Lecture 9 Part II General Pathology

Lecture 9 part II General Pathology 2024-2025 Pathology of Infectious Diseases How Microorganisms Cause Disease o They can contact or enter host cells and directly cause cell death. o They may release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis. o They can induce host immune responses that, although directed against the invader, cause additional tissue damage. Mechanisms of Viral Injury ➢ A major determinant of tissue tropism; is the presence of viral receptors on host cells. Viruses possess specific cell surface proteins that bind to particular host cell surface proteins. Many viruses use normal cellular receptors of the host to enter cells. In some cases, host proteases are needed to enable binding of virus to host cells; for instance, a host protease cleaves and activates the influenza virus hemagglutinin. ➢ The ability of the virus to replicate inside some cells but not in others depends on the presence of cell type-specific transcription factors that recognize viral enhancer and promoter elements. ➢ Physical circumstances, such as chemicals and temperature, contribute to tissue tropism. As enteroviruses replicate in the intestine in part because they can resist inactivation by acid, bile and digestive enzymes Rhinoviruses infect cells only within the upper respiratory tract because they replicate optimally at the lower Temp. Mechanisms of Bacterial Injury Bacterial damage to host tissues depends on the ability of the bacteria to; • Adhere to host cells • Invade cells and tissues • Deliver toxins. • Bacterial Virulence Pathogenic bacteria have virulence genes that encode proteins conferring these properties. Virulence genes frequently are found grouped together in clusters called pathogenicity islands. A small number of virulence genes can determine whether a bacterium is harmful. Bacterial Adherence to Host Cells by: Adhesins that Bind to host cells or extracellular matrix or by filamentous proteins called pili on their surfaces Example: E. coli that cause urinary tract infections uniquely express a specific pilus expressed on uroepithelial cells. Pili on N. gonorrhea bacteria mediate adherence of the bacteria to host cells and also are targets of the host antibody response. (Escape from immunity) Virulence of Intracellular Bacteria 1 The growth of bacteria in cells (intracellular) may allow them to escape from certain immune effectors' mechanisms, such as antibodies and complement, or may facilitate spread of the bacteria in the body, as when macrophages carry M. tuberculosis from the lung to other sites. How mechanisms for entering host cells: Some bacteria use the host immune response to enter macrophages. Coating of bacteria with antibodies or the complement protein C3b (opsonization) elicits phagocytosis of bacteria by macrophages Like many bacteria, M. tuberculosis (activates the alternative complement pathway). Some gram- negative bacteria use a type III secretion system to enter epithelial cells.(needle-like structures ) projecting from the bacterial surface that bind and form pores in the host cell membrane through which proteins are injected that mediate rearrangement of the cell cytoskeleton and facilitate bacterial entry. Intracellular bacteria have different strategies for interacting with the host cell. (Replicate rapidly, and lyse the host cell within hours.) eg. Shigella and E. coli inhibit host protein synthesis, Although most bacteria in macrophages are killed when the phagosome fuses with the acidic lysosome to form a phagolysosome, certain bacteria elude this host defense. As M. tuberculosis blocks fusion of the lysosome with the phagosome, allowing the bacteria to proliferate unchecked within the macrophage.Other bacteria avoid destruction in macrophages by escaping from the phagosome. Bacterial Toxins • Endotoxins (part of cells ) • Exotoxins Bacterial endotoxin is a lipopolysaccharide (LPS) that is a component of the outer membrane of gram-negative bacteria. LPS activates protective immunity in several ways ( cytokines and chemokines) of the immune system which enhance T lymphocyte activation.However, high levels of LPS play an important role in ✓ ✓ ✓ ✓ septic shock, disseminated intravascular coagulation (DIC) acute respiratory distress syndrome, mainly through induction of excessive levels of cytokines such as TNF. Exotoxins Are secreted proteins that cause cellular injury and disease? Classified according to their mechanism and site of action into: Enzymes. ( proteases, hyaluronidases, coagulases, fibrinolysins). Toxins are altering intracellular signaling or regulatory pathways. Most of these toxins have an active (A) component with enzymatic activity and a binding (B) component that binds cell surface receptors and delivers the A protein into the cell cytoplasm. A-B toxins are made by many bacteria including Bacillus anthracis, V. cholerae, and Corynebacterium diphtheriae. 2 Superantigens Stimulate very large numbers of T lymphocytes leading to massive T lymphocyte proliferation and cytokine release. The high levels of cytokines lead to capillary leak and consequent shock. Superantigens made by S. aureus and S. pyogenes cause toxic shock syndrome (TSS). Neurotoxins ( Clostridium botulinum and Clostridium tetani) inhibit release of neurotransmitters, resulting in paralysis. (Respiratory failure) Enterotoxins affect the gastrointestinal tract in different ways to cause varied effects, including nausea and vomiting (S. aureus), voluminous watery diarrhea (V. chol erae), or bloody diarrhea (C. difficile). Immune Evasion by Microbes How are the means to resist and evade the immune system. Which important determinants of microbial virulence and pathogenicity, include: (1) Antigenic variation (2) Resistance to innate immune defenses (3) Impairment of effective T cell antimicrobial responses by specific or nonspecific immunosuppression. (1) Antigenic variation: Some microbes can evade immune responses by varying the antigens they express. Neutralizing antibodies, block the ability of microbes to infect cells and recruit effector mechanisms to kill pathogens. To escape recognition, microbes use many strategies that involve genetic mechanisms for generating antigenic variation. The low integrity of viral RNA polymerases (in HIV and many respiratory viruses including influenza virus) and reassortment of viral genomes (influenza viruses) create viral antigenic variation. (2) Resistance to innate immune defenses: Some microbes have devised methods for actively resisting immune defenses: Cationic antimicrobial peptides, including defensing, cathelicidins, and thrombocidins, provide important initial defenses against invading microbes. These peptides bind the bacterial membrane and form pores, killing the bacterium by hypoosmotic lysis. Bacterial pathogens (Shigella spp., aureus) avoid killing by making surface molecules that resist binding of antimicrobial peptides or that inactivate or down regulate antimicrobial peptides by various mechanisms. Phagocytosis and killing of bacteria by polymorphonuclear leukocytes or neutrophils (PMNs) and monocytes constitute a critical host defense against extracellular bacteria. The carbohydrate capsule on the surface of many bacteria that cause pneumonia or meningitis ( S. pneumonia, N. meningitides, H. influenzae) makes them more virulent by preventing phagocytosis of the organisms by neutrophils. 3 Proteins on the surface of bacteria (S. aureus & S.Pyogenes) inhibit phagocytosis. Viruses can produce molecules that inhibit innate resist interferons (IFNs) produce soluble homologues of IFN- α/β or IFN-ɣ receptors that bind to and inhibit actions of secreted IFNs. Viruses also may inactivate or inhibit double- stranded RNA- dependent protein kinase (PKR), a key mediator of the antiviral effects of IFN. Some viruses encode within their genomes homologues of cytokines, chemokines, or their receptors that act in various ways to inhibit immune responses. viruses have developed strategies to block apoptosis in the host cell, which may give the viruses time to replicate, persist or transform host cells. (3) Some microbes produce factors that decrease recognition of infected cells by CD4+ helper T cells and CD8+ cytotoxic T cells.Several DNA viruses (e.g., herpes viruses, including HSV, CMV, and EBV) can bind to or alter localization of major histocompatibility complex (MHC) class I proteins, impairing peptide presentation to CD8+ cells.Herpes viruses can target MHC class II molecules for degradation, impairing antigen presentation to CD4+ T helper cells. Viruses also can infect leukocytes to directly compromise their function (e.g., HIV infects CD4+ T cells, macrophages, and dendritic cells). Spectrum of Inflammatory Responses to Infection There are five major histologic patterns of tissue reaction in infections: ➢ ➢ ➢ ➢ ➢ Suppurative Mononuclear/ granulomatous Cytopathic- cytoproliferative Necrosis Chronic inflammation / scarring Suppurative (Purulent) Inflammation characterized by increased vascular permeability leukocytic infiltration predominantly of neutrophils.The neutrophils are attracted to the site of infection by release of chemoattractants from the'' pyogenic" bacteria and host cells. Neutrophil enzymes cause liquefactive necrosis. Morphology: Collections of neutrophils give rise to localized liquefactive necrosis, forming abscesses. The necrotic tissue and inflammatory cells constitute pus, and bacteria that evoke pus formation are called "pyogenic". tiny microabscesses ( infected heart valve) distended, pus-filled fallopian tubes caused by N. gonorrhoeae, diffuse involvement of the meninges during H. influenzae infection, entire lobes of the lung during pneumonia. S. pneumoniae usually spares alveolar walls in the lung, and even lobar streptococcal pneumonias typically resolve completely without permanent damage.S. aureus and Klebsiella pneumoniae destroy alveolar walls and form abscesses that heal with scar formation. 4