Viral Pathogenesis: an Overview — Questions

The cytopathic effect is the visible morphological change a virus produces in the cells it infects, and its pattern is often characteristic enough to suggest the agent.

Cell rounding, detachment, and lysis. The commonest effect: infected cells round up, detach from the monolayer, and lyse. Seen with the enteroviruses and many other lytic viruses.

Syncytium (giant-cell) formation. Viral fusion proteins fuse an infected cell with its neighbours into a multinucleated giant cell. Characteristic of the paramyxoviruses, respiratory syncytial virus, measles virus, and herpes simplex virus.

Inclusion bodies. Aggregates of viral components or altered cell regions, in the nucleus or cytoplasm. Intranuclear inclusions occur in herpesvirus and adenovirus infection (the Cowdry type A inclusion of herpesviruses); cytoplasmic inclusions include the Negri bodies of rabies and the inclusions of the poxviruses.

Cell rounding in grape-like clusters. Adenoviruses round cells into characteristic clusters.

Vacuolation and ballooning. Some viruses produce cytoplasmic vacuoles or swollen, ballooned cells.

Not every virus is cytopathic in culture: rubella virus and many others replicate without an obvious effect and are detected by other means. The severity of the cytopathic effect in culture does not predict the severity of human disease.

A complete answer traces how a virus reaches the central nervous system, how it crosses into it, and how it injures it.

Reaching the central nervous system. Most encephalitic viruses arrive through the blood, after a primary infection and viraemia seed the cerebral vasculature. Two haematogenous routes exist: virus in the vessels of the meninges or choroid plexus crosses into the cerebrospinal fluid and infects the ependyma and underlying brain, or virus crosses the blood-brain barrier directly. It may infect the endothelium, be carried across inside infected leukocytes (as with the human immunodeficiency virus, HIV, and measles), or, as with West Nile virus, exploit a barrier made leaky by inflammatory cytokines. The alternative is the neural route: retrograde axonal transport along peripheral nerves, used by rabies virus and, on reactivation, by herpes simplex and varicella-zoster virus.

Injuring the brain. Disease arises from direct neuronal infection and from the immune response to it. The histological hallmarks are neuronal necrosis, neuronophagia (engulfment of dying neurons), and perivascular cuffing by mononuclear cells, the last reflecting the immune response itself. The balance of direct and immune-mediated injury varies: rabies virus is barely cytopathic yet uniformly lethal through functional neuronal failure, herpes simplex produces necrotising temporal-lobe damage, and in others the immune infiltrate drives much of the harm.

Outcome depends on the virus, the region infected, and the vigour and timing of the immune response, which is also why oedema in the closed cranial compartment is so dangerous.

Herpes simplex virus illustrates the full arc of a latent, neurotropic infection, from a productive primary infection to lifelong carriage with reactivation.

Entry and lytic replication. The virus enters through skin or mucosa, usually at a site of minor abrasion, and replicates productively in epithelial cells, producing the vesicles of primary oral (herpes simplex virus type 1) or genital (type 2) infection.

Neuro-invasion. From the epithelium the virus enters the endings of sensory nerves and its capsids travel by retrograde axonal transport to the neurons of the corresponding sensory ganglion, the trigeminal ganglion after oral infection and the sacral ganglia after genital infection.

Latency. In these long-lived, non-dividing neurons the virus establishes latency: the genome persists as a circular episome, lytic genes are silenced, and only the latency-associated transcripts are expressed. With no viral antigen displayed and little major histocompatibility complex on neurons, the latently infected cell is effectively invisible to cytotoxic T cells and antibody.

Reactivation. Triggers such as stress, ultraviolet light, fever, or immunosuppression provoke reactivation, the resumption of productive replication. New virus travels by anterograde axonal transport back to the periphery, producing recurrent lesions near the original site. Reactivation is the cellular event; the repeat clinical episode is the recurrence. Asymptomatic shedding occurs between episodes and accounts for much transmission.

After a virus enters the blood for the first time (the primary viraemia, often clinically silent), it seeds secondary organs. Replication there releases a much larger, higher-titre wave into the blood, the secondary viraemia, which carries the virus to the target organs responsible for the characteristic disease.

Option A describes the primary, not the secondary, viraemia. Cell-associated virus (B) and lymphatic spread (D) are real features of dissemination but do not define the secondary viraemia, a plasma-phase event. Low-level virus during latency (E) belongs to persistent infection, not the stepwise viraemia of an acute systemic infection.

Poliovirus destroys a narrow set of cells although its receptor is widespread, which shows tropism is multi-factorial. A cell must be both susceptible (carry the receptor) and permissive (supply the intracellular factors the virus needs and lack restriction) before it yields progeny. The mismatch between CD155 distribution and the neurons poliovirus actually kills is the classic demonstration.

Receptor distribution matters but is not sufficient (A). Route of entry shapes the initial distribution without setting target-organ tropism (C). Viruses have defined tropisms rather than infecting every cell (D), and the receptor enables, not blocks, entry (E).

A complete answer follows the ordered stages of pathogenesis and anchors them to one worked example.

The sequence. A virus first crosses a body surface at its portal of entry and undergoes primary replication at or near that site. From there it spreads beneath the epithelium into the lymphatics and reaches the draining lymph nodes. Replication there delivers virus into the blood as a primary viraemia, usually clinically silent, which seeds secondary organs. Replication in those organs releases a much larger secondary viraemia, which carries the virus to the target organ responsible for the characteristic disease. Injury to that organ produces symptoms, and shedding from an accessible surface allows transmission. The incubation period is the time these sequential steps take, and the outcome turns on whether the developing immune response halts the virus before it reaches its target.

Poliovirus as the example. Poliovirus enters by the faecal-oral route and replicates in the lymphoid tissue of the gut, the Peyer patches. It spreads to the blood as a primary viraemia, replicates in secondary sites, and seeds a second viraemia. In a small minority it invades the central nervous system, by crossing the blood-brain barrier or via peripheral nerves, and replicates in and kills the anterior horn motor neurons, causing paralysis. Most infections are asymptomatic because circulating antibody clears the virus before it reaches the central nervous system, which is exactly why the kinetics of the antibody response decide the outcome.