Infectious Diseases PDF

IN THE NAME OF GOD DR LADAN FATAHI CLINICAL AND ANATOMICAL PATHOLOGIST AJUMS 1400-1401 Immune Evasion by Microbes After bypassing host tissue barriers, infectious microorganisms must also evade host innate and adaptive immunity to successfully proliferate and be transmitted to the next host. * St...

IN THE NAME OF GOD DR LADAN FATAHI CLINICAL AND ANATOMICAL PATHOLOGIST AJUMS 1400-1401 Immune Evasion by Microbes After bypassing host tissue barriers, infectious microorganisms must also evade host innate and adaptive immunity to successfully proliferate and be transmitted to the next host. * Strategies include: ---Remaining inaccessible to host defenses, either in areas not reachable by antibodies or mononuclear cells (e.g., GI tract lumen or epidermis), inside cells, cyst, rapid, or enshrouded within host proteins. ---Constantly changing antigenic repertoires ---Inactivating antibodies or complement, resisting phagocytosis, or growing within phagocytes after ingestion (Innate immune resistance) ---Suppressing the host adaptive immune response, e.g. by inhibiting MHC expression and antigen presentation to T cytotoxic.  HOW MICROORGANISMS CAUSE DISEASE High virulence connotes the capacity to cause disease in an otherwise healthy population; Low virulence implies that the agent causes disease only in particularly susceptible populations (for example, certain bacterial strains can only infect previously damaged heart valves). Opportunistic infections are those in which normally nonpathogenic organisms produce disease in an immunocompromised host. Location in the body is also important in whether a pathogen causes disease. Thus, E. coli organisms in the colon are completely normal, whereas E. coli infecting the lungs is a cause of pneumonia, and E. coli infecting the urinary bladder causes cystitis.  Mechanisms of Viral Injury Viruses can directly damage host cells by entering them and replicating at the host's expense. The predilection to infect certain cells and not others is called tissue tropism and is determined by several factors: --Host-cell receptors for a particular virus --Cell type-specific transcription factors that recognize viral enhancer and promoter sequences --Physical barriers  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. * For example, HIV glycoprotein gp120 binds to CD4 on T cells and to the chemokine receptors CXCR4 (mainly on T cells) and CCR5 (mainly on macrophages).///// 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. *For example, the JC virus, which causes leukoencephalopathy, replicates specifically in oligodendroglia in the CNS, because the promoter and enhancer DNA sequences regulating viral gene expression are active in glial cells but not in neurons or endothelial cells.  Physical circumstances, such as chemicals and temperature, contribute to tissue tropism. *For example, ///Enteroviruses replicate in the intestine in part because they can resist inactivation by acids, bile, and digestive enzymes. ///Rhinoviruses infect cells only within the upper respiratory tract because they replicate optimally at the lower temperatures characteristic of this site. Once viruses are inside host cells, they can injure or kill host cells in several ways: --Lysis of host cells --Immune cell-mediated killing --Alteration of apoptosis pathways --Induction of cell proliferation and transformation --Inhibition of host cell DNA, RNA, or protein synthesis --Damage to plasma membranes --Damage to cells involved in antimicrobial defense  Direct cytopathic effects. Viruses can kill cells by preventing synthesis of critical host macromolecules, by producing degradative enzymes and toxic proteins, or by inducing apoptosis. Antiviral immune responses. Viral proteins on the surface of host cells may be recognized by the immune system, and lymphocytes may attack virus-infected cells. Cytotoxic T lymphocytes (CTLs) are important for defense against viral infections, but CTLs also can be responsible for tissue injury. *Acute liver failure during hepatitis B infection may be accelerated by CTL-mediated destruction of infected hepatocytes (a normal response to clear the infection).  Transformation of infected cells into benign or malignant tumor cells. ///Different oncogenic viruses can stimulate cell growth and survival by a variety of mechanisms, including expression of virus-encoded oncogenes, antiapoptotic strategies, and insertional mutagenesis (in which the insertion of viral DNA into the host genome alters the expression of nearby host genes).  Mechanisms of Bacterial Injury The ability of bacteria to cause disease (virulence) depends on their ability to (1) adhere to host cells (pili”fimbria”//////////fibrilla ) (2) invade cells and tissues (3) deliver toxins that damage cells and tissues Strep. Ecoli pyogen  Bacterial Adherence to Host Cells Adhesins are bacterial surface molecules that bind to host cells Fibrilla cover the surface of gram-positive bacteria: Streptococcus pyogen Fimbria (or pili) are filamentous proteins on Gram-negative bacteria: Ecoli, N. genorrhea Virulence of Intracellular Bacteria Facultative intracellular bacteria infect epithelial cells (Shigella and enteroinvasive E. coli), macrophages (M. tuberculosis, Mycobacterium leprae), or both (S. typhi). The virulence factors of intracellular bacteria concern their ability to (1) bind and enter cells, and (2) survive within them.  Bacterial Endotoxin Bacterial endotoxin is a lipopolysaccharide (LPS) that is a major component of the outer cell wall of gram-negative bacteria. LPS is composed of a long-chain fatty acid anchor (lipid A) connected to a core sugar chain. (All gram-negative bacteria.) Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a specific receptor (CD14) on monocytes, macrophages, and neutrophils. Engagement of CD14 results in intracellular signaling via an associated Toll-like receptor (TLR-4), causing cell activation and production of effector cytokines. TLR-4 engagement on endothelial cells also causes endothelial activation and a net prothrombotic state. **Host response to LPS: * Low LPS concetration: cytokines >> Activation T lymphocytes * High LPS concentration: cytokines TNF, IL1, IL12 >> Septic shock, DIC, ARDS.  Bacterial Exotoxins Exotoxins are secreted proteins that directly cause cellular injury and frequently underlie disease manifestations. ** Some exotoxins are bacterial enzymes (proteases, hyaluronidases, coagulases, fibrinolysins) ** Many exotoxins alter intracellular signaling or regulatory pathways. Neurotoxins, such as those produced by Clostridium botulinum and Clostridium tetani, inhibit release of neurotransmitters, resulting in paralysis. Patterns of Inflammatory Responses to Infection In normal individuals, the patterns of host responses are fairly stereotyped for different classes of microbes Neutrophil-rich acute suppurative inflammation is typical of many bacteria ("pyogenic" bacteria) and some fungi. Mononuclear cell infiltrates are common in many chronic infections and some acute viral infections. Granulomatous inflammation is the hallmark of Mycobacterium tuberculosis and certain fungi. Cytopathic and proliferative lesions are caused by some viruses. Suppurative Inflammation This pattern is the reaction to acute tissue damage, characterized by increased vascular permeability and leukocytic exudates, predominantly neutrophils. Collections of neutrophils may 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." Typically, these are extracellular bacteria. The sizes of such lesions can vary : * from tiny microabscesses formed by bacteria seeding from an infected heart valve, * to distended, pus-filled fallopian tubes caused by N. gonorrhoeae, * to diffuse involvement of the meninges during H. influenzae infection, * to entire lobes of the lung during pneumonia. The extent to which the lesions are destructive depends on their location and the organism involved. * 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. * Bacterial pharyngitis resolves without sequela. * Untreated acute bacterial infection can destroy a joint in a few days.  Mononuclear and Granulomatous Inflammation Diffuse mononuclear interstitial infiltrates are a common feature of all chronic inflammatory processes. Which mononuclear cell predominates within the inflammatory lesion depends on the host immune response to the organism. * lymphocytes predominate in HBV infection, * plasma cells are common in the primary and secondary lesions of syphilis. Granulomatous inflammation is a distinctive form of mononuclear inflammation usually evoked by infectious agents that resist eradication (e.g., M. tuberculosis, Histoplasma capsulatum, schistosome eggs) 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 Response These reactions are usually produced by viruses and are characterized by sparse inflammation and either cell death (cytopathic response) or proliferation (cytoproliferative response).  Some viruses replicate within cells and make viral aggregates that are visible as inclusion bodies (e.g., CMV, HSV, HBV)  induce cells to fuse and form polykaryons (e.g., measles, herpesviruses).  Focal cell damage may cause epithelial cells to become discohesive and form blisters (e.g., varicella-zoster virus).  Viruses can also cause epithelial cells to proliferate and take unusual forms (e.g., venereal warts caused by HPV or the umbilicated papules of molluscum contagiosum caused by poxviruses).  Viruses can cause dysplastic changes and cancers in epithelial cells and lymphocytes  Necrotizing Response  Some organisms produce potent toxins that cause such rapid and severe necrosis that tissue damage is the dominant feature (e.g., C. perfringens).  E. histolytica can cause colonic ulcers and liver abscesses with extensive tissue destruction and liquefactive necrosis without a prominent inflammatory infiltrate.  By entirely different mechanisms, 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. Infections in People with Immunodeficiencies  Inherited or acquired defects in immunity often impair only part of the immune system, rendering the affected persons susceptible to specific types of infections. * Patients with antibody deficiency, as in X-linked agammaglobulinemia, : severe bacterial infections by extacellular bacteria and a few viral infections (rotavirus and enteroviruses). * Patients with T cell defects are susceptible to infections with intracellular pathogens, notably viruses and some parasites.  Patients with: * deficiencies in early complement components are particularly susceptible to infections by encapsulated bacteria, such as S. pneumonia. * deficiencies of the late components of complement are associated with Neisseria infections. *Deficiencies in neutrophil function lead to increased infections with S. aureus, some gram-negative bacteria, and fungi.  Acquired immunodeficiencies have a variety of causes, the most important being infection with HIV, which causes AIDS. HIV infects and kills CD4+ helper T lymphocytes, leading to profound immunosuppression and a multitude of infections.  Other causes of acquired immunodeficiency include infiltrative processes that suppress bone marrow function (e.g., leukemia), immunosuppressive drugs (such as those used to treat certain autoimmune diseases), and hemopoietic stem cell transplantation. Diseases of organ systems other than the immune system also can make patients susceptible to disease due to specific microorganisms. * People with cystic fibrosis commonly get respiratory infections caused by P. aeruginosa. *Lack of splenic function in persons with sickle cell disease makes them susceptible to infection with encapsulated bacteria such as S. pneumoniae. *Burns destroy skin, removing this barrier to microbes, allowing infection with pathogens such as P. aeruginosa. * Malnutrition impairs immune defenses TECHNIQUES FOR DIAGNOSING INFECTIOUS AGENTS  The histopathology of various infections provides an important clue as to etiology.  Some infectious agents can be directly identified in H&E-stained sections (e.g., CMV or herpesvirus inclusion bodies; bacterial clumps, which usually stain blue; Candida and Mucor among the fungi; most protozoans; and all helminths).  many infectious agents are best visualized by special stains that identify organisms on the basis of their cell wall or cell coat characteristics, including Gram, acid- fast, silver, mucicarmine, and Giemsa stains;  Microorganisms can also be identified after labeling with specific antibody probes.  Regardless of the staining technique, organisms are usually best visualized at the advancing edge of a lesion rather than at its center, particularly if there is necrosis. THANKS FOR YOUR ATTENTION