viral pathogenesis steps

Another example is the movement of viral proteins from an infected to an uninfected cell. Viral pathogenesis is the subject of many authoritative texts, and the reader is referred to one such text for detailed treatment of many of the important concepts developed here in necessarily shorter form. For example, smaller RNA viruses often have genomes of less than 10,000 nucleotides, whereas poxviruses or herpesviruses may have genomes greater than 200,000 nucleotides in length. Dissemination of viruses from the blood to the CNS can be via infected T cells or monocytes, which traffic into the CNS, via infection of the brain’s capillary endothelial cells with viral replication within these cells, via transport of virus across the brain’s capillary endothelial cells (transcytosis) without viral replication within these cells, via induction of proinflammatory cytokines (innate immunity) that increase the permeability of the BBB, or via the CSF. Ebola has adapted to infect guinea pigs and mice. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Included within the scope of pathogenesis are the stepwise progression of infection from virus entry through dissemination to shedding, the defensive responses of the host, and the mechanisms of virus clearance or persistence. An important alternative approach is to study the pathogenesis of an animal virus that is related to a human virus in an animal host. Viral pathogenesis in general is discussed in Chapters 7 and 8, and for specific viruses in Chapters 11 through 33; however, viral pathogenesis will be discussed briefly here. 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. 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. Poliovirus pathogenesis provides an excellent example of how pathogenesis can be broken down into a series of steps that culminate in either virus-induced disease or viral control. Given this complexity, it is worth considering how the questions of pathogenesis are formulated and placed in context for interpretation. Viruses must be able to utilize host metabolic and regulatory systems to optimize their growth, survival, and spread. Viral Genetics as a Tool for Analysis of Pathogenesis. Inflammation, killing of virus-infected cells by the immune system, or deposition of immune complexes are examples. Inactivation of host cellular protein synthesis is a hallmark of many virus infections. One key determinant of viral tropism is the cognate interaction between the viral cell attachment protein(s) and receptor(s) present on host cells. These dissimilarities are often used to argue against the utility of such animal models. We use cookies to help provide and enhance our service and tailor content and ads. Pathogenic mechanisms include implantation of the virus at a body site (the portal of entry), replication at that site, and then spread to and multiplication within sites (target organs) where disease or shedding of virus into the environment occurs. Viral pathogenesis deals with the interaction between a virus and its host. The need to understand human infection, combined with the complexities of doing human studies, has led to the use of animal models to ask pathogenesis questions that cannot be effectively answered via human studies. The size of the viral genome puts boundaries on the number of genes that a virus can use for pathogenesis and replication. BYU-Idaho Academic Support 869 views. 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. This chapter will focus on integrating classical concepts of pathogenesis with more current molecular understanding of viruses. For example, a virus may be highly virulent if directly inoculated into the central nervous system (CNS) but unable to cause disease if inoculated into the periphery, whereas a related virus with a mutation allowing it to cross the blood–brain barrier into the CNS can cause lethal disease following either peripheral or intracranial inoculation. Even for viruses that utilize the establishment of latency as a primary strategy, intermittent reactivation and replication may be required to maintain latency and to spread from host to host. Studies taking advantage of genetic differences between viral strains are as old as the study of pathogenesis itself. concepts in viral pathogenesis By Horatio Alger, Jr. 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. 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. The cells targeted by viruses during infection… These capacities are encoded in the viral genome, by alleles of individual, Any gene essential for replication contributes to virulence, because viruses must replicate to complete their life cycle. Comparisons between viral strains can identify correlates of virulence or attenuation but do not necessarily shed light on the mechanisms responsible for the phenomena observed. 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). During the acute stage of infection, EBV causes rapid B-cell expansion (a nonequilibrium process) that is then brought under control by the expansion of virus-specific T cells, which act to maintain the virus in a latent state (an equilibrium process). Viral Pathogenesis: From Basics to Systems Biology, Third Edition, has been thoroughly updated to cover topical advances in the evolving field of viral pathogenesis, while also providing the requisite classic foundational information for which it is recognized.. Viral pathogenesis as the result of the action of a series of host genes. 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. The consequences of viral infections depend on the interplay between a number of viral … William C. Summers, in Viral Pathogenesis (Third Edition), 2016. For example, EBV infection is associated with the development of B-cell lymphomas. Viruses produce cellular injury by either direct destruction of the infected cell or by alteration in cell physiology. Virus particles can contain virulence determinants that are not encoded in their genomes. Model of poliovirus pathogenesis as a series of sequential stages. While the T-cell chimeric antigen receptor approach has currently been directed to cancer immunotherapy, it may also prove efficacious against infectious disease targets. 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). Analogously, one determines the function of the viral gene by mutating the gene; however, mutating the gene can change the process of infection sufficiently to complicate interpretation of any differences observed in pathogenesis. Viral pathogenesis seeks to understand how a virus interacts with its host at multiple levels. For example, viremia may continue after a virus has entered the CNS to cause encephalitis. Thus, viral pathogenesis has once again moved to a new historical level, and our evolving insights are the subject of many chapters in this 3rd edition of Viral Pathogenesis. Viral pathogenesis is the integrated result of many complex factors unique to a particular virus, a particular species, and an individual host. A subject this broad cannot be treated in a single entry, and this article focuses on the dissemination of viruses and their pathogenicity. There are two types of animal models for human viral disease. Step III: Early Transcription. This step is the first step of the viral infection journey ( Virus Pathogenesis) .This is concerned with how the virus enters the host’s body. An ongoing pandemic of coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1). Abstract. 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). Virulence comes in many forms, from the induction of rapid death as for variola major (the causative agent in smallpox) to the induction of tumors over prolonged periods, as is the case with certain papillomaviruses or herpesviruses, to the induction of organ failure over many years, as is the case with chronic HBV or HCV infection. Viral pathogenesis involves several steps that must occur for the virus to infect and cause disease in the host: virus entry into the host, primary virus replication, virus spread within the host, infection of cells with special affinities for the virus (cell tropism), cellular injury, host immune response, viral clearance or persistence, and viral shedding and transmission. These mechanisms constitute viral, Subversion of Host Molecules and Mechanisms. Viruses are obligate parasites of living cells that cannot live independent of an intricate relationship with an infected cell. Virus entry occurs either through the mucosa of the respiratory, gastrointestinal tract, or urogenital tract, by transcutaneous inoculation into the blood stream through blood transfusion or insect vector bites, and by maternal–fetal transmission across the placenta. Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. The process of associating new viruses with both viral and nonviral diseases continues to this day, with new viruses constantly emerging or being identified as responsible for already described diseases. Of course, like any biological event, disease is often a complex combination of direct damage by virus in concert with host immune responses. From: Handbook of Clinical Neurology, 2014, M.T. For infections to occur, the virus has to hijack host factors and evade the host immune response for efficient replication. With the advent of genomics, proteomics, and many other recent technical advances, it has now become possible to describe the virus–host “interactome” in much greater detail. Not all human viruses can replicate in animals. 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. The lentivirus human immunodeficiency virus (HIV) causes AIDS by interacting with a large number of different cells in the body and escaping the host immune response against it. The examples we have selected range over many aspects of pathogenesis, including virology, immunology, host responses, and vaccines. 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. 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. Copyright © 2020 Elsevier B.V. or its licensors or contributors. By evaluating such viruses, one can link structural and biochemical properties of a protein to specific aspects of pathogenesis, thus making loss-of-function genetic approaches a fundamental part of current pathogenesis research. 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. Virulence—the relative capacity of a virus to cause disease—determines the relationship between infection and disease. For example, studies designed to identify genes that regulate resistance to influenza infection between two mouse strains have identified multiple quantitative trait loci (QTL) that contribute to disease susceptibility. 12:53. The extent to which allelic variations in host genes control viral pathogenesis is only now being appreciated. Pathogenesis is a process in which an initial infection becomes a disease. However, even using clonal virus stocks for inoculation of genetically identical mice of the same sex and age results in viral titers in tissues that vary considerably (even by orders of magnitude) from one mouse to the next. Viral pathogenesis seeks to understand how a virus interacts with its host at multiple levels. The original documents available online make fascinating reading, and the video lectures are a great introduction to the subjects. It is this relationship between the signs and symptoms of disease and the presence of infection with specific viruses that has led to the close link between clinical observations of the natural history of disease and the science of viral pathogenesis. 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. For example, transgenic expression of the poliovirus or measles virus receptors in mice confers susceptibility to intracerebral infection with poliovirus or measles virus. Dividing viral pathogenesis into stages is a very useful way to conceptualize the infectious process but has significant limitations. VIRAL PATHOGENESIS The processby whichvirusescause disease. There are many ways to look at infection—three of which are presented here as a basis for understanding viral pathogenesis. There is a rich body of knowledge on plant viral diseases and prion diseases that will not be addressed in this chapter. For example, Ebola Reston, which is not associated with human disease, is less virulent in humans than Ebola Zaire. Shomu's Biology 32,183 views. Five approaches have been taken to overcome this hurdle. However, virulence is much more complex than simply the efficacy of replication. Authors ... (G4s) in viruses has boomed, providing powerful evidence for the regulatory role of G4s in key viral steps. In some cases, the normal functions of the host cell may be sufficient for the virus to replicate. 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)). In the fourth approach, mice are used as hosts for human tissue allografts that can then be infected with human viruses. In the third approach, the virus is expressed as a transgene in a live animal, allowing the replication cycle of the virus to proceed in certain cells even though the host is nonpermissive for infection. Viral Pathogenesis This lecture will define and discuss the basic principles of viral pathogenesis, the entire process by which viruses cause disease. Therefore, virulence reflects host resistance to infection functioning in counterpoint to viral virulence genes and determinants with the outcome for the host hanging in the balance. Viralpathogenesis: time courseof typicalinfection Innate Adaptiveimmunity. Signs and symptoms of disease can also result from tissue damage caused by host immune responses. The mixture of viruses present in the host at a given time is a, Control of Acute Versus Chronic Infection, The distinctions between acute and chronic or persistent infection are very important. TRIMs can use different mechanisms to inhibit viral entry, uncoating, replication, or viral release, ultimately resulting in reduction of viral pathogenesis (Fig. An example of a bottleneck in infection exerting a selective pressure comes from HIV infection. Events that occur in a cell independent of events outside of the infected cell are termed, Most viruses have evolved mechanisms to counter host innate and adaptive immunity or to bypass intrinsic cellular resistance molecules so that the virus can complete the infectious process and spread to a new host. Even highly virulent viruses often establish infection in a greater number of hosts than they cause disease. What events turn an asymptomatic persistent infection into a lethal disease? Clinical Observations Define Fundamental Pathogenesis Questions. Insights into disease etiology and progression, the two major aspects of pathogenesis, are paramount in the prevention, management and treatment of various diseases. Many different tools must be used to understand the complex process of viral pathogenesis. Viral pathogenesis describes the processes by which viral infections cause diseases and involves virus–host interactions at the cellular and systemic level that determine whether a virus will cause a disease, what form that disease takes, and how severe the disease will be. Some viruses can persist in the host for a prolonged period of time. Increasing knowledge of the mechanisms of viral pathogenesis and immunity holds out great hope for generations of better animal models. Pathogenesis is the process by which virus infection leads to disease. For example, the crystal structure of a viral immune evasion protein allows predictions as to protein function during infection, The complexity of directly testing molecular mechanisms. Is a particular disease caused by direct virus damage or by immune responses (or a combination of both)? In the second approach, the host is genetically engineered to allow analysis of a human virus. While Virchow’s insight that the cell is the seat of disease remains intact after nearly two centuries, viral pathogenesis now requires our detailed understanding not only of the cell, but its interactions with the virus, as well as the interplay between the infected cell and the entire host organism. It is commonly assumed that viruses that replicate efficiently in the host are more virulent than viruses that replicate less efficiently, and indeed replication is an important determinant of the severity of disease in many cases. 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. It is not necessarily true that viral virulence determinants exert their effects in host cells actually infected by the virus. Virus uses cellular trafficking machinery. In turn, these steps are dictated by the structure and replication strategy of the virus. These problems are addressed by studying multiple distinct mutations in a protein, analysis of the expression of other viral proteins, or, when possible, complementing the mutation by expressing the protein in trans from another location in the virus. Pathogenesis also encompasses the disease processes that result from infection, variations in viral pathogenicity, and the genetic basis of host resistance to infection or disease. We hope that these individual stories will inspire some of our readers to consider the opportunities for future research in viral pathogenesis. In some cases, as for HBV or hepatitis C virus (HCV), a proportion of persons become chronically infected while others are cured. 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. 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. The viral genes and host immune, Equilibrium and Nonequilibrium States in Pathogenesis, A fundamental concept in pathogenesis is that acute infection is a nonequilibrium state, whereas chronic infection is a metastable equilibrium between virus and host. Characterization of the histopathology and cellular localization of SARS-CoV-2 in the tissues of patients with fatal COVID-19 is critical to further understand its pathogenesis and transmission and for public health prevention measures. Viral Pathogenesis Part 3 - Duration: 4:52. Other aspects of pathogenesis, including tropism, the host response to infection, and interactions between the virus and host tissues, play key roles in viral virulence. This is not always the case; many independent events may be going on at the same time in the host. This problem is further compounded because many events and processes are going on at the same time. Viral pathogenenesis as stochastic events followed by selection by bottlenecks in infection. 4:52. This will make it possible to target responses to subdominant epitopes not normally recognized in the immune response. Others are more recently developed and have only been applied in limited circumstances. Reliance on naturally occurring strains of virus has strict limitations for defining pathogenesis mechanisms, because it is only by luck that genetic variation occurs between strains in a manner that allows a specific hypothesis to be tested. The majority of viral infections are subclinical.It is not in the interest of the virus to severely harm or kill the host. The EBV EBNA1 protein plays an important role in the maintenance of latent EBV infection in B lymphocytes. 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. Such cell tropism is usually mediated by specific cell surface receptors on the host cell with which the virus envelope or capsid can interact to initiate infection. For example, this will enhance the induction of neutralizing influenza antibodies in the elderly (Limberis et al., 2013; Balazs et al., 2013), or by modulating the specificity of T cells to recognize antigenic determinants using chimeric antigen receptors for cancer vaccines (Jensen and Riddell, 2014). Viruses need to establish infections in host cells in order to multiply. Some viruses, such as HIV, persist via both continuous replication and establishment of latency, presenting a particularly difficult challenge for the host immune system.

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