support

Potential host cost

Competition for cellular machinery

Disturbed cellular metabolism

Greater burden during high viral output

Cellular injury arises from the effects of infection, not merely the physical presence of a virion.

Slide 24 · Viral protein synthesis can become injurious

Viral mRNA production

Large viral protein output

Normal cell homeostasis disrupted

Viral protein accumulation also creates stress when folding and processing capacity are exceeded.

Slide 25 · Viral assembly is not the only injurious phase

Before assembly

Loss of host biosynthesis; Metabolic disturbance

During protein production

Misfolded proteins and ER stress

After antigen display

Host-cell killing by antiviral lymphocytes

Injury can originate during multiple phases of infection.

Slide 26 · Direct cytopathic injury has distinct routes

Biosynthetic shutdown

Essential host DNA, RNA or protein synthesis fails

Viral products

Degradative enzymes or toxic viral proteins

Proteostasis failure

Misfolded viral proteins trigger ER stress and apoptosis

Different viral products can converge on loss of cell viability.

Slide 27 · Host macromolecular shutoff disables the cell

Viral inhibition of host synthesis

Loss of essential macromolecules

Functional decline

Cell death

Inhibition may affect host DNA, RNA, or proteins, depending on the virus.

Slide 28 · Poliovirus disrupts cap-dependent translation

Poliovirus product

Host cap-binding protein inactivated

Host mRNA translation impaired

Host translation is selectively inhibited during poliovirus infection.

Slide 29 · Poliovirus preserves its own translation

Host-cell mRNAs

Require host cap-binding function

Translation markedly reduced

Poliovirus mRNAs

Translation remains functional

Viral protein production continues

Selectivity allows viral production while disabling essential host protein synthesis.

Slide 30 · Viral enzymes and toxic proteins injure cells

Some viruses produce degradative enzymes that harm host components.

Other viral proteins have direct toxic effects within infected cells.

The result may be loss of cellular integrity or an essential function.

Slide 31 · Viral protein excess challenges proteostasis

High viral protein synthesis

Unfolded / misfolded proteins

ER stress response

Protein burden is a separate mechanism from inhibition of host translation.

Slide 32 · ER stress can activate cell-death programs

Protein folding disturbance

ER stress signaling

Pro-apoptotic pathways

Cell death

Excessive proteostasis stress can activate apoptotic signaling.

Slide 33 · Viral replication may culminate in cell lysis

Intracellular viral replication

Progressive cellular injury

Loss of membrane integrity / cell lysis

Cell lysis is one possible cytopathic endpoint, not a property of every virus.

Slide 34 · Cell fusion is another cytopathic endpoint

Adjacent cells

Multinucleated fused cell

Fusion is a cytopathic alteration that can produce multinucleated cells.

Slide 35 · Viral inclusions indicate altered intracellular content

Inclusion formation

Accumulated viral components or altered host material

Recognizable intracellular change

Pathologic interpretation

A morphologic clue in some infections

Not proof of one universal injury mechanism

Inclusions are morphologic clues that require pathogen-specific interpretation.

Slide 36 · Metabolic derangements link replication to dysfunction

Viral replication and protein output

Disturbed host metabolism

Functional cell injury

Host metabolic alterations provide another route from replication to cellular dysfunction.

Slide 37 · Direct cytopathy: Mechanism-to-effect map

Mechanism

Primary host disturbance

Possible consequence

Macromolecular shutoff

Reduced host synthesis

Cell failure / death

Viral toxic products

Host component damage

Cytopathic injury

Misfolded protein burden

ER stress

Pro-apoptotic signaling

Lysis / fusion

Membrane integrity altered

Loss of cell structure

“Possible” matters: No single outcome applies to all viruses.

Slide 38 · An infected cell can become an immune target

Cytotoxic T cell

Recognition of viral antigen

Virus-infected cell

Successful host antiviral defense can itself produce tissue injury.

Slide 39 · Cytotoxic T cells are both protective and injurious

Protective action

Recognize infected cells

Eliminate sites of viral replication

Pathologic consequence

Loss of infected functional cells

Tissue inflammation and injury

The same effector response can clear infection and damage an organ.

Slide 40 · HBV and HCV: Hepatocyte injury is largely host-mediated

HBV / HCV infection of hepatocytes

Host T cells (and possibly NK cells)

Infected-hepatocyte killing

Hepatic injury

Host immune killing is a major driver of hepatocyte damage in viral hepatitis.

Slide 41 · Direct cytopathy and immune injury are not synonyms

Question

Direct cytopathy

Antiviral immune injury

Primary effector

Virus-induced intracellular damage

Host antiviral effectors

Cell loss arises from

Replication / toxic effects / stress

Immune recognition and killing

Interpretive pitfall

Assume every infection is lytic

Assume inflammation reflects only viral toxicity

Both mechanisms may operate together.

Slide 42 · Inflammation can amplify damage beyond infected cells

Recognition of infected cells

Host inflammatory response

Collateral tissue injury

Inflammatory damage is a consequence of protective immunity when excessive or prolonged.

Slide 43 · Systemic cytokine effects in severe viral infection

Severe viral infection

Cytokine-mediated systemic inflammation

Organ dysfunction / tissue injury

Cytokine-mediated inflammation contributes to some severe cases of COVID-19.

Slide 44 · Receptor-defined targets and immune effectors differ

Where infection begins

Receptor expression

Cell-lineage permissivity

Local physical environment

Where injury develops

Direct viral effects

Immune-cell killing

Inflammatory amplification

Targeting the infected cell and causing tissue damage are distinct causal questions.

Slide 45 · Immune evasion affects the trajectory of infection

Reduced recognition

MHC presentation altered

Weakened antiviral signaling

Interferon pathways inhibited

Extended persistence

Apoptosis suppressed or latency established

These mechanisms provide necessary context for chronic infection and tissue injury.

Slide 46 · Viral interference with MHC limits T-cell recognition

Viral alteration of MHC localization

Reduced peptide presentation

Impaired antiviral T-cell recognition

HSV, CMV and EBV exemplify interference with antigen-presentation pathways.

Slide 47 · Some viruses inhibit interferon pathways

Decoy receptors

Soluble homologues neutralize IFN activity

JAK/STAT inhibition

Cytokine receptor signals interrupted

PKR antagonism

IFN-induced antiviral effect weakened

Interferon resistance can arise at distinct molecular checkpoints.

Slide 48 · Preventing apoptosis may extend viral survival

Viral anti-apoptotic proteins

Survival of infected host cell

Time for replication, latency or transformation

A virus may delay death even when later injury remains possible.

Slide 49 · Latency minimizes viral gene expression

Infected cell persists

Few or no viral genes expressed

Reduced immune surveillance

Potential later reactivation

Latent HSV/VZV may persist in neurons; Latent EBV persists in B cells.

Slide 50 · Chronic infection can produce T-cell exhaustion

Prolonged antigenic stimulation

PD-1–associated T-cell exhaustion

Reduced antiviral potency

Exhausted antiviral T-cell responses are described in HIV, HBV and HCV infection.

Slide 51 · Immune escape and injury can coexist

Immediate viral advantage

Less elimination of infected cells

Opportunity for persistence

Potential host cost

Prolonged infection

Ongoing immune activation and tissue damage

Reduced immune clearance can coexist with persistent, injurious inflammation.

Slide 52 · Oncogenic viruses alter growth and survival

Oncogenic viral infection

Pro-growth / pro-survival signals

Clonal expansion / transformation

Viral transformation is the third principal injury category in this section.

Slide 53 · Virus-encoded oncogenes can drive proliferation

Viral oncogene expression

Cell-growth and survival pathways stimulated

Neoplastic transformation

The key concept is direct stimulation of cell growth and survival pathways.

Slide 54 · Viral proteins may disable tumor suppressors

Viral protein expression

Key tumor suppressor pathways inactivated

Growth restraint is lost

Transformation

Loss of tumor-suppressor function removes an important restraint on proliferation.

Slide 55 · Chronic inflammation provides another cancer route

Persistent viral infection

Chronic inflammatory injury

Pro-carcinogenic tissue environment

Cancer association

Inflammation-associated cancer risk does not require a virus-encoded oncogene.

Slide 56 · Separate direct transformation from indirect risk

Pathway

Immediate driver

Interpretation

Virus-directed transformation

Oncogenes or suppressor inactivation

Directly alters growth/survival

Inflammation-associated carcinogenesis

Chronic immune-mediated inflammation

Fosters tumor development

Important distinction

Oncogenic association ≠ one mechanism

Do not infer a viral oncogene for HBV/HCV

Cancer associations cannot be interpreted without specifying the causal route.

Slide 57 · Injury phenotype depends on timing and mechanisms

Early infection

Entry and permissive replication

Active infection

Direct stress and immune recognition

Persistent infection

Latency or exhausted host responses

Long-term consequence

Chronic injury or altered growth

This is an integrative teaching schematic; Stages are possible routes, not a universal natural history.

Slide 58 · Integrated mechanisms of viral injury

Layer

Question

Representative consequence

Tropism

Which cells can support infection?

Selective tissue targeting

Direct cytopathy

How does replication impair cells?

Shutdown / ER stress / lysis

Host immunity

How are infected cells cleared?

CTL-mediated damage

Transformation

How are growth controls altered?

Neoplastic potential

Determine tissue targeting before attributing the pattern of cellular injury.

Slide 59 · Applied example: Interpret HIV receptor use

A virus binds CD4 but also requires a chemokine receptor for efficient cellular entry.

1

Which two chemokine receptors are identified for HIV gp120?

2

How can different host-cell receptor patterns contribute to tropism?

Slide 60 · Applied example: Explain poliovirus cytopathy

An infected cell loses translation of most host mRNAs, yet viral protein synthesis continues.

1

Identify the host factor that poliovirus inactivates.

2

Explain why the effect favors viral replication at host-cell expense.

Slide 61 · Applied example: Explain JC virus targeting

Viral surface attachment does not fully explain oligodendroglial disease.

1

Identify the intracellular host determinant responsible for restricted replication.

2

Explain why permissive gene expression matters after entry.

Slide 62 · Applied example: Interpret viral hepatitis injury

An HBV-infected liver shows injured hepatocytes and host inflammatory activity.

1

Which effector mechanism is emphasized for hepatocyte loss?

2

Why is it incorrect to equate the amount of injury with direct viral toxicity?

Slide 63 · Morphologic and functional consequences are distinct

Observation

Mechanistic inference

Interpretive limit

Cell lysis or fusion

Possible cytopathic effect

Not universal among viruses

Viral inclusions

Altered intracellular viral/host content

Not a unique diagnosis without context

Immune-cell injury

Host response damages tissue

Virus may not directly lyse cells

Transformation

Growth regulation altered

Requires pathway-specific support

Do not mistake a consequence for evidence of only one cause.

Slide 64 · Synthesize: Five questions about viral tissue injury

Where?

Which cells and tissues are permissive?

How entry?

Which receptor or cofactor is used?

Direct damage?

Is host synthesis or proteostasis disrupted?

Host damage?

Are immune effectors injuring infected cells?

Long-term?

Could infection persist or alter growth?

Use these questions to structure a clinicopathologic explanation.

Slide 65 · References

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition. Elsevier; 2026.