Steps in Viral Pathogenesis
المؤلف:
Stefan Riedel, Jeffery A. Hobden, Steve Miller, Stephen A. Morse, Timothy A. Mietzner, Barbara Detrick, Thomas G. Mitchell, Judy A. Sakanari, Peter Hotez, Rojelio Mejia
المصدر:
Jawetz, Melnick, & Adelberg’s Medical Microbiology
الجزء والصفحة:
28e , p437-441
2025-10-25
41
Specific steps involved in viral pathogenesis are the following: viral entry into the host, primary viral replication, viral spread, cellular injury, host immune response, viral clearance or establishment of persistent infection, and viral shedding.
A. Entry and Primary Replication
Most viral infections are initiated when viruses attach and enter cells of one of the body surfaces—skin, respiratory tract, gastrointestinal tract, urogenital tract, or conjunctiva. The majority of these enter their hosts through the mucosa of the respiratory or gastrointestinal tract (Table 1). How ever, some viruses can be introduced directly into tissues or the bloodstream through skin wounds, needles (eg, hepatitis B and C and human immunodeficiency virus [HIV]), blood transfusions, or insect vectors (arboviruses).
Table1. Common Routes of Viral Infection in Humans
After entry, the viral nucleic acid and virion-associated proteins interact with cellular macromolecules to ultimately produce new virions that are released from the host cell by shedding or cell lysis. The specific mechanisms of viral replication are highly variable and can be quite complex, relying on one or more intermediate stages of production. The released virions are then able to attach and infect other cells in the immediate vicinity, causing local spread of infection.
B. Viral Spread and Cell Tropism
Some viruses, such as influenza viruses (respiratory infections) and noroviruses (gastrointestinal infections), produce disease at the portal of entry and typically do not spread systematically. Others can spread to distant sites (eg, cytomegalovirus [CMV], HIV, and rabies virus) and cause additional disease manifestations (Figure1). Mechanisms of viral spread vary, but the most common route is via the bloodstream or lymphatics. The presence of virus in the blood is called viremia. Virions may be free in the plasma (eg, enteroviruses and togaviruses) or associated with particular cell types (eg, measles virus) (Table 2). Viruses may multiply within those cells (eg, Epstein-Barr virus [EBV] is lymphotrophic and can replicate within white blood cells as it spreads). Some viruses travel along neuronal axons to spread within the host (eg, rabies migrates to the brain, herpes simplex virus [HSV] travels to ganglia to produce latent infection).
Fig1. Mechanisms of spread of virus through the body in human viral infections. + indicates possible sites of viral replication; large arrows indicate sites of shedding of virus, with illustrative examples of diseases in which that route of excretion is important. Transfer from blood is by transfusion with hepatitis B and by mosquito bite in certain arboviral infections. SSPE, subacute sclerosing panencephalitis. (Modified from Mims CA, White DO: Viral Pathogenesis and Immunology. Copyright © 1984 by Blackwell Science Ltd. With permission from Wiley.)
Table2. Viruses Spread Via the Bloodstream
Viruses tend to exhibit organ and cell-type specificities, or viral tropism. Tropism determines the pattern of systemic illness produced during a viral infection. As an example, hepatitis B virus has a tropism for liver hepatocytes, and hepatitis is the primary disease caused by the virus.
Tissue and cellular tropism by a given virus usually reflect the presence of specific cell surface receptors for that virus. Receptors are components of the cell surface with which a region of the viral surface (capsid or envelope) can specifically interact and initiate infection. Receptors are cell constituents that function in normal cellular metabolism but also happen to have an affinity for a particular virus. The identity of the specific cellular receptor is known for some viruses but is unknown in many cases.
The level of cell surface receptor expression and post translational modifications affect the ability of viruses to infect various cell types. For example, influenza virus requires cellular proteases to cleave virally encoded hemagglutinin in order to enable viruses to infect new cells, and expression of a glycolytic enzyme (neuraminidase) to release newly formed virions. Multiple rounds of viral replication will not occur in tissues that do not express the appropriate proteins.
C. Cell Injury and Clinical Illness
Destruction of virus-infected cells in the target tissues and physiologic alterations produced in the host by the tissue injury are partly responsible for the development of disease. Some tissues, such as intestinal epithelium, can rapidly regenerate and with stand extensive damage better than others, such as the brain. Some physiologic effects may result from nonlethal impairment of specialized functions of cells, such as loss of hormone pro duction. Clinical illness from viral infection is the result of a complex series of events, and many of the factors that determine degree of illness are unknown. General symptoms associated with many viral infections, such as malaise and anorexia, may result from host response functions such as cytokine production. Clinical illness is an insensitive indicator of viral infection; inapparent infections by viruses are very common.
D. Recovery from Infection
Following a viral infection, the host will succumb, recover, or establish a chronic infection. Recovery mechanisms include both innate and adaptive immune responses. Interferon (IFN) and other cytokines, humoral and cell-mediated immunity, and possibly other host defense factors are involved. The relative importance of each component differs with the virus and the disease.
The importance of host factors in influencing the outcome of viral infections is illustrated by an incident in the 1940s in which 45,000 military personnel were inoculated with yellow fever virus vaccine that was contaminated with hepatitis B virus. Although the personnel were presumably subjected to comparable exposures, clinical hepatitis occurred in only 2% (914 cases), and of those only 4% developed serious disease. The genetic basis of host susceptibility remains to be determined for most infections.
In acute infections, recovery is associated with viral clearance and viral-specific antibody production. Establishment of a chronic infection involves complex interplay between viral and host immune factors, and the virus may enter a life-long latent state, or subsequently reactivate and cause disease months to years later.
E. Virus Shedding
The last stage in pathogenesis is the shedding of infectious virus into the environment. This is a necessary step to maintain a viral infection in populations of hosts. Shedding usually occurs from the body surfaces involved in viral entry (see Figure 1). Shedding occurs at different stages of disease depending on the particular agent involved. During viral shedding, an infected individual is infectious to contacts. In some viral infections, such as rabies, humans represent dead end infections, and shedding does not occur. Two examples of the pathogenesis caused by disseminated viral infections are shown in Figure 2.
Fig2. Schematic illustrations of the pathogenesis of disseminated viral infections (mousepox and poliomyelitis). These viruses attach and replicate locally, spreading through the lymphatics and bloodstream to distant sites where they multiply further and can produce disease, followed by shedding into the environment from the initial site of infection. CNS, central nervous system. (Courtesy of F Fenner.)
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