For example, although poxviruses are very different from small RNA viruses, such as poliovirus, there are remarkable parallels between the models of poliovirus infection (see, Conceptualizing Viral Pathogenesis as the Interaction Between Stochastic Events and Bottlenecks in Infection, It is important to recognize that the process of infection has, in addition to a series of predictable events that occur in sequence, an element of stochastic variation that contributes to real variability to the outcome of infection. For example, transgenic expression of the poliovirus or measles virus receptors in mice confers susceptibility to intracerebral infection with poliovirus or measles virus. Bi-specific antibodies allow for dual targeting against different epitopes on the surface of pathogens (Byrne et al., 2013). In many cases, infection is apparently harmless to the host and does not result in disease. First, loss-of-function genetic analysis depends on whether a viral property can truly be attributed to a specific mutation. Model of poliovirus pathogenesis as a series of sequential stages. Tropism is the capacity of a virus to infect or damage specific cells, tissues, or species. For example, viremia may continue after a virus has entered the CNS to cause encephalitis. The portal of entry can also be the place where the virus causes the disease which is the target tissue which we will discuss in the second bullet point. This chapter provides an overview of these basic concepts of viral pathogenesis, with emphasis on the interactions of viruses with their host cells and organisms. Although many studies have focused on the impact of variation in a single gene on viral susceptibility, it is clear that susceptibility or resistance to viral infections is a complex phenotype regulated by multiple interacting genes and gene networks. In these cases, the transition from acute to chronic is arbitrarily defined as the time when most patients have cleared acute infection. Finally, as the methodology for expressing engineered molecules improves, it is increasingly possible to modulate immune function through the expression of novel molecules, or through genetic delivery of antibodies (Johnson et al., 2009; Balazs et al., 2011). The size of the viral genome puts boundaries on the number of genes that a virus can use for pathogenesis and replication. When an infected person exposes an uninfected person to the diverse HIV quasispecies that develops during chronic infection, the viruses that emerge in the new host represents only a subset of the viruses in the inoculum. This is nicely illustrated by the identification of Kaposi’s sarcoma (KS) herpesvirus, where epidemiology studies suggested that HIV status alone was not an accurate predictor of KS risk, indicating that an additional co-factor was responsible for KS. Human viruses can be studied in animals that are susceptible to infection either because the virus does not exhibit species tropism or because tropism restrictions are overcome via genetic. Virulence—the relative capacity of a virus to cause disease—determines the relationship between infection and disease. This virology tutorial explains the step by step process of viral pathogenesis and the mode of causing viral infection. The increased success of virus-like particles as vaccines is encouraging, because the immunogen closely resembles native virus and elicits effective immunity while the particle is unable to replicate and cause adverse responses. Some viruses, such as HIV, persist via both continuous replication and establishment of latency, presenting a particularly difficult challenge for the host immune system. Key questions include the source (an infected human, animal, or insect vector), the transmission mechanism, and how the virus is shed and transmitted. Viruses need to establish infections in host cells in order to multiply. Once inside the host, viruses can spread from the initial site of infection to the CNS via either the hematogenous route (viremia) or via the peripheral nervous system, and the two modes of spread are not mutually exclusive (Nathanson and Murphy, 2007). Viral pathogenesis, the way in which a virus produces a disease, involves a complex interaction between the virus and the infected organism. Viral Pathogenesis Viral pathogenesis is the process by which a viral infection leads to disease. For example, Ebola Reston, which is not associated with human disease, is less virulent in humans than Ebola Zaire. Cell-Intrinsic Versus Cell-Extrinsic Mechanisms, Because infected cells live in a tissue in the host, they are affected both by events that occur inside the cell and by events that influence the cell from the outside. A reactivated virus may spread and initiate an epidemic among susceptible contacts eg. TRIMs can use different mechanisms to inhibit viral entry, uncoating, replication, or viral release, ultimately resulting in reduction of viral pathogenesis (Fig. Robert W. Doms, in Viral Pathogenesis (Third Edition), 2016. In this case, the transition between acute and chronic infection is defined as the time required for clearance of the initial burst of viral replication and establishment of equilibrium between the host and the virus. Of course, like any biological event, disease is often a complex combination of direct damage by virus in concert with host immune responses. N. Nathanson, in Encyclopedia of Virology (Third Edition), 2008. This chapter will focus on integrating classical concepts of pathogenesis with more current molecular understanding of viruses. Often, this is done using a loss-of-function genetic approach in which an entire viral gene is deleted or in which a mutation is used to ablate a specific biochemical function of a viral protein. In the first, one studies a human virus in infected animals. An ongoing pandemic of coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). First, dividing pathogenesis into stages creates the impression that events are both sequential and depend on each other. Clinical questions that drove poliovirus pathogenesis research through the first half of the past century included why poliomyelitis emerged in the 20th century, what mechanisms were responsible for paralysis, and how did protective immunity work. In biology, a pathogen (Greek: πάθος pathos "suffering", "passion" and -γενής -genēs "producer of") in the oldest and broadest sense, is any organism that can produce disease.A pathogen may also be referred to as an infectious agent, or simply a germ.. Understanding viral pathogenesis, the mechanism by which disease develops, is an important consideration in developing effective treatments. As this is not a very useful concept, viral genes essential for replication in permissive cells are termed. Viral pathogenesis, particularly the study of viral assembly, has contributed to a better understanding of synthetic biology, which will facilitate new approaches to the production of safe and more effective vaccines. In some cases, as for HBV or hepatitis C virus (HCV), a proportion of persons become chronically infected while others are cured. Viruses are obligate parasites of living cells that cannot live independent of an intricate relationship with an infected cell. However, viral proteins often have multiple independent functions—a property particularly well documented for RNA viruses. Increasing knowledge of the mechanisms of viral pathogenesis and immunity holds out great hope for generations of better animal models. Virulence can be conferred by viral promoters or other cis elements in the viral genome or noncoding RNAs. During virus latency, the virus persists in a dormant (non-replicating) form, but can reactivate intermittently to an infectious form (e.g., HSV-1 and HSV-2). One example of this is paracrine regulation of tissue pathology by virus-encoded cytokines. This variation is not experimental error or noise but is rather a real phenomenon relevant to understanding infection. pathogenesis of aids how does hiv cause aids? It is the early event in viral replication, and occurs before viral DNA synthesis begins. Pathogenesis describes the set of physical, chemical or biological elements that lead to the generation of a disease and its evolution. A search of the recent literature accessed by Entrez using the term, Productive, Abortive, and Latent Infection, Acute Versus Chronic or Persistent Infection. Some viruses produce diseases at sites distant from their portal of entry. This is not always the case; many independent events may be going on at the same time in the host. The term pathogen came into use in the 1880s. Philip E. Pellett, ... Thomas C. Holland, in Handbook of Clinical Neurology, 2014. Examples of the types of questions asked by those with an interest in viral pathogenesis include: What are the molecular differences between the attenuated version of a virus (used as a vaccine) and its highly virulent “parent”? In other cases, essentially all hosts become chronically infected, as is seen with herpesviruses or lentiviruses such as human immunodeficiency virus (HIV). Infection viewed as a series of steps with a predictable outcome Viewsof viralpathogenesis. Is a particular disease caused by direct virus damage or by immune responses (or a combination of both)? Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. The cells targeted by viruses during infection survive, differentiate, and function in a tissue that has an intimate relationship with other tissues and physiologic processes in the body. There is an essential tension between these two approaches; in one the “real” pathogen is studied, and in the other a “natural” infection is studied. The previously discussed ways to conceptualize viral pathogenesis are highly focused on the virus, but it has been clear since the earliest studies of viral pathogenesis that hosts differ significantly in genetic susceptibility to infection. This is often accomplished by. Authors ... (G4s) in viruses has boomed, providing powerful evidence for the regulatory role of G4s in key viral steps. Living in tissues and spreading from host to host represent processes only approximated in cell culture or biochemical experimentation. Both cell-intrinsic and cell-extrinsic factors may alter viral tropism. For details of specific viral infections, refer to chapters on individual viruses. There are many ways to look at infection—three of which are presented here as a basis for understanding viral pathogenesis. These advances may permit targeting of highly conserved and vulnerable structures—normally protected by the virus—that can induce broad protective responses immune responses (reviewed in refs (Nabel and Fauci, 2010; Nabel, 2013)). Copyright © 2020 Elsevier B.V. or its licensors or contributors. Transport of the virus is from neuron to neuron via the synapses (Griffin, 2003). Key questions include the source (an infected human, animal, or insect vector), the transmission mechanism, and how the virus is shed and transmitted. Together with assays for prior infection such as serology or molecular detection of chronic virus infection, epidemiology can define the relationship between infection, immunity, and disease. Since there were many Nobel prizes for research relevant to viral pathogenesis, we decided to use some of these as illustrations. Virus particles can contain virulence determinants that are not encoded in their genomes. The reasons for the occurrence of significant variations even when conditions of infection are apparently homogeneous are not clear but likely involve several different factors, including epigenetic changes within the host, specific interactions between viruses and certain host genes that confer disease, Selective pressures at bottlenecks in infection can select mutants from within the viral quasispecies that have a fitness advantage (see. In contrast to the nonspecific syndromes commonly associated with virus infection, the presence of specific symptoms or signs of disease such as hepatitis, immunodeficiency, pocks on the skin, or paralysis provides important clues as to the nature of the pathogenic process. 2020;54:101-131. doi: 10.1016/bs.armc.2020.04.001. This problem is further compounded because many events and processes are going on at the same time. Progression of chronic infection to disease often reflects a change in this equilibrium (see. Infectious clone technology now exists for most virus families, and by applying directed mutagenesis strategies to these molecularly cloned viruses, mechanistic hypotheses can be tested directly. Bacterial Pathogenesis Pathogenesis is defined as the origination and development of a disease. It is likely that pathogenesis researchers will use such molecular signatures to distinguish between infections with different viruses and to define host genes involved in viral pathogenesis. Viral pathogenesis as the result of the action of a series of host genes. Mutations in CCR5 confer resistance to HIV infection. Viruses that spread via the peripheral nervous system do so within the dendrites and axons of the nerve fibers, and virus replicates in either the cytoplasm or the nucleus of the neurons (Nathanson and Murphy, 2007). Thus, advent of sequencing, structural biology, and directed mutagenesis of viral genomes as tools for pathogenesis research has been a turning point for pathogenesis as an experimental science. There are two types of animal models for human viral disease. In truth, each has its advantages and each its limitations. The concept of tropism is rapidly evolving with the recognition that essentially every aspect of the viral infectious process within a cell or tissue can be a determinant of tropism. Excellent examples of this approach are the analysis of infection with filoviruses such as Ebola or Marburg that are very difficult to study in infected patients. The mechanism of this infection event is a primary theme. Abstract. For example, several genes might be important for an aspect of pathogenesis such that mutation of any one of them would give a phenotype; however, no single gene is independently sufficient for the virus to perform a certain task, A third limitation of loss-of-function genetics is that the identification of an important role for a gene at a given step in pathogenesis does not provide information on the mechanisms responsible for the phenotype observed. The route of infection of a host varies with the virus and can be via mucosal membranes of the respiratory tract, gastrointestinal tract, urogenital tract or the conjunctiva of the eye or by breaching the skin (arthropod injection, animal bite, or needlestick) (Nathanson and Murphy, 2007). To avoid biases inherent in comparing different types of disease, virulence is properly used to compare the disease-inducing capacity of related viruses, such as different strains of the same virus. Click to share on Twitter (Opens in new window), Click to share on Facebook (Opens in new window), Click to share on Google+ (Opens in new window), Picornaviridae: The Viruses and their Replication, Virology: From Contagium Fluidum to Virome. We use cookies to help provide and enhance our service and tailor content and ads. Dividing viral pathogenesis into stages is a very useful way to conceptualize the infectious process but has significant limitations. Inflammation, killing of virus-infected cells by the immune system, or deposition of immune complexes are examples. Viruses can circulate in the blood either associated with cells (monocytes, B cells, T cells) or free in the plasma, or both, depending on the virus. In other cases, host cellular processes may be insufficient or have deleterious effects on the virus. However, many principles and mechanisms of viral pathogenesis have first been described in animal models and later proven relevant in humans. These mechanisms constitute viral, Subversion of Host Molecules and Mechanisms. Smallpox was known before variola virus was identified, and rabies virus was propagated in animals and an effective vaccine was developed by Pasteur before the virus was characterized. The determination of whether one virus (e.g., Ebola virus) is more virulent than another virus (e.g., papillomavirus) represents a qualitative judgment, because it involves determining whether virus-induced hemorrhagic fever (as is seen with Ebola virus) is worse than metastatic cancer (as is seen with papillomaviruses). Pathogenesis of Viral Infection Mark T. Heise Herbert W. Virgin Introduction to Viral Pathogenesis Viral pathogenesis is the series of steps that occurs when a virus infects the host. This approach is particularly useful for viruses that fail to replicate in nonhuman systems and has been applied to viruses such as HIV, In the fifth approach, the virus is manipulated in a specific way to allow infection of the animal to be used as a model. For example, a neurotropic virus such as West Nile Virus can cause encephalitis or paralysis, whereas a virus with tropism for CD4 T cells such as HIV causes immunodeficiency. Viral genome moves from virion-produced cell to adjacent naive cells. Viral Genetics as a Tool for Analysis of Pathogenesis. Importantly, although the mechanistic details underpinning the pathogenesis of different viruses will differ significantly, the broad stages of the systemic infection process outlined for poliovirus pathogenesis are also relevant for a wide array of other viral pathogens. For example, if a certain amino acid is important for binding of a host protein by a viral protein, and that same mutation causes the virus to be defective in pathogenesis, it is plausible that the phenotype observed, Interactions Between Host and Viral Genes in the Study of Pathogenesis, Defining the mechanism of action of a viral protein or gene. Virus uses cellular trafficking machinery. Thus, viral pathogenesis can be conceptualized as a series of stochastic events with the process of infection determined by strong selective pressures in the host referred to as bottlenecks in infection (. The consequences of viral infections depend on the interplay between a number of viral …