General Pathology Infectious Diseases 2024-2025 PDF

Lecture 9 part II General Pathology Dr. Ali Alkhafaji Pathology of Infectious Diseases 2024-2025 How Microorganisms Cause Disease o They can contact or enter host cells and directly ca...

Lecture 9 part II General Pathology Dr. Ali Alkhafaji Pathology of Infectious Diseases 2024-2025 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 Mononuclear and Granulomatous Inflammation Diffuse Predominantly mononuclear Interstitial infiltrates are a common feature of all chronic inflammatory processes, but development of such changes as an acute process often constitutes a response to viruses, intracellular bacteria, or intracellular parasites. Morphology mononuclear cell predominates within the inflammatory lesion Lymphocytes predominate in HBV infection, whereas plasma cells are common in the primary and secondary lesions of syphilis. Granulomatous inflammation Mononuclear inflammation usually evoked by infectious agents that resist eradication (M. Tuberculosis) is capable of stimulating strong T cell- mediated immunity. Granulomatous inflammation is characterized by accumulation of activated macrophages called " epithelioid" cells, which may fuse to form giant cells. In some cases, there is a central area of caseous necrosis. Cytopathic- Cytoproliferative Reaction Cytopathic- Cytoproliferative Reactions usually are produced by viruses. The lesions are characterized by cell necrosis or cellular proliferation, usually with sparse inflammatory cells. Morphology Some viruses replicate within cells and make viral aggregates that are visible as inclusion bodies (e.g., herpesviruses or adenovirus) or induce cells to fuse and form multinucleated cells called polykaryons (e.g., measles virus or herpesviruses). Focal cell damage in the skin may cause epithelial cells to become detached, forming blisters. Some viruses can cause epithelial cells to proliferate (e.g., venereal warts caused by HPV). Finally, viruses can contribute to the development of malignant neoplasms. Tissue Necrosis Some organisms that secrete powerful toxins can cause such rapid and severe necrosis (gangrenous necrosis) that tissue damage is the dominant feature. Because few inflammatory cells are present, necrotic lesions resemble infarcts with disruption or loss of basophilic nuclear staining and preservation of cellular outlines. Viruses can cause widespread necrosis of host cells associated with inflammation, as exemplified by destruction of the temporal lobes of the brain by HSV or the liver by HBV. Chronic Inflammation and Scarring Many infections elicit chronic inflammation, which can either resolve with complete healing or lead to extensive scarring. Morphology M. tuberculosis causes constrictive fibrous pericarditis. Chronic HBV infection may cause cirrhosis of liver in which dense fibrous septa surround nodules of regenerating hepatocytes. 5 Actinomycosis: it is a localized but gradually spreading chronic suppurative disease affecting particularly the lower jaw. The causative organism is Actinomyces israelii, wide spread in nature gram positive, branching filamentous anaerobes found as normal commensals in mouth, gut and female genital tract. The disease most commonly affects young adult males. Sites of infection of Actinomycosis 1- In the mouth --- the microorganism gain an entrance following tooth extraction, carious tooth or after maxillofacial injury. 2- In abdominal actinomycosis--- in ileocaecal region. 3- Pulmonary actinomycosis. 4- pelvic actinomycosis---- involve fallopian tubes and ovaries and its strongly associated with presence of intra- uterine contraceptive devices. Microscopically: chronic suppuration with multiple abscess formation, each containing one or more colonies of the organism the so called honeycomb abscess. Fibrous septa between abscesses are lined by granulation tissue which contains foamy cells (lipid-laden macrophages). In the centre is the pus containing actinomyces colonies, which are sometimes visible by naked eye as small yellow or grey, gritty granules (sulphur granules). Bacterial infection of blood The presence of bacteria in blood is classified into bacteraemia septicaemia pyaemia. Bacteraemia: Indicates the presence of low virulence bacteria in the blood in small numbers in normal subjects, or in individuals with minor, subclinical lesions but they do not multiply. Streptococcus viridians may be cultured from the blood after vigorous tooth brushing. The importance of bacteraemia is that, whenever, bacteria enter the blood, they may settle in various parts of the body & cause lesions Septicaemia : Means the presence & multiplication of bacteria in the blood, especially the rapid multiplication of highly pathogenic bacteria, the term thus implies a serious infection with profound toxaemia, in which the bacteria have overwhelmed the host defenses. If the septicaemia is not rapidly fatal, foci of suppuration may develop in various parts of the body as a result of haematogenous spread. 6 Pyaemia: literally means pus in the blood. A localized pyogenic infection is mainly the cause, when toxic injury to the endothelium of the veins involved in the lesion results in thrombosis, & the bacteria multiply in the thrombus & becomes heavily infiltrated by polymorphs that broken by their digestive enzymes, then fragments of these septic thrombi may be carried off in the blood causing pyaemia. Pyogenic bacterial infection (suppuration) It is an important variant of acute bacterial inflammation. It shows the usual course of acute inflammation with special features.Pyogenic Bacteria: It is applied to the bacteria which causes suppuration. The common pyogenic bacteria are Staphylococcus aureus and Streptococcus pyogens. Abscess: It is a cavity formed which contains polymorphs rich (purulent) exudates or pus in some bacterial infections (emigration of polymorphs is intense). Suppuration: is the process of abscess formation. Composition of pus 1- Inflammatory exudates containing very large numbers of neutrophil polymorphs which gives it an opaque appearance (recent pus- living neutrophils, old pus- mostly they are dead, degenerated and digested). Release of DNA from these cells accounts for the sticky nature of pus. 2- Some red cells especially in newly formed pus. 3- Fragments of tissue debris. 4- Fibrin. 5- Old pus contains an increased number of macrophages as well as cholesterol crystals and globules of fat. The pathogenesis process of abscess formation (suppuration) As the pyogenic bacterial infection progresses, local bacterial spread results in enlargement of the lesion, and unless the bacteria are destroyed rapidly, the tissue in the center undergoes necrosis due to : 1- High concentrations of powerful toxins produced by pyogenic bacteria. 2- The pressure of inflammatory edema slows the blood flow. 3- Sometimes thrombosis due to endothelial injury. Subsequently the central dead cells and tissue frame work will be digested by lysosomal enzymes released from phagocytic polymorphs infiltrated from the surrounding inflamed tissue; gradually a space or abscess cavity containing fluid is formed. Gradually an abscess may become enclosed in a layer of granulation tissue (the pyogenic membrane), and its outer layer matures to a fibrous tissue. 7 Ebola virus Ebola virus is an RNA virus belonging to filovirus, it cause a hemorrhagic disease with high mortality rate in human in several regions of Africa. Infections with Ebola virus either (Zaire strain) and (Sudan strain) have cause an Ebola Hemorrhagic Fever which is a fetal African Disease. Recent field evidence has implicated several species of fruit bats as the natural reservoir of Ebola virus. Morphology The virus undergoes massive replication in endothelial cells, mononuclear phagocytes and hepatocytes. Necrosis is most severe in the liver, spleen, kidney and lymph node. The lungs are hemorrhagic and petechial hemorrhagic are present in skin , mucous membrane and internal organs. Special Techniques for Identifying Infectious Agents Some infectious agents can be seen in hematoxylin and eosin (H&E)- stained sections (e.g., the inclusion bodies formed by CMV and herpes simplex virus (HSV); bacterial clumps, which usually stain blue; Candida and Mucor among the fungi). special stains (Gram, acid-fast silver, mucicarmine, and Giemsa stains) or after labeling with specific antibodies. Acute infections can be diagnosed serologically by detecting pathogen- specific antibodies in the serum. The presence of specific immunoglobulin M (IgM) antibody shortly after the onset of symptoms is often diagnostic. Nucleic acid- based tests, collectively called molecular diagnostics, are used routinely to detect pathogens. Nucleic acid amplification techniques, such as polymerase chain reaction (PCR) and transcription mediated amplification, are used for diagnosis of gonorrhea, chlamydial infection, tuberculosis, and herpes encephalitis. Molecular assays are much more sensitive than conventional testing for some pathogens. PCR testing of cerebrospinal fluid (CSF) for HSV encephalitis has a sensitivity of about 80%, whereas viral culture of CSF has a sensitivity of less than 10%. Similarly, nucleic acid tests for genital Chlamydia detect 10% to 30% more infections than does conventional Chlamydia culture. For other infections, such as gonorrhea, the sensitivity of nucleic acid testing is similar to that of culture. Quantitative nucleic acid amplification tests are used to guide the medical management of infections with human immunodeficiency virus (HIV), HBV and hepatitis C virus (HCV). 8 Special Techniques for Identifying Infectious Agents Gram stain Most bacteria Acid-fast stain Mycobacteria, nocardiae(modified) Silver stains Fungi Periodic acid-Schiff Fungi, amebae Mucicarmine Cryptococci Giemsa Leishmaniae.Plasmodium Antibodies All classes Culture All classes DNA probes All classes 9