Chapter 7 Study Notes: Pathogenicity and Virus Mechanisms
Chapter 7: Pathogenicity
Pathogenicity Overview
Pathogenicity: The capacity of one organism to cause disease in another organism.
Complexity: Pathogenicity is a complex and variable property among different organisms.
Definition of Disease: A disease represents a departure from normal physiological parameters.
This can manifest in several ways:
Transient and Minor Conditions: Examples include slightly elevated temperature or feelings of lethargy.
Chronic Pathologic Conditions: These conditions can manifest as severe symptomatology that may ultimately lead to death.
Multi-Factorial Nature: Most disease states are multi-factorial, involving several contributing factors.
Virus Diseases
The course of virus infection represents a balance between host and virus, which indicates the extent and severity of virus pathogenesis.
Symptoms: Most symptoms experienced by the host are attributable to side effects of the immune response rather than direct viral effects.
Symptoms such as inflammation, fever, headaches, and skin rashes are typically not directly caused by viruses.
Mechanism: Cells of the immune system release potent chemicals such as interferons and interleukins that result in collateral damage to host tissues.
Virus Pathogenesis
Abnormal and Rare Situations: Virus pathogenesis can be seen as abnormal and rare since the majority of virus infections do not lead to disease.
Host Survival Argument: It is sometimes posited that viruses would disappear if they killed their hosts, but this is not necessarily true.
Ideal Viral Behavior: Ideally, a virus would evade immune responses or hide to minimize damage.
Key Aspects of Virus Pathogenesis:
Direct Cell Damage: Resulting from virus replication.
Immune Activation or Suppression: Damage that is a consequence of the immune system's response to the viral infection.
Cell Transformation: Changes in the cellular structure or function caused by viruses.
Mechanisms of Cellular Injury
A number of common phenotypic changes are recognized in virus-infected cells, referred to as cytopathic effects (CPE):
Altered shape of infected cells.
Detachment from the substrate.
Cell lysis (destruction).
Membrane fusion leading to syncytia (multinucleated cells).
Changes in membrane permeability.
Formation of inclusion bodies within the cell.
Induction of apoptosis (programmed cell death).
Necrosis vs. Apoptosis
Necrosis:
Characterized by the release of cellular components due to lysis, causing localized inflammatory responses.
Often leads to damage concerning adjacent cells or tissues, termed "bystander cell damage."
Apoptosis:
A tightly regulated process that relies on complex molecular pathways.
It is characterized by:
Cell shrinkage.
Condensation and clumping of chromatin.
A regular pattern of DNA fragmentation.
"Blebbing" of cellular contents into small membrane-bound vesicles that are subsequently engulfed by phagocytic cells, preventing inflammation.
Importance of Apoptosis
Apoptosis, or programmed cell death, plays a vital role in tissue remodeling and in the immune system's ability to eliminate infected cells.
Two primary modes of cell death are recognized:
Necrosis (unregulated cell death).
Apoptosis (regulated cell death).
Apoptotic Mechanisms
Various factors induce apoptosis including:
Fas Ligand (FasL) and Tumor Necrosis Factor (TNF) among other activators.
Activation of initiator and effector caspases which carry out the apoptotic process.
Key Regulators: Proteins such as Bcl-2 influence the outcomes of these pathways, differentiating between survival and cell death.
Mechanisms of Cell-Mediated Immunity
Non-Specific Killing Mechanism: Not restricted by Major Histocompatibility Complex (MHC).
Involves Natural Killer (NK) cells and their response to virus antigens.
Release of perforin, leading to cell destruction.
Specific Killing Mechanism: Restricted by MHC.
Involves Cytotoxic T Lymphocytes (CTLs) that recognize virus-infected cells through T Cell Receptors (TCR).
Induces apoptosis in virus-infected cells via cytotoxic pathways.
Induction of Apoptosis by Immune Cells
Immune effector cells like CTLs and NK cells induce apoptosis by:
Release of cytotoxins like perforin and granzymes.
Expressing Fas ligand on their surface,
The trimerization of Fas receptor (FasR) leads to the Death-Inducing Signaling Complex (DISC).
Comparison of Necrosis and Apoptosis: Apoptosis is favored to avoid inflammation damage associated with necrosis.
Induction and Repression of Apoptosis
Apoptosis is a crucial innate immune response against virus infection.
The regulation of apoptosis can be complex, involving interruptions caused by viral infections.
Triggers may include receptor signaling, protein kinase R (PKR) activation, p53 activation, transcriptional disregulation, or foreign protein expressions from viruses.
Anti-Apoptotic Mechanisms in Viruses
To evade the immune response, viruses have developed mechanisms to repress apoptosis:
Inhibition of pro-apoptotic proteins such as Bcl-2 homologs.
Caspase inhibition, preventing the execution of the apoptosis pathway.
Inhibition of signaling through receptors such as Fas and TNF.
Inhibition of tumor suppressor p53 and other pathways.
Cell Transformation by Viruses
Transformation Definition: Refers to changes in the morphological, biochemical, or growth parameters of a cell, sometimes resulting in tumors.
Not all transformed cells lead to cancer.
Carcinogenesis (Oncogenesis): A complex, multi-step process with cellular transformation being only the initial step.
Phenotypic Changes in Transformed Cells:
Loss of anchorage dependence.
Loss of contact inhibition.
Colony formation in semi-solid media.
Decreased requirements for growth factors.
Characteristics of Viral Cell Transformation
Transformation of a cell by a virus is considered a single-hit process, where a single virus can transform one cell.
The viral genome persists within the transformed cell, usually integrating into the host cell's chromatin.
The replication of viral genomes in transformed cells often leads to limited expression of certain viral genes with infrequent productive infection.
Frequenty, transformation linked to replication-defective virus genomes.
Role of Oncogenes and Tumor Suppressor Genes in Transformation
Transformation is mediated by proteins encoded by oncogenes:
Proto-oncogenes: Such as myc, fos, ras.
Tumor Suppressor Genes: Include p53 and Rb.
DNA Repair Genes: Such as BRCA1 are also involved in maintaining genome integrity.
Types of Oncogenes
Classification of oncogenes based on origin and function including:
Growth factor(s) such as sis.
Growth factor receptors like erbB, fms, kit and others.
Membrane-bound protein kinases and G proteins involved in signal transduction.
Nuclear oncogenes function as transcriptional regulators or cell cycle regulators.
Cell Transformation by Retroviruses
Not all retroviruses have cellular transforming capabilities. For example, HTLV versus HIV.
Retroviruses can be categorized:
Acute Transducing Retroviruses: Can transform cells due to the presence of viral oncogenes (v-oncs).
Cis-activating and Trans-activating Retroviruses: Do not have v-oncs but can still influence cell transformation.
Transformation occurs when oncogenes are activated via mechanisms such as structural changes or disruption of normal regulatory control.
Mechanisms of Transformation by Retroviruses
Acutely Transducing Retroviruses: Contain oncogenes derived from cellular genes and can produce transforming proteins that alter function and cellular localization.
Example: Rous Sarcoma Virus (RSV) possesses v-src oncogene that causes transformation.
These proteins can be products of fusion with viral sequences, leading to abnormal functionality.
Structure of Transforming Retroviruses
Examples of chronic transforming retroviruses include Avian Leukosis Virus (ALV) and their associated oncogenes and structural features.
Discussed various structural genes and RNA processing that leads to an active transforming capability.
Insertional Activation Mechanisms
Not all retroviruses transform cells through transduction; alternative mechanisms include:
Insertional Cis-activation: Where a virus integrates near a cellular oncogene and upregulates it.
Trans-activation: Involves virus-coded factors that upregulate gene expression governing transformation.
Trans-Activating Mechanisms in Human T-cell Leukaemia Virus (HTLV)
HTLV Tax Gene: Acts in trans to stimulate transcription from the virus LTR and interacts with transcription factors activating cellular gene transcription.
Cell transformation can lead to tumor formation; however, this is not simultaneous and requires additional events and chromosomal instability.
Cell Transformation by DNA Viruses
The genes responsible for cell transformation in DNA tumor viruses typically have no cellular equivalents.
Focus on interactions with nuclear proteins affecting cell cycle control, particularly tumor suppressors like p53 and Rb.
Cell Cycle Overview
Overview of cell cycle phases (G1, S, G2, M) with emphasis on G1 phase arrest mediated by p53 and Rb.
p53 Tumor Suppressor Function
p53: Acts as a crucial regulator in cell cycle control and mediates responses to cellular stress including DNA damage.
Form complexes with viral oncoproteins impacting the cell cycle arrest.
Rb Tumor Suppressor Function
Rb (Retinoblastoma protein): Interacts with the transcription factor E2F to inhibit transcription critical for DNA synthesis and progression.
Disruption of Rb function (by viral proteins like E1A) leads to unrestricted cell cycle progression.
SV40 T-Antigen Functions
SV40 Large T-Antigen: Binds directly with both p53 and Rb, thus interfering with their regulatory roles in the cell cycle. This enhances viral DNA replication.
Adenoviral E1A Protein Role
E1A protein: A trans-acting transcriptional regulator that interacts with Rb, facilitating viral replication, while also potentially stimulating host DNA replication.
The combined effects of E1A and E1B manage to promote cell division and evade apoptosis to enhance cell transformation.
Quiz 19 Topics
Discussion on whether a poxvirus would cause cancer and the underlying rationale for the specified answer.