Viral Pathogenesis: an Overview

Pathogenesis, from the Greek pathos, suffering or disease, and genesis, origin, is the biological and molecular mechanism by which a disease develops, progresses, and manifests in a host. For a virus, it is the sequential chain of events that runs from the first exposure to the appearance of clinical disease: entry across a body surface, local replication, spread to a target organ, tissue injury, the immune response, and an outcome of recovery, persistence, or death. The chain is remarkably consistent and specific for each virus, which is what makes it possible to analyse an infection as an ordered series of stages rather than a single event.

For the clinical virologist the value of this view is analytical. Tracing a virus through the host, from the cell it first infects to the organ it ultimately damages, reveals how the agent exploits host biology and where that exploitation can be interrupted. The same reasoning connects the laboratory to the bedside: it explains which specimen will contain the virus and when, why one antiviral must be given early and another works late, and why a vaccine delivered to one surface protects while the same antigen given elsewhere does not. The emergence of SARS-CoV-2 showed, at global scale, how a newly introduced respiratory virus exploits human physiology to cause disease across whole populations, and how rapidly an understanding of its pathogenesis had to be assembled to guide diagnosis, treatment, and control.

This article maps the journey itself: how a virus establishes infection, enters the host, spreads within it, targets particular organs, produces disease, and is shed to begin the cycle again. Its focus is the molecular and cellular biology of entry, spread, and shedding within the host. The external epidemiological framework of transmission between hosts, direct and indirect contact, horizontal and vertical routes, vector-borne and environmental spread, is the province of the epidemiology topic and is only touched on here where it bears on the cellular events. The reasons one infection is mild and another lethal, the viral virulence determinants and host factors that decide outcome, and the longitudinal patterns infection settles into, acute, latent, and chronic, are the subjects of the companion articles in this topic.

Establishing an infection

An infection succeeds only when three conditions are met together. There must be an inoculum containing enough viable virus to establish infection; the virus must reach and interact with susceptible cells able to support its replication; and the host’s innate immunity and any pre-existing adaptive immunity must be insufficient to abort the infection at once. A failure of any one of the three prevents infection, which is why the size of the dose, the accessibility of susceptible cells, and the immune state of the host all shape whether exposure leads to disease.

The amount of infectious virus in a sample is its infective titre, measured as the highest dilution that still causes infection and expressed as a median infective dose (ID50), a median tissue culture infective dose (TCID50), or a median lethal dose (LD50) per unit volume. One such infectious unit corresponds to many more than a single virion, because a large proportion of particles in any preparation are non-infective and because most encounters between an infective particle and a susceptible cell still fail to establish infection. The infecting dose is therefore a statistical quantity rather than a fixed count of particles. Volume contributes as well as concentration: a large inoculum such as a unit of transfused blood can deliver an infecting dose even at low virus concentration, and inactivation by the environment or a disinfectant is progressive, so partial treatment lowers infectivity without abolishing it.

Portals and routes of entry

The body presents a nearly continuous epithelium to the outside world, the keratinised epidermis externally and the mucosae of the respiratory, alimentary, and urogenital tracts internally. A virus must be taken up by, or pass through, this barrier to begin an infection, and the surface it uses is a major determinant both of the disease that follows and of the virus’s epidemiology. After entry, replication may remain localised to the surface or spread to become systemic. Each virus exploits a characteristic portal that matches its cellular tropism, so the route of entry predicts the initial site of replication and, often, the first clinical signs.

Respiratory tract

The respiratory tract is the single most important portal. It is defended by a blanket of mucus from goblet cells and by the coordinated beating of cilia that sweeps trapped particles upward, the mucociliary escalator, backed by secretory immunoglobulin A (IgA), the antibody class that guards mucosal surfaces. The size of an inhaled droplet decides where it lands: large droplets deposit on the nasal turbinates, intermediate droplets reach the trachea and bronchi, and particles below about five micrometres are carried to the alveoli, where they can infect alveolar epithelium directly and produce a viral pneumonia. Some respiratory-entry viruses remain local, while others use the tract only as a gateway to systemic disease.

Viruses initiating infection through the respiratory tract:

Pattern of disease	Viruses
Local respiratory symptoms	Rhinoviruses and some enteroviruses; SARS-CoV, MERS-CoV and the common-cold coronaviruses OC43, 229E and NL63; parainfluenza viruses, respiratory syncytial virus and human metapneumovirus; influenza virus; most adenoviruses
Generalised disease, usually without initial respiratory symptoms	Mumps and measles viruses; rubella virus; varicella-zoster virus; some enteroviruses; polyomaviruses; parvovirus B19; Hantaan virus; South American haemorrhagic fever viruses; variola virus (smallpox, now eradicated)

Alimentary tract

The alimentary tract is reached by ingestion and exposes virus to acid, bile, and proteolytic enzymes, to a mucus layer backed by secretory IgA, and to the churning of peristalsis. Viruses that establish intestinal infection are characteristically resistant to acid and bile, and for some, cleavage of an outer capsid protein by an intestinal protease actually increases infectivity. The microfold cells (M cells) overlying the Peyer patches of the ileum sample the lumen and pass virus to the mononuclear cells beneath, delivering it toward the draining lymph nodes and the bloodstream. Some viruses enter by this route yet cause no intestinal disease at all.

Viruses initiating infection through the alimentary tract:

Route and effect	Viruses
Via mouth or oropharynx	Herpes simplex virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6
Intestinal tract, producing enteritis	Rotaviruses; noroviruses and sapoviruses; human astroviruses; enteric adenoviruses (HAdV-40, HAdV-41)
Intestinal tract, producing generalised disease without alimentary symptoms	Many enteroviruses including polioviruses; hepatitis A virus; hepatitis E virus
Intestinal tract, usually symptomless	Some adenoviruses; some enteroviruses; reoviruses

Skin

The keratinised outer layer of the skin, the stratum corneum, is impervious to virus unless it is breached, by minor trauma, by the bite of an arthropod or animal, or by injection, inoculation, or transfusion. Once past it, virus may replicate in the epidermis alone, as the papillomaviruses do, or in the underlying dermal cells, from where progeny may be carried by blood, lymph, or nerves to distant sites. Langerhans cells, the dendritic cells of the epidermis, take up virus and transport it to local lymph nodes. Whether the infection scars depends on its depth: a virus confined to the epidermis above an intact basement membrane heals cleanly, as in recurrent herpes simplex, whereas damage to the basement membrane, as in monkeypox, leaves a scar.

Genitourinary tract

The genitourinary tract is protected by its mucosal lining, by mucus, and by the low pH of the vagina, but minute tears and abrasions during sexual activity, together with the exchange of fluids, allow virus to enter. Two patterns occur. Herpes simplex virus type 2 and the papillomaviruses produce local lesions on the genitalia and perineum and spread by contact, while others, among them HIV, the human T-lymphotropic viruses (HTLV-1 and HTLV-2), and the hepatitis B and C viruses, produce no local lesion yet are efficiently sexually transmitted.

Conjunctiva

The conjunctiva is far less resistant than skin but is constantly cleansed by tears and wiped by the lids, so entry is favoured by abrasion, as in dusty environments. Virus reaches the eye by aerosol, on contaminated fingers, through ophthalmic instruments, or from swimming-pool water, and the diseases that result range from conjunctivitis to the recurrent keratitis of herpes simplex. Systemic spread is rare but documented, as in the paralysis that can follow enterovirus 70 conjunctivitis, and Marburg and Ebola viruses can persist in the anterior chamber of the eye long into convalescence.

Viruses entering through the skin, genital tract, or eye:

Route	Viruses
Skin, minor trauma	Papillomaviruses; molluscum contagiosum, cowpox, orf and milker’s nodes viruses; herpes simplex viruses; hepatitis B virus
Skin, arthropod bite (mechanical)	Tanapox virus
Skin, arthropod bite (with replication in the arthropod)	Many alphaviruses; many flaviviruses; La Crosse, sandfly fever and Rift Valley fever viruses; Colorado tick fever virus
Skin, animal bite	Rabies virus; herpes B virus
Skin, injection or inoculation	Hepatitis B virus; hepatitis C virus; HIV and HTLVs; cytomegalovirus and Epstein-Barr virus; Ebola virus
Genital tract	Genital papillomaviruses; herpes simplex viruses; HIV and HTLV-1; hepatitis B virus; hepatitis C virus
Conjunctiva	Several adenoviruses; enterovirus 70; herpes simplex viruses; vaccinia virus

Vertical transmission

Vertical transmission, from mother to fetus or newborn, takes three distinct forms.

The first is germ-line transmission, in which viral genomic DNA carried in the chromosomes of ovum or sperm, or as an episome, may predispose the offspring to disease in later life. This is well documented in animals and accounts for the large tracts of endogenous retroviral DNA in the human genome, roughly eight per cent of it, although no human disease has yet been shown to be transmitted this way.

The second is transplacental transmission during pregnancy, usually following infection of the placenta from a maternal viraemia. The consequences range from inapparent infection through postnatal disease to congenital malformation, premature labour, and stillbirth. Rubella virus (the congenital rubella syndrome), cytomegalovirus (a leading infective cause of congenital abnormality), and Zika virus are the important examples, and HIV and hepatitis B virus can be transmitted both transplacentally and at delivery.

The third is perinatal transmission, acquired at birth from infected genital secretions or maternal bowel contents. Herpes simplex viruses and coxsackieviruses acquired this way can be far more severe than the same infection later in life, because the newborn’s immune system is immature.

Mechanisms of virus spread within the body

A virus that stays at its entry surface causes localised disease; one that penetrates beneath it can disseminate to distant organs. The route a virus takes through the body, and the speed with which it travels, set both the incubation period and the organs that will be damaged.

Surface spread is rapid, because progeny released into the fluid film over an epithelium reach neighbouring cells at once, aided by coughing, sneezing, or peristalsis. The direction in which a virus is released from a polarised epithelial cell decides whether it stays put or invades. Apical release, toward the lumen, favours local spread and prompt shedding and is used by the paramyxoviruses, respiratory syncytial virus, and influenza. Basolateral release, toward the underlying tissue, opens the way to the sub-epithelial spaces and to dissemination by lymph, blood, and nerve, as with HIV at a mucosal surface. A surface-restricted infection is not therefore mild: rotavirus can denude the intestinal lining and cause fatal dehydration, and circulating cytokines from a purely local infection can produce systemic fever, headache, and myalgia.

Several distinct properties hold a virus at the surface, and it disseminates only when these are overcome.

Restraint on spread	Mechanism
Directional budding	Apical release sheds virus into the lumen rather than into the tissue
Basement-membrane barrier	The virus cannot cross the basement membrane unless it is damaged
Receptor and permissiveness limits	Cells in distant organs lack the receptor or cannot support replication
Circulating antibody	Neutralising antibody in plasma and tissue fluid blocks dissemination
Temperature sensitivity	A strain grows at the cooler surface (33 degrees C) but not in deeper tissue at 37 degrees C
Restricted activating protease	A fusion protein needs cleavage by a protease confined to one site, such as the gut or airway

Once beneath the epithelium, virus enters the lymphatic capillaries that underlie every cutaneous and mucosal surface and travels to the draining lymph node. There, macrophages and dendritic cells in the marginal sinus may destroy it, present its antigen and trigger adaptive immunity, or, for viruses that replicate in these cells, carry it onward. Many important viruses replicate in monocytes and macrophages, among them measles, dengue, and several herpesviruses, and the normal recirculation of these cells through the body becomes an efficient route of dissemination.

The bloodstream is the most rapid vehicle of all, able to seed virus to any organ within minutes. The first appearance of virus in the blood, the primary viraemia, is usually clinically silent and is recognised only by the distant infection it initiates. Replication in those first target organs releases far more virus as a secondary viraemia, which seeds the organs responsible for the characteristic disease. Virus may travel free in the plasma, as the enteroviruses and most flaviviruses do, or bound to blood cells and serum proteins, as with hepatitis B and C viruses. Virus carried inside leukocytes is shielded from antibody and can be delivered to distant tissues even after the immune response has begun, a strategy of measles, cytomegalovirus, and Kaposi sarcoma-associated herpesvirus.

Macrophages are pivotal to this phase. They are efficient phagocytes present in the plasma, the alveoli, the sub-epithelial tissue, and above all the sinusoids of liver, spleen, and bone marrow. Whether they clear a virus or spread it depends on the virus, the macrophage, and the host. A virus that survives within a macrophage is carried through the body inside it, the Trojan Horse mechanism that delivers HIV into the central nervous system. Antibody and complement coating a virion can paradoxically increase its uptake into macrophages through their Fc and complement receptors, and where the virus can then replicate in the macrophage, this antibody-enhanced entry becomes a route to worse disease, seen most clearly in dengue.

To leave the blood and enter a tissue, virus must cross the vascular wall, which it does most readily in capillaries and venules where flow is slow and the wall thinnest. The wall takes three forms that differ in how easily virus passes. Continuous endothelium, in the central nervous system, muscle, skin, and lung, is the tightest. Fenestrated endothelium, in the renal glomerulus, intestinal villi, choroid plexus, and endocrine glands, has pores that let virus through. Sinusoidal endothelium, in liver, spleen, and bone marrow, is the most open and brings blood-borne virus into direct contact with resident macrophages. Virus crosses by passive movement through fenestrae, by replicating in and growing across the lining, by transcytosis through the cell without replication, or by diapedesis inside a trafficking leukocyte. A viraemia is sustained only while new virus enters the blood as fast as the macrophages remove it, which is why impairing macrophage function, as measles does, raises the level of circulating virus.

Some viruses bypass the blood entirely and travel within nerves. Herpesvirus capsids move along the axoplasm of sensory nerves from the periphery to the dorsal root ganglion, where herpes simplex and varicella-zoster virus usually halt and establish lifelong persistence, later travelling back out to the skin on reactivation. Rabies virus is amplified in striated muscle at the site of a bite, enters peripheral nerves at the neuromuscular junction, and ascends to the central nervous system within the axon at roughly two hundred to four hundred millimetres a day; rarely, it reaches the brain directly through the olfactory neurons, the only neurons linking a body surface to the central nervous system. This neural route, walled off from antibody and from cytotoxic T cells, is what makes the long and variable incubation of rabies possible and what gives post-exposure prophylaxis its window to act. The length of the incubation period in general reflects the length of this journey, a few days when disease arises at the site of entry and one to several weeks when the virus must traverse two viraemias to reach a distant target organ.

Tropism and target organs

Tropism is the predilection of a virus for a particular cell type or organ, and it determines what disease results, because the disease is set by what the virus infects: a neurotropic virus causes encephalitis, a virus tropic for CD4 T cells causes immunodeficiency. The obvious determinant is the distribution of the entry receptor, but receptor distribution alone does not explain tropism. The poliovirus receptor, CD155, is present on neurons throughout the nervous system and on cells of the adrenal, lung, and kidney, yet poliovirus destroys the anterior horn motor neurons and spares the rest. A virus may also use different receptors on different cells: the HIV envelope binds CD4 together with the co-receptor CCR5 on macrophages or CXCR4 on T-cell lines, and which co-receptor a strain uses shapes the cells it infects. Beyond the receptor, productive infection needs the right intracellular conditions, so tropism is multi-factorial.

Determinant of tropism	How it restricts infection
Receptor distribution	The entry receptor is present only on certain cells, or only at certain times
Temperature	Replication is favoured at a particular temperature, as for rhinoviruses at 33 degrees C in the upper airway
Activating protease	A protease that cleaves an attachment or fusion protein is restricted to particular tissues
Intracellular factors	Cell-type-specific transcription factors or other host cofactors are needed for replication
Innate and adaptive immunity	Local restriction factors or an immune response exclude the virus from some tissues
Anatomical barriers	Physical barriers such as the blood-brain barrier limit access
Route of entry	The portal of entry sets the initial distribution of virus

Almost any organ can be infected through the blood, but most viruses have a defined tropism, and the clinical weight of an infection follows the role of the organ it targets: the liver in yellow fever and the hepatitis viruses, the parotid and salivary glands in mumps, the synovium in rubella and the arthritogenic alphaviruses. Infection of an organ that sheds to the exterior, such as the salivary glands, the kidney tubules, or the accessory sex organs, also opens a route of transmission in saliva, urine, or semen.

The central nervous system is reached from the blood by two routes, and along nerves by a third. Virus in the vessels of the meninges or choroid plexus can cross into the cerebrospinal fluid and infect the ependyma and underlying brain; some enteroviruses cross the meningeal vessels and stay there, causing a self-limiting meningitis, while others progress into the parenchyma and cause encephalitis. Most encephalitic viruses instead cross the blood-brain barrier directly, some by infecting the endothelium, some carried across inside infected leukocytes, as in HIV and measles, and some, such as West Nile virus, by exploiting a barrier made leaky by inflammatory cytokines. The neural route is taken by rabies and, on reactivation, by herpes simplex and varicella-zoster virus. Whatever the route, the histology of viral encephalitis shows three hallmarks: necrosis of neurons, neuronophagia (the engulfment of dying neurons), and perivascular cuffing by mononuclear cells, the last a marker of the immune response itself.

When the skin is the target organ, reached through the blood, it produces the rashes that are often diagnostic of a systemic viral infection. A rash evolves through stages as infection moves from the dermal vessels into the epidermis, and the stage, distribution, and character of the lesions point to the agent.

Lesion	What it represents	Examples
Macule	Dilatation of superficial dermal vessels	Rubella (may go no further)
Papule	Oedema and inflammatory infiltrate raising the lesion	Measles
Vesicle	Epidermal infection separating epidermis from dermis with fluid	Herpes simplex, varicella-zoster, smallpox
Pustule	Infiltration by neutrophils	Smallpox
Petechia or haemorrhage	Severe vessel damage with a coagulation defect or thrombocytopenia	Viral haemorrhagic fevers

The fetus is a target of particular consequence. Most maternal infections spare it, but some blood-borne viruses cross the placenta with grave effect. The congenital rubella syndrome, recognised by Norman Gregg in 1941, follows placental infection during a maternal viraemia: virus spreads through the developing fetal vasculature, and damage to fetal vessels with consequent ischaemia produces defects most marked in the organs forming at the time of infection, hence the deafness, cataracts, and cardiac and brain defects of early-gestation infection. Congenital cytomegalovirus infection likewise causes hepatosplenomegaly, thrombocytopenia, microcephaly, and neurodevelopmental impairment.

Mechanisms of disease production

Arrival at a target organ does not by itself constitute disease; disease follows from the injury that replication there inflicts. That injury arises principally in two ways, with a third that acts over a longer term. The virus may damage the cell directly, or, for a virus that does not itself kill the cell, the immune response to the infection may inflict the damage; over years, some viruses instead drive the cell toward cancer. Distinguishing direct from immune-mediated injury is one of the central interpretive tasks of clinical virology, because it determines whether treatment should target the virus, the host response, or both.

Direct cell injury

Direct injury takes several recognisable forms. A cytocidal virus may kill the cell outright by lysis, releasing progeny as the cell disintegrates; others fuse infected cells with their neighbours into multinucleated syncytia, as the paramyxoviruses do, spreading the genome without exposing it to antibody. Many cytopathic infections leave a histological signature, the inclusion body, an aggregate of viral components or an altered cell region that marks the infected cell. A virus may instead trigger apoptosis, the cell’s own programmed death, or disturb a cell’s function without killing it: the rotavirus non-structural protein NSP4 acts as a functional enterotoxin, driving the secretion of chloride and water that produces the watery diarrhoea of rotavirus infection while the enterocyte still lives.

The severity of disease does not track how cytopathic a virus appears in culture. Some enteroviruses lyse cultured cells dramatically yet cause only inapparent human infection, while rabies virus is barely cytocidal yet uniformly lethal. Where the damage falls matters more than how much occurs: the loss of cells in skin or striated muscle is tolerated, whereas the same loss in heart or brain is not, and oedema that is trivial elsewhere is dangerous when it raises intracranial pressure, floods the alveoli, or disturbs cardiac conduction. Direct injury also tends to amplify itself and to invite bacteria. In the respiratory tract it spreads as a daisy chain, the destruction of a few epithelial cells exposing and damaging their neighbours and stripping the protective mucus, until denudation of the airway brings secondary bacterial infection, alveolar damage, and the obstruction by mucus plugs that together produce the acute respiratory distress syndrome (ARDS).

Immune-mediated injury

The second route to disease is immune-mediated, and for a non-cytocidal virus it is essentially the whole of the disease. The same effectors that clear an infection, the cytotoxic T cells, the inflammatory cytokines, the antibody and complement, also injure tissue, and their dysregulation produces some of the most dangerous viral syndromes, from the cytokine storm of severe respiratory and haemorrhagic infections to the chronic immune destruction of the liver in viral hepatitis. A related mechanism, antibody-dependent enhancement, allows a sub-neutralising antibody to worsen rather than block infection, and post-infectious autoimmunity through molecular mimicry can outlast the virus entirely. These immune-mediated mechanisms are the subject of viral immunopathology, where they are treated in full.

Oncogenic transformation

A third route to disease operates over years rather than days. Instead of killing the infected cell, some viruses drive it toward unregulated proliferation, integrating their genome or expressing proteins that disable the cell’s growth controls. The oncogenic viruses cause cancer in this way and account for a substantial share of human malignancy, among them the cervical and oropharyngeal cancers of human papillomavirus, the hepatocellular carcinoma of chronic hepatitis B and C, and the lymphomas of Epstein-Barr virus.

The principal routes to virus-induced tissue damage, with the home of each:

Mechanism	Nature of the injury	Examples
Cell lysis	Direct death of the infected cell, releasing progeny	Many enteroviruses, influenza
Syncytium formation	Fusion of infected with neighbouring cells	Respiratory syncytial virus, measles, HIV
Apoptosis	Virus triggers the cell’s programmed death	Many viruses
Functional toxin	A viral protein disturbs cell function without killing it	Rotavirus (NSP4)
Cytotoxic T cell injury	Immune killing of infected cells (see immunopathology)	Hepatitis B and C
Cytokine storm	Dysregulated systemic inflammation (see immunopathology)	SARS-CoV-2, avian influenza, Ebola
Antibody-dependent enhancement	Sub-neutralising antibody increases infection (see immunopathology)	Dengue
Autoimmunity	Cross-reactive response to host tissue (see immunopathology)	Measles, influenza, Epstein-Barr virus
Oncogenic transformation	Infected cell driven to unregulated growth (see oncogenesis)	HPV, hepatitis B and C, EBV, HHV-8

Shedding

The journey ends, from the virus’s point of view, in shedding, the release of infectious virus that allows it to reach a new host. Virus is shed from the surfaces it reaches: in respiratory secretions, in faeces, in saliva, urine, semen, and breast milk, and from skin lesions. The direction of release at the cellular level shapes this, apical budding delivering virus straight back to the lumen and the environment. What matters clinically is the timing of shedding relative to symptoms, because it defines both the period of greatest transmissibility and the window in which the virus is most readily detected. In many respiratory infections shedding peaks around the onset of symptoms and then declines, and children typically shed more virus, and for longer, than adults, which is part of why they drive transmission. The site of shedding also directs the laboratory: it is the reason a stool sample finds an enterovirus, a nasopharyngeal swab an influenza virus, and a genital swab a herpes simplex virus.

General patterns of infection

Across the agents, these journeys resolve into a small number of longitudinal patterns that shape prognosis and management. An acute infection rises to a peak and is then cleared, with lasting or transient immunity. A persistent infection is not cleared: it may settle into latency, the virus lying dormant in a long-lived cell with the capacity to reactivate, or into chronic active infection, with continuing replication and slowly progressive tissue injury. These patterns, the markers that distinguish them, and the mechanisms of persistence and latency are the subject of the dedicated patterns of infection article.

Clinical and therapeutic significance

Read as a sequence, the course of an infection is also a sequence of points at which it can be interrupted. The route of entry defines the means of prevention, from the mucosal immunity an oral or intranasal vaccine elicits to the barrier precautions that block a percutaneous or mucosal exposure. The pattern of spread explains why antiviral and immune intervention is most effective early, before a secondary viraemia has seeded the target organs, and why the slow neural ascent of rabies leaves time for post-exposure vaccine and immunoglobulin to act where treatment after symptom onset cannot. Tropism and the site of shedding direct the laboratory to the organ and secretion where the virus will be found, and the timing of shedding indicates when in the illness a test will detect it. The incubation period sets the limits of quarantine and the window for prophylaxis. Each stage of the journey, in short, is also a decision point for diagnosis, treatment, and control, which is why a working command of pathogenesis underlies so much of clinical virological practice.

References and recommended reading

• Burrell CJ, Howard CR, Murphy FA. Pathogenesis of Virus Infections. In: Fenner and White’s Medical Virology, 5th edition, Chapter 7. Academic Press / Elsevier; 2017. The principal source for the requirements for infection, the routes of entry (Tables 7.1 to 7.3), the mechanisms of spread within the body (Table 7.4), tropism and target organs (Table 7.6; the evolution of a rash), and the direct mechanisms of disease production.
• Morrison TE, Heise MT. Pathogenesis of Viral Infection. In: Fields Virology, 7th edition, Volume 4, Chapter 8. Wolters Kluwer; 2023. The current reference for the sequential-stages framework of pathogenesis, the poliovirus paradigm, and the multi-factorial determinants of viral tropism.