Disease Pathways

An Atlas of Human Disease Signaling Pathways

Anastasia P. Nesterova, Anton Yuryev, Eugene A. Klimov, Maria Zharkova, Maria Shkrob, Natalia V. Ivanikova, Sergey Sozin, Vladimir Sobolev

• Publisher: Elsevier
• Year: 2019
• ISBN:
  9780128170878
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Disease Pathways: An Atlas of Human Disease Signaling Pathways is designed to fill a void of illustrated reviews about the cellular mechanisms of human diseases. It covers 42 of the most common non-oncologic diseases and illustrates the connections between the molecular causes of the disease and its symptoms. This resource provides readers with detailed information about the disease molecular pathways, while keeping the presentation simple.

Pathway models that aggregate the knowledge about protein–protein interactions have become indispensable tools in many areas of molecular biology, pharmacology, and medicine. In addition to disease pathways, the book includes a comprehensive overview of molecular signaling biology and application of pathway models in the analysis of big data for drug discovery and personalized medicine.

This is a must-have reference for general biologists, biochemists, students, medical workers, and everyone interested in the cellular and molecular mechanisms of human disease.

• Over 145 full-color illustrations of the molecular and cellular cascades underlying the disease pathology.
• Disease pathways are based on computational models from Elsevier's Disease Pathway Collection, published for the first time outside of Pathway Studio® commercial software.
• Each relationship on the pathway models is supported by references to scientific articles and can be examined at freely available online resources.

II

Human disease pathways

Chapter 2

Infectious diseases

Abstract

The treatment of viral infections is a well-known challenge, and therefore their pathogenesis has been intensively investigated. In this chapter, we review three examples of relatively well-understood viral infections. The interactions of viral proteins and the viral genome with human polymerases, transcription factors, and other proteins that regulate cell cycle progression is the main focus of research on the pathogenesis of viral infections.

Keywords

HIV; HTLV; Human papillomavirus; Viral latency; T cells; T lymphocytes

Outline

• Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)
• Human T-cell leukemia virus infection and leukemia progression
• Human papillomavirus infection and cancer

In general, infectious diseases can be described as diseases that can be spread from one person to another and are caused by bacteria, viruses, fungi, and other parasitic organisms (World Health Organization (WHO), https://www.who.int/topics/infectious_diseases). The treatment of viral infections is a well-known challenge, and therefore their pathogenesis has been intensively investigated. In this chapter, we review three examples of relatively well-understood viral infections.

Viruses are intracellular parasites, which rely on proteins and other cellular building blocks of the host cell to replicate themselves. The interactions of viral proteins and the viral genome with human polymerases, transcription factors, and other proteins that regulate cell cycle progression is the main focus of research on the pathogenesis of viral infections.

There are several key steps during the development of any viral infection. At first the virus must penetrate the host cell; then the viral genomes often integrate into the host genome and, finally, activation of viral gene transcription and replication. The suppression of cellular antiviral response and of the host’s immune response to viral proteins is important as well. Viruses must support the survival of an infected cell for successful replication; therefore resistance to apoptosis of infected cells is considered another critical research topic.

The listed mechanisms have been studied in detail for many viruses. Human immunodeficiency virus (HIV) is the most well-studied one due to the social concerns about the related acquired immunodeficiency syndrome (AIDS). T cells are the primary target cell type for HIV. Human T-cell leukemia virus (HTLV) is similar to HIV because it is also an RNA-containing virus that affects T cells. Comparing HIV and HTLV infections gives insights into different strategies employed by similar viruses.

Human papillomavirus (HPV) is responsible for the most common viral infection of the reproductive tract according to WHO. Two types of HPV (types 16 and 18) cause most cases of cervical cancer and are responsible for precancerous cervical lesions. From a biological point of view, HPV provides an example of the pathogenesis of a DNA-containing virus that targets nonimmune human cells.

Chapter 2.1

Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)

Acquired immunodeficiency syndrome (AIDS) is a result of infection by the human immunodeficiency virus (HIV), which progressively weakens the cellular immune system leading to the development of secondary (opportunistic) infections and/or malignancies.

The human immunodeficiency virus (HIV) is a retrovirus that is responsible for causing acquired immunodeficiency syndrome (AIDS). HIV infection does not necessarily mean a person has AIDS.

(Ferri and Ferri, 2018).

HIV is a single-stranded RNA lentivirus (a genus of retroviruses) categorized as either type 1 or 2. While HIV-1 is the predominant pathogenic retrovirus in humans, disease caused by HIV-2 tends to progress less rapidly than that of HIV-1. HIVs are transmitted by sexual contact, contact with blood or other body fluids of infected individuals, from mother to child during pregnancy, baby delivery, or breastfeeding.

Symptoms of HIV infection or AIDS depend on the stage of the disease. During the earliest acute stage of HIV infection (which occurs during the first weeks following infection until the formation of HIV-specific antibodies), signs of viral infection may manifest due to high levels of systemic viral replication and a permanent loss of mucosa-associated CD4 + T cells, which express the glycoprotein cluster of differentiation 4 (CD4) and C-C chemokine receptor type 5 (CCR5).

During the chronic stage, which lasts 8–10 years, the levels of viral replication decrease. Chronic HIV infection is usually asymptomatic but may include nonspecific symptoms such as lymphadenopathy, fatigue, weight loss, diarrhea, and different skin changes such as dermatitis or signs of opportunistic viral and fungal infections (Mogensen et al., 2010; Sugden et al., 2016). Advanced disease is characterized by other opportunistic infections, indicator diseases, and malignancies such as pneumonia and lymphoma (Sokoya et al., 2017).

If the HIV infection is confirmed, AIDS is diagnosed with a CD4 + T-cell count < 14% of total lymphocytes. Although, based on the Department of Health and Human Services (DHHS) Guidelines of 2015, active antiretroviral therapy (ART) of HIV should be started with any CD4 cell count. During combined ART the level of plasma HIV falls below the level of detection, which is 50 copies of viral RNA per 1 mL of plasma (Van Lint et al., 2013). ART helps prevent AIDS development and turns it from a life-threatening to a chronic disease (Ferri and Ferri, 2018).

Genetics can change the HIV sensitivity and disease progression. Individuals with deletions in the CCR5 gene, which encodes a cell surface receptor needed for HIV entry into a host cell, have delayed disease progression (Li et al., 2014). Also, one infected person in 300 individuals can maintain a normal CD4 + T-cell count. That individual is referred to as an “elite controller.” Elite controllers are a heterogeneous group of people with strong anti-HIV immune responses due to polymorphisms in the HLA genes and related effective CD8 + T-cell response (Sokoya et al., 2017; Van Lint et al., 2013).

HIV targets several cell types including T-cell subsets, monocytes, macrophages, and dendritic cells (DCs) through different recognition mechanisms. However, the primary target of HIV is mucosal CD4 + memory T cells expressing CD4 + and CCR5 and mucosal macrophages expressing CCR5. The formation of viral synapses and the accumulation of HIV in mucosal macrophages are important for HIV progression. Following HIV penetration of the host cell, the virus modulates transcriptional regulation, mRNA processing, intracellular protein transport, and the cytoskeleton to maintain viral reproduction.

Pathway 1. HIV entrance to the host cell and viral reproduction (Fig. 1).

Fig. 1 Pathway 1: HIV entrance to the host cell and viral reproduction.

In the acute stage o...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Foreword: The future of medical discovery
• Preface
• Guide and legend
• I: Introduction
• II: Human disease pathways
• III: Pathway analysis perspectives/advantages
• Glossary and index
• Links
• Index