Molecular Pathology and the Dynamics of Disease

Maika G. Mitchell

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128146118
• Topic: Diritto
• Subtopic: Scienza forense

Molecular Pathology and the Dynamics of Disease bridges the basic science of, and primary clinical literature on, human disease. Topics covered include several major disease areas, such as inflammation and host response, vascular disease, obesity, weight regulation and appetite, cancer biology, drug development, and gene- and cell-based therapeutics that are all presented in a way that emphasizes the interplay between clinical care and investigation. As new technologies and techniques are constantly changing and laboratory scientists plays a critical role in validating data used by clinicians in diagnosing patients, this book provides a timely guide that includes a clinical, research and theory perspective.

• Assimilates theoretical knowledge with practical lab work
• Provides a needed clinical perspective, along with research and theory
• Highlights the impact of basic science on the practice of medicine

Chapter 1

Molecular Pathology Introduction and Research Review

Abstract

Molecular pathology, a rapidly expanding discipline connecting pathology and molecular biology, is providing a deeper insight and understanding of the molecular basis of the etiology and pathogenesis of human disease. This well-laid-out book covers the basic principles of molecular pathology, explains the most important molecular diagnostic techniques in user-friendly language, and describes their applications across a broad range of human diseases and problems, including cancer, hereditary disorders, identity testing, and infectious diseases.

Keywords

Pathogenesis; pathology; molecular medicine

Molecular pathology, a rapidly expanding discipline connecting pathology and molecular biology, is providing a deeper insight and understanding of the molecular basis of the etiology and pathogenesis of human disease. This well-laid-out book covers the basic principles of molecular pathology, explains the most important molecular diagnostic techniques in user-friendly language, and describes their applications across a broad range of human diseases and problems, including cancer, hereditary disorders, identity testing, and infectious diseases.

Pathogenesis Overview and Review

Pathogenesis is the process by which an infection leads to disease. Pathogenic mechanisms of viral disease include (1) implantation of virus at the portal of entry, (2) local replication, (3) spread to target organs (disease sites), and (4) spread to sites of shedding of virus into the environment. Factors that affect pathogenic mechanisms are (1) accessibility of virus to tissue, (2) cell susceptibility to virus multiplication, and (3) virus susceptibility to host defenses. Natural selection favors the dominance of low-virulence virus strains.

Direct cell damage and death from viral infection may result from (1) diversion of the cell’s energy, (2) shutoff of cell macromolecular synthesis, (3) competition of viral mRNA for cellular ribosomes, and (4) competition of viral promoters and transcriptional enhancers for cellular transcriptional factors such as RNA polymerases, and inhibition of the interferon (IFN) defense mechanisms. Indirect cell damage can result from integration of the viral genome, induction of mutations in the host genome, inflammation, and the host immune response.

Viral affinity for specific body tissues (tropism) is determined by (1) cell receptors for virus, (2) cell transcription factors that recognize viral promoters and enhancer sequences, (3) ability of the cell to support virus replication, (4) physical barriers, (5) local temperature, pH, and oxygen tension enzymes and nonspecific factors in body secretions, and (6) digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses.

Virions implant onto living cells mainly via the respiratory, gastrointestinal, skin-penetrating, and genital routes although other routes can be used. The final outcome of infection may be determined by the dose and location of the virus as well as its infectivity and virulence.

Most virus types spread among cells extracellularly, but some may also spread intracellularly. Establishment of local infection may lead to localized disease and localized shedding of virus.

Viremic: The most common route of systemic spread from the portal of entry is the circulation, which the virus reaches via the lymphatics. Virus may enter the target organs from the capillaries by (1) multiplying in endothelial cells or fixed macrophages, (2) diffusing through gaps, and (3) being carried in a migrating leukocyte.

Neural: Dissemination via nerves usually occurs with rabies virus and sometimes with herpesvirus and poliovirus infections.

The incubation period is the time between exposure to virus and onset of disease. During this usually asymptomatic period, implantation, local multiplication, and spread (for disseminated infections) occur.

Depending on the balance between virus and host defenses, virus multiplication in the target organ may be sufficient to cause disease and death.

Although the respiratory tract, alimentary tract, urogenital tract, and blood are the most frequent sites of shedding, diverse viruses may be shed at virtually every site.

Infection of the fetus as a target “organ” is special because the virus must traverse additional physical barriers, the early fetal immune and interferon defense systems may be immature, transfer of the maternal defenses are partially blocked by the placenta, the developing first-trimester fetal organs are vulnerable to infection, and hormonal changes are taking place.

Pathogenesis is the process by which virus infection leads to disease. 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. Most viral infections are subclinical, suggesting that body defenses against viruses arrest most infections before disease symptoms become manifest. Knowledge of subclinical infections comes from serologic studies showing that sizeable portions of the population have specific antibodies to viruses even though the individuals have no history of disease. These inapparent infections have great epidemiologic importance: they constitute major sources for dissemination of virus through the population, and they confer immunity.

Many factors affect pathogenic mechanisms. An early determinant is the extent to which body tissues and organs are accessible to the virus. Accessibility is influenced by physical barriers (such as mucus and tissue barriers), by the distance to be traversed within the body, and by natural defense mechanisms. If the virus reaches an organ, infection occurs only if cells capable of supporting virus replication are present. Cellular susceptibility requires a cell surface attachment site (receptor) for the virions and also an intracellular environment that permits virus replication and release. Even if virus initiates infection in a susceptible organ, replication of sufficient virus to cause disease may be prevented by host defenses.

Other factors that determine whether infection and disease occur are the many virulence characteristics of the infecting virus. To cause disease, the infecting virus must be able to overcome the inhibitory effects of physical barriers, distance, host defenses, and differing cellular susceptibilities to infection. The inhibitory effects are genetically controlled and therefore may vary among individuals and races. Virulence characteristics enable the virus to initiate infection, spread in the body, and replicate to large enough numbers to impair the target organ. These factors include the ability to replicate under certain circumstances during inflammation, during the febrile response, in migratory cells, and in the presence of natural body inhibitors and interferon. Extremely virulent strains often occur within virus populations. Occasionally, these strains become dominant as a result of unusual selective pressures. The viral proteins and genes responsible for specific virulence functions are only just beginning to be identified.

Fortunately for the survival of humans and animals, most natural selective pressures favor the dominance of less virulent strains. Because these strains do not cause severe disease or death, their replication and transmission are not impaired by an incapacitated host. Mild or inapparent infections can result from absence of one or more virulence factors. For example, a virus that has all the virulence characteristics except the ability to multiply at elevated temperatures is arrested at the febrile stage of infection and causes a milder disease than its totally virulent counterpart. Live virus vaccines are composed of viruses deficient in one or more virulence factors; they cause only inapparent infections and yet are able to replicate sufficiently to induce immunity.

The occurrence of spontaneous or induced mutations in viral genetic material may alter the pathogenesis of the induced disease, e.g., HIV. These mutations can be of particular importance with the development of drug resistant strains of virus.

Disease does not always follow successful virus replication in the target organ. Disease occurs only if the virus replicates sufficiently to damage essential cells directly, to cause the release of toxic substances from infected tissues, to damage cellular genes or to damage organ function indirectly as a result of the host immune response to the presence of virus antigens.

As a group, viruses use all conceivable portals of entry, mechanisms of spread, target organs, and sites of excretion. This abundance of possibilities is not surprising considering the astronomic num...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Chapter 1. Molecular Pathology Introduction and Research Review
• Chapter 2. Challenges in Molecular Pathology
• Chapter 3. Review of Clinical Human Medical Genetics
• Chapter 4. Molecular Medicine in Action
• Chapter 5. Mechanisms of Disease
• Index