Viral Pathogenesis Samuel Baron, Michael Fons


FIGURE 45-3 Virus spread through bloodstream during a generalized infection



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FIGURE 45-3 Virus spread through bloodstream during a generalized infection. Numbers indicate sequence of events.

Incubation Period

During most virus infections, no signs or symptoms of disease occur through the stage of virus dissemination. Thus, the incubation period (the time between exposure to virus and onset of disease) extends from the time of implantation through the phase of dissemination, ending when virus replication in the target organs causes disease. Occasionally, mild fever and malaise occur during viremia, but they often are transient and have little diagnostic value.



The incubation period tends to be brief (1 to 3 days) in infections in which virus travels only a short distance to reach the target organ (i.e., in infections in which disease is due to virus replication at the portal of entry). Conversely, incubation periods in generalized infections are longer because of the stepwise fashion by which the virus moves through the body before reaching the target organs. Other factors also may influence the incubation period. Generalized infections produced by togaviruses may have an unexpectedly short incubation period because of direct intravascular injection (insect bite) of a rapidly multiplying virus. The mechanisms governing the long incubation period (months to years) of persistent infections are poorly understood. The persistently infected cell is often not lysed, or lysis is delayed. In addition, disease may result from a late immune reaction to viral antigen (e.g., arenaviruses in rodents), from unknown mechanisms in slow viral infections during which no immune response has been detected (as in the scrapie-kuru group), or mutation in the host genetic material resulting in cellular transformation and cancer.



FIGURE 45-4 Virus spread through nerves during a generalized infection. Numbers indicate sequence of events.

Multiplication in Target Organs

Virus replication in the target organ resembles replication at other body sites except that



    • the target organ in systemic infections is usually reached late during the stepwise progression of virus through the body,

    • clinical disease originates there.

At each step of virus progression through the body, the local recovery mechanisms (local body defenses, including interferon, local inflammation, and local immunity) are activated.

Thus, when the target organ is infected, the previously infected sites may have reached various stages of recovery. Figure 45-2 illustrates this staging of infection and recovery in different tissues during a spreading surface infection. Circulating interferon and immune responses probably account for the termination of viremia, but these responses may be too late to prevent seeding of virus into the target organ and into sites of shedding. Nevertheless, these systemic defenses can diffuse in various degrees into target organs and thereby help retard virus replication and disease.

Depending on the balance between virus and host defenses (see Chs. 49 and 50), virus multiplication in the target organ may be sufficient to produce dysfunction manifested by disease or death. Additional constitutional disease such as fever and malaise may result from diffusion of toxic products of virus replication and cell necrosis, as well as from release of lymphokines and other inflammatory mediators. Release of leukotriene C4 during respiratory infection may cause bronchospasm. Viral antigens also may participate in immune reactions, leading to disease manifestations. In addition, impairment of leukocytes and immunosuppression by some viruses may cause secondary bacterial infection.

Shedding of Virus

Because of the diversity of viruses, virtually every possible site of shedding is utilized (Table 45-2); however, the most frequent sites are the respiratory and alimentary tracts. Blood and lymph are sites of shedding for the arboviruses, since biting insects become infected by this route. HIV is shed in blood and semen. Milk is a site of shedding for viruses such as some RNA tumor viruses (retroviruses) and cytomegalovirus (a herpesvirus). Several viruses (e.g., cytomegaloviruses) are shed simultaneously from the urinary tract and other sites more commonly associated with shedding. The genital tract is a common site of shedding for herpesvirus type 2 and may be the route through which the virus is transmitted to sexual partners or the fetus. Saliva is the primary source of shedding for rabies virus. Cytomegalovirus is also shed from these last two sites. Finally, viruses such as tumor viruses that are integrated into the DNA of host cells can be shed through germ cells.





Congenital Infections

Infection of the fetus is a special case of infection in a target organ. The factors that determine whether a target organ is infected also apply to the fetus, but the fetus presents additional variables. The immune and interferon systems of the very young fetus are immature.



  • This immaturity, coupled with the partial placental barrier to transfer of maternal immunity and interferon, deprive the very young fetus of important defense mechanisms.

  • Another variable is the high vulnerability to disruption of the rapidly developing fetal organs, especially during the first trimester of pregnancy.

  • Furthermore, susceptibility to virus replication may be modulated by the undifferentiated state of the fetal cells and by hormonal changes during pregnancy. Although virus multiplication in the fetus may lead to congenital anomalies or fetal death, the mother may have only a mild or inapparent infection.

To cause congenital anomalies, virus must reach the fetus and multiply in it, thereby causing maldeveloped organs. Generally, virus reaches the fetus during maternal viremia by infecting or passing through the placenta to the fetal circulation and then to fetal target organs. Sufficient virus multiplication may disrupt development of fetal organs, especially during their rapid development (the first trimester of pregnancy). Although many viruses occasionally cause congenital anomalies, cytomegalovirus and rubella virus are the most common offenders. Virus shedding by the congenitally infected newborn infant may occur as a result of persistence of the virus infection at sites of shedding.

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Albrecht T, Boldogh I, Fons M et al: Cell activation signals and the pathogenesis of human cytomegalovirus. Intervirology 31:68, 1990

Coen DM: Acyclovir-resistant, pathogenic herpesviruses. Trends Microbiol 2:481, 1994

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Grieder FB, Davis NL, Aronson JF, et al: Specific restrictions in the progression of Venezuelan equine encephalitis virus-induced disease resulting from single amino acid changes in glycoproteins. Virology 206:994, 1995

Singh IP, Chopra AK, Coppenhaver, DH et al: Vertebrate brains contain a broadly active antiviral substance. Antiviral Research 27:375, 1995

Strayer DS, Laybourne KA, Heard HK: Determinants of the ability of malignant fibroma virus to induce immune dysfunction and tumor dissemination in vivo. Microb Pathos 9:173, 1990

Wold WE, Hermiston TW, Tollefson AE: Adenovirus proteins that subvert host defenses. Trends Microbiol 2:437, 1994








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