Anne Moscona and Anne A. Gershon
Viruses can only survive by entering and parasitizing the cells of a host. Because viruses cannot live independently of their interaction with the parasitized host cell, all viruses have evolved strategies for coexisting with cells, while these cells continue to carry out physiologic functions as part of specific tissues or organs. It is the complex interplay between viral and host properties that determines the relationship that the virus will experience with its host in vivo, whether resulting in disease or not. The interplay between viral and host features thus determines the pathogenesis of infection.
Pathogenesis has generally been conceptualized as the series of sequential steps starting with entry of the virus into host cells, and progressing through survival of the virus and dissemination of the virus in the host, to shedding of the virus from the host to spread to new individuals where the virus continues its life cycle. In the animal host, every virus must overcome a series of defenses in order to enter, disseminate, and localize in the ideal target tissue; replicate; and shed to infect new hosts. At each stage, the host possesses specific mechanisms to inhibit the survival of the virus, and the virus has evolved ways to counteract these mechanisms. Some of these strategies for evading host defenses are common to different viruses. Considering viral pathogenesis in this way as the stepwise unfolding of events within the host is useful and simple because thus far we know far more in most cases about the virus itself than we do about the host side of the complex interplay. When applying this model of viral pathogenesis, however, often the steps may not occur sequentially, but rather several steps may be occurring at the same time, or several alternate pathways may be taken simultaneously.
As new understanding of the host contributions to viral pathogenesis emerges, the impact that an individual’s genetic makeup has on susceptibility to infectious disease has become clear. In fact, recent data suggest that an error in a single gene is enough to dramatically alter an individual’s susceptibility to viral infections.1 It is becoming apparent that pathogenesis should likely, in the future, be conceptualized as a balance between the viral agent and the host’s immunologic and genetic makeup.
GENETIC SUSCEPTIBILITY TO INFECTION
For respiratory syncytial virus (RSV), several abnormal underlying conditions that predispose to severe forms of disease have been enumerated, and include prematurity, preexisting lung disease, and various forms of immunodeficiency. However, it is not yet known why some apparently normal infants and children proceed from initial infection to severe lower respiratory tract disease, whereas others experience a relatively mild, self-limited illness. Recent evidence now points to a major role for genetic susceptibility. Certain alleles of IL-4,10 and of the IL-4 receptor,11 are associated with more severe disease, and promoter variants of IL-10, IL-9, and TNF-α genes likely also influence disease severity.12
SERIES OF STEPS IN VIRAL INFECTION
ENTRY
Entry into the host is the step that allows a virus to establish infection in host cells, after overcoming environmental, anatomic, or innate immune mechanisms to gain access to its target. The virus can enter in infected cells that can be injected for example via the mouth parts of infected arthropods; can be contained in droplets or fomites shed from an infected host, or can be inhaled or ingested as free virus. The six portals through which viruses can enter the human body include five epithelial surfaces: skin, conjunctiva, respiratory tract, gastrointestinal tract, and genitourinary tract. Viruses can also enter via the interface between the mother and germ cell or developing fetus.
The barriers to viral entry include general anatomic barriers, defenses based on the immune system’s recognition of patterns (eg, via Toll receptors),2 other innate immune mechanisms, and adaptive immune responses. Epithelial tissues are now recognized to be active immune organs, containing specialized dendritic cells that serve as sentinels for invasion, which when activated by viruses can initiate the induction of immune responses. Lymphocytes are also present in epithelia, generating protective immune responses at this barrier. The epithelial cells themselves can also produce a cellular antiviral response, all taking place before the virus even reaches the stage of inactivation by antibodies and complement.
SPREAD
When a virus passes through the superficial epithelial barriers, and confronts the intrinsic cellular resistance to infection it then can spread. Most viruses spread locally from cell to cell; some remain at or near the site of entry, whereas others cause viremia and spread widely. Spread of viruses can occur vertically via the placenta or the germ line. Transplacental spread is an important mechanism for several human pathogens, including the herpesviruses human cytomegalovirus (HCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV), hepatitis viruses B and C, and HIV. Spread via the germ line is the mechanism whereby human endogenous retro-viruses enter the human genome; the consequences of this spread to humans are only beginning to be understood.3 Systemic spread of viruses through the infected host can occur via the blood, the lymphatic system, or the nerves. The most important route of dissemination for non-CNS viruses is the bloodstream during viremia. Viruses may circulate either free or cell associated, depending on the individual virus, and may invade tissues from the bloodstream. A number of important human viruses spread through the axons of peripheral nerves and are thus carried to the CNS.
TROPISM
Cell and tissue tropism of viruses is determined by the interplay between the specific viral feature, the required conditions for replication, and host features. These include cellular receptors, innate antiviral immunity, intrinsic cellular resistance, the presence of immunoprivilege,8 and the state of differentiation of the cell or tissue.9 Innate immune detection of virus infection is mediated by host pattern recognition receptors including RNA helicases RIG-I and MDA5 and several members of Toll-like receptors (TLR) such as TLR3, TLR7 and TLR9. Of these, RIG-I, MDA5 and TLR3 function as sensors for double-stranded RNA species that are produced by many viruses during replication, and trigger interferon-β induction.4,5 Examples of intrinsic cellular resistance include proteins such as the APOCBEC antiviral proteins that corrupt the genome of invading viruses by inducing mutations, and TRIM5α interferes with the uncoating of retrovirus, thereby preventing the successful reverse transcription and transport to the nucleus of the viral genome.6,7 Immunoprivilege refers to the ineffectivity of the immune system in clearing virus infection from specific tissues; for example, CD8 T cells may be more effective at eliminating infection from MHC class I expressing hepatocytes than from neurons that do not express MHC class I molecules. As suggested previously, the list of host features that determines tropism lengthens as we learn more.
FATE
The successful establishment of a virus in its target tissue may, but does not necessarily, result in damage or disease. The variables that determine the outcome of infection lie in the interplay between features of the virus, including the many factors that determine virulence, and features of the host. One determinant of susceptibility to viral infections that is particularly relevant in pediatrics is age. Many viral infections are far more severe in younger than older hosts. One example of this difference is hepatitis B virus (HBV) exposure. Most adults infected with HBV clear the infection, whereas exposed neonates have a very high level of chronic infection. The actual determinants of disease are not fully understood for most viruses. In large part, the outcome of infection depends on whether the virus is cleared from the infected tissue; whether the immune system, in efforts to clear the virus, damages host tissue; and whether the virus induces autoimmune responses.
Infected cells may be killed either directly by the virus in its subversion of cell metabolism, or by triggering cell-intrinsic programmed cell death pathways (apoptosis). Virus-infected cells can also be killed by lysis of infected cells by the complement system, or via the effector molecules released by NK cells or cytotoxic T cells. Some viruses, despite rapid clearance by the immune system, manage to cause significant tissue damage (eg, variola). Other viruses are less likely to be cleared by the immune system, and result in latent, chronic, or progressive infection (eg, hepatitis B). Some viruses can cause either type of infection—acute or persistent—in different patients (eg, measles causes both acute disease and subacute sclerosing panencephalitis [SSPE]). Even during beneficial immune responses, the immune system can cause significant tissue damage, and in many cases, virus-induced pathology is actually caused by the immune response and is referred to as immunopathologic.
One variant of immunopathology is virus-induced autoimmunity, which can arise either through molecular mimicry or during persistent virus infections without evidence for cross-reactive antigens. Many viruses can, under certain conditions, cause persistent infections that last for the lifetime of the host. Such viruses can only accomplish this feat by maintaining their own genome and evading host immune responses, without destroying the host. Herpesviruses, for example, cause latent infections in the nervous or lymphoid system that may remain silent for the individual’s lifetime or reactivate, especially in the setting of immunosuppression, to cause another disease such as HSV rash or encephalitis, and zoster, due to VZV. Certain herpesviruses such as Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV8) can also reactivate and cause malignancy such as lymphoma and Kaposi sarcoma, respectively. Other viruses associated with persistent infection and development of cancer include hepatitis B and C viruses, and human papilloma viruses 16 and 18.
SHEDDING AND TRANSMISSION
Viruses that cause acute infection generally are shed heavily from the host in bodily secretions, to allow for spread to the next host. Persistently infecting viruses may shed very little, but nonetheless enough for eventual transmission. The strategies used by viruses for shedding depend on their ability to survive for brief periods under various environmental conditions. Common strategies for transmission include contamination of hands by bodily secretions; inhalation of aerosolized virus; direct person-to-person contact, including sexual or skin contact; and indirect person-to-person contact via blood. Transmission can also occur via contaminated water, food, or biologics, for viruses that can survive these environments. Efficient transmission is a key to survival of the virus and perpetuation of the viral life cycle.
SPECIFIC EXAMPLES OF VIRAL PATHOGENESIS
The preceding chapter focused on the stepwise model of viral pathogenesis. Only general principles could be provided since each virus has evolved individualized mechanisms to infect and survive in the host. As noted, the resistance to infection to a specific virus may vary depending upon host genetics, age and the size of a viral inoculation. Detailed examples showing the specific molecular mechanism of the pathogenesis of infection with the Paramyxoviridaeviruses, specifically human parainfluenza viruses (HPIVs) and respiratory syncytial viruses (RSVs), that are major causes of bronchiolitis; and of latent viral infection varicella-zoster virus (VZV) are provided on the DVD.