Infectious Diseases PDF

# Techniques for Identifying Infectious Agents | Technique | Infectious Agent(s) | | :-------------------------------------------- | :-------------------------------------------------------------- | | Gram stain...

# Techniques for Identifying Infectious Agents | Technique | Infectious Agent(s) | | :-------------------------------------------- | :-------------------------------------------------------------- | | Gram stain | Most bacteria | | Wet Mount/Calcofluor-white/Fungi-fluor | Fungi | | Acid-fast stain | Mycobacteria, nocardiae (modified) | | Silver stain | Fungi, legionellae, Pneumocystis | | Periodic acid-Schiff stain | Fungi, amebae | | Mucicarmine stain | Cryptococci | | Giemsa stain | Leishmaniae, Plasmodium | | Antibodies | All classes | | Culture | All classes | | DNA probes and polymerase chain reaction | All classes | | Proteomic methods/mass spectrometry | Bacteria, mycobacteria, fungi | ## How Microorganisms Cause Disease Infectious agents establish infection and damage tissues by any of **three mechanisms**: - They can contact or enter host cells and directly cause death of infected cells. - They can release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis. - They can induce host immune responses that, although directed against the invader, cause additional tissue damage. Thus, the defensive responses of the host can be a mixed blessing, helping to overcome the infection but also contributing to tissue damage. ## 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, or deliver toxins. ## Injurious Effects of Host Immune Responses - **Granulomatous inflammation.** Infection with *M. tuberculosis* results in a delayed hypersensitivity response and the formation of granulomas, which sequester the bacilli and prevent its spread, **but** also produce tissue damage (caseous necrosis) and fibrosis. - **T-cell-mediated inflammation.** Damage from HBV and HCV infection of hepatocytes is due mainly to the immune response to the infected liver cells and **not** to cytopathic effects of the virus. - **Innate immune inflammation.** Pathogen and damaged host cells, activating the immune system and leading to inflammation - **Humoral immunity.** Poststreptococcal glomerulonephritis can develop after infection with *S. pyogenes*. It is caused by antibodies that bind to streptococcal **antigens** and form **immune complexes**, which deposit in renal glomeruli and produce nephritis. - **Chronic inflammatory diseases.** In inflammatory bowel disease an important early event may be compromise of the intestinal epithelial barrier, the entry of both **pathogenic and commensal microbes** and their interactions with local immune cells, resulting in inflammation. The cycle of inflammation and epithelial injury may be an important component of the disease, with microbes playing the central role. - **Cancer.** Viruses HBV, HCV, and bacteria, such as *H. pylori* are associated with cancers, presumably because these microbes trigger chronic inflammation with subsequent tissue regeneration, which provides fertile ground for the development of cancer ## Immune Evasion by Microbes After bypassing host tissue barriers, infectious microorganisms must also evade host innate and adaptive immunity mechanisms to successfully proliferate and be transmitted to the next host. **Strategies include the following:** - Anti-genic variation - Inactivating antibodies or complement - Resisting phagocytosis (e.g., by producing a capsule) - Escaping the phagosome - Viral latency - Suppressing the host adaptive immune response (e.g., by inhibiting antigen presentation and disrupting interferon pathways) ### Antigenic variation. Neutralizing antibodies against microbial antigens **block** the ability of microbes to infect cells and recruit immune cells to **kill** pathogens. To escape recognition, microbes use many strategies that involve genetic mechanisms for generating antigenic variation. **Mechanisms of Anti-genic Variation** | Mechanism | Agent(s) | Example | Disease | | :--------------------------------------- | :------------------------- | :--------------------------- | :-------- | | High mutation rate | HIV | AIDS | | | Genetic reassortment | Influenza virus | Influenza | | | Genetic rearrangement | Influenza virus | Influenza | | | (e.g.. gene recombination, gene | Rotavirus | Diarrhea | | | conversion, site-specific inversion) | | | | | | *Borrelia burgdorferi* | Lyme disease | | | | *Neisseria gonorrhoeae* | Gonorrhea | | | | *Trypanosoma spp.* | African sleeping sickness | | | Large diversity of serotypes | *Plasmodium spp.* | Malaria | | | | *Rhinoviruses* | Colds | | | | *Streptococcus pneumoniae* | Pneumonia, meningitis | | ### Modification of surface proteins. Host cationic antimicrobial peptides, including defensins, cathelicidins, and thrombocidins, provide important initial defenses against invading microbes. These peptides bind the bacterial membrane and form pores, killing the bacterium by osmotic lysis. Bacterial pathogens (*Shigella spp.*, *S. aureus*) avoid killing by making surface molecules that resist binding of anti-microbial peptides, or that inactivate or downregulate anti-microbial peptides. ### Overcoming antibodies and complement. Host defense includes coating of bacteria with antibodies or the complement protein C3b (psonization) to facilitate phagocytosis by macrophages. However, *M. tuberculosis* subverts the complement response by activating the alternative complement pathway in the extracellular environment, and complement products coat the bacteria, resulting in uptake of the organism by monocytes; by this means, the organism reaches its site of replication. - Many bacteria (such as *Shigella*, enteroinvasive *E. coli*, *M. tuberculosis*, *M. leprae*) use the inside of cells as a “hideout" that allows them to escape from antibodies and complement ### Resisting phagocytosis and bacterial killing in phagosomes. 1- Phagocytosis and killing of bacteria by neutrophils and macrophages constitute a critical host defense against extracellular bacteria. The carbohydrate capsule on the surface of many bacteria that cause pneumonia or meningitis makes them more virulent by **preventing** phagocytosis of the organisms by neutrophils. 2- Macrophages usually kill bacteria by fusion of the phagosome with the lysosome to form a phagolysosome. *M. tuberculosis* blocks fusion of the lysosome with the phagosome, allowing the bacteria to **proliferate unchecked** within the macrophage. 3- *Legionella* produces a pore-forming protein called listeriolysin O and two phospholipases that degrade the phagosome membrane, allowing the bacteria to escape into the cytoplasm and avoid destruction in the macrophage ### Escaping the inflammasome. The activation of inflammasome is one pathway of innate immune responses to microbes. It is stimulated by microbial products and the activation of caspases, which induce the secretion of the pro-inflammatory cytokines IL-1 and IL-18 and induce a form of cell death called pyroptosis. Both inflammation and cell death limit microbial virulence and replication. *Yersinia* and *Salmonella*, express virulence proteins that **inhibit** the formation of the mature inflammasome, suppress caspase activation, block signaling pathways that are required for inflammasome activation. ### Disruption of interferon pathways. Interferons (IFNs), which are mediators of early antiviral defense. Some viruses produce soluble homologues of IFN receptors that bind to and block the actions of secreted IFNs, or produce proteins that **inhibit** intracellular JAK/STAT signaling downstream of IFN receptors. ### Decreased T-cell recognition: DNA viruses (e.g., HSV, CMV, and EBV) can bind to or alter the localization of major histocompatibility complex (MHC) class I proteins, impairing peptide presentation to CD8+ cytotoxic T cells. Viruses also can infect leukocytes to directly compromise their function (e.g., HIV infects CD4+ T cells, macrophages, and dendritic cells). **Mechanisms used by viral and bacterial pathogens to evade innate and adaptive immunity.** - Modulation of surface structure to avoid recognition (e.g., antigenic variability) - Inhibition of phagosome-lysosome fusion - Inhibition of phagocytosis - Escape from phagosome - Modulate: Signal transduction, Gene expression, Cell death - Inhibition of antigen presentation - Hide from immune surveillance: viral latency - Viral cytokines or soluble receptor homologues ## Patterns of Host Responses to Microbes - **Neutrophil-rich acute suppurative inflammation** is typical of infections with 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 infection with *M. tuberculosis* and certain fungi. - **Cytopathic and proliferative lesions** are caused by some viruses. - **Necrosis** results from tissue-damaging toxins produced by microbes such as *C. perfringens*. - **Chronic inflammation and scarring** represent the final common pathway of many infections. ## Tuberculosis Chronic granulomatous disease that affects the lung, intestine, kidney, bones, and other organs, caused by the following species of mycobacteria: - **Mycobacterium Tuberculosis**: Aerobic, alcohol acid-fast bacilli (AAFB), stains by Zeil Nelson method (ZN), cultured in Lewenstein Jenson media (L.J media). - **Mycobacteria Bovis**: Encountered from cow's milk causes abdominal tuberculosis. - **Atypical Mycobacteria**: Causes opportunistic disease in immune-compromised individuals and includes, *M. avium, M. Intracellular, M. scrafulatum, M. kansassi.* ### Primary Tuberculosis Primary tuberculosis occurs in persons who are exposed to the bacillus for the first time, i.e. non-immunized. In the lung primary complex is formed, which is composed of primary lesion and enlarged hilar lymph nodes. - **Primary Lesion (Gohn's Focus)**: It is a subplueritic lesion of 1-2cm diameter in the midzone of the lung. Microscopically it shows central caseation and granuloma. - **Hilar Lymphadenopathy**: The bacillus reaches the draining lymph node where extensive reaction takes place causing enlargement of lymph node and caseation, the lesion here is larger than that in the primary lesion. **Primary lesions granulomas** - A diagram showing a primary lesion containing lymphocytes, plasma cells, epitheliod macrophages, fibroblasts, giant cells, and a central necrosis. - A diagram showing a subpleural lesion and the hilar lymph node. ### Secondary (Post-Primary) TB This occurs because of a re-infection, a reactivation of dormant disease, or direct progression of primary TB to disseminated disease. Granulomas of secondary TB are found most often in the lung apices, kidneys, meninges, marrow and other organs. Granulomas fail to get rid of mycobacterial infection are the major cause of tissue damage in secondary TB. Cavities are a common feature of secondary TB, and necrotic lesions may rupture into vessels or airways spreading mycobacteria throughout the body or releasing them in airspaces. | | Primary T.B | Secondary T.B | | :------------ | :-------------------------------------------- | :------------------------------------------------ | | Occurs in | (childhood) | (adulthood) | | | 1st time infection | 2nd time infection | | | Non immunized persons | In a patient had lry infection or B.C.G vaccine | | Methods of | exogenous by | | | infection: | | | | | - Inhalation | - Endogenous due to reactivation. | | | - Ingestion | - Exogenous due to reinfection. | | | - Direct contact | | | Site of 1ry | Lung, Intestine, Tonsils, Skin, Nose | Any site, but mainly lung & intestine | | complex: | | | | Reaction of | Reaction of the body against bacilli | Reaction of the body against bacilli | | the body | Primary complex | Tubercles in solid organs. | | against bacilli | | | ## Syphilis A chronic infective granuloma caused by spirochete microorganisms (*treponema pallidum*) **Transmitted mainly by:** 1. Direct sexual intercourse 2. Non-venereal type by touching the syphilitic lesion. 3. Blood transfusion 4. Transplacental transmission from infected mother to her fetus **The disease has three stages: primary, secondary, and tertiary** | Stage of syphilis | Primary | Secondary | Tertiary | | :--------------- | :------------------------------- | :------------------------------------- | :----------------------------- | | Duration | Two weeks from infection | Two months from 1ry | 2-10 years from 2ry | | Name of the | Chancre formation | Condyloma lata | Gumma formation | | lesion | | | | | Affected organs | Skin and mucous membranes | All organs | CVS, CNS...gummas in all organs |