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General Pathology of Infectious Diseases (General Principles of Microbial…

- - - - Prs on surface that inhibit phagocytosis: prs A (S. aureus) + M (S. pyogenes). Many make prs that kill phagocytes, prevent migration, or diminish oxidative burst.
      - carb capsule on many bacteria that cause pneumonia or meningitis (S. pneumoniae, N. meningitidis, H. influenzae) prevent phagocytosis
    - - produce soluble homologues of IFN-α/β or IFN-γ Rs that bind to + inhibit actions of secreted IFNs
      - produce prs that inhibit IC JAK/STAT signaling downstream of IFN Rs.
      - inactivate or inhibit dsRNA–dependent pr kinase (PKR) (key mediator of antiviral effects of IFN
      - encode within their genomes homologues of cytokines, chemokines, or their Rs to inhibit immune responses.
      - developed strategies to block apoptosis in host cell
- - - - mechanisms for entering host cells
        
        Some use host immune response to enter MQs: Coating of bacteria w/ Abs or C3b (opsonization)--> MQ phagocytosi; ex: M. tuberculosis *alternative complement pathway in opsonization w/ C3b-->uptake by host MQs
        
        Some gram(-): type III secretion system to enter epith cells. (needle-like structures projecting from bacterial surface that bind + form pores in host cell membr through which prs injected that mediate rearrangement of cell cytoskeleton + facilitate bacterial entry)
        
        Listeria monocytogenes can manipulate cell cytoskeleton to spread directly from cell to cell, perhaps allowing bacteria to evade immune defenses.
      - interacting w/ host cell
        
        Shigella + E. coli inhibit host pr synth, replicate rapidly, and lyse host cell within hrs.
        
        M. tuberculosis blocks fusion of lysosome + phagosome,
        
        escaping from phagosome: L. monocytogenes produces a pore-forming pr called listeriolysin O + two phospholipases that degrade phagosome membrane, allowing bacteria to escape into cytoplasm
    - - Exotoxins (prs secreted)
        
        • Es. (proteases, hyaluronidases, coagulases, fibrinolysins), but role in disease understood in only few cases. ex: exfoliative toxins are proteases produced by S. aureus that cleave prs that hold keratinocytes together--> epidermis detach from deeper skin.
        
        • Toxins: alter IC signaling / regulatory pathways.
        
        components: (Bacillus anthracis, V. cholerae, C. diphtheriae)
        most have an active (A) component w/ E activity + a binding (B) component that binds cell surface Rs and delivers A pr into cell cytoplasm.
        
        effect: depend on binding specificity of B + cellular pathways affected by A. Anthrax toxin has 2 alternate As, edema factor (EF) and lethal factor (LF),--> enter following binding to + mediate different pathologic effects Figure 8–8
        
        • SuperAgs stimulate very large #s of T by binding to conserved portions of the T cell R--> massive T prolif + cytokine release--> capillary leak--> consequent shock. Superantigens made by S. aureus + S. pyogenes cause toxic shock syndrome (TSS).
        
        • Neurotoxins produced by Clostridium botulinum and Clostridium tetani inhibit release of NTs--> paralysis; do not kill neurons: A cleave prs involved in secretion of NTs; Tetanus + botulism can result in death from respiratory failure
        
        • Enterotoxins: nausea and vomiting (S. aureus), voluminous watery diarrhea (V. cholerae), or bloody diarrhea (C. difficile)
      - endotoxins (components of bacterial cell): LPS (component of outer membrane of gram (-)):
        
        components
        
        similiar in all:
        -a long-chain FA anchor (lipid A): binds to CD14 on host leukocytes + complex then binds TLR4--> cell activation + inflammatory responses.
        -a core sugar chain
        
        variable carb chain (O Ag; used to serotype strains)
        
        Responses to
        
        beneficial: activates protective immunity in several ways (induction of important cytokines, :arrow_up: expression of costimulatory molecules)--> enhance T lymphocyte activation.
        
        harmful: high levels--> imp role in septic shock, DIC, and ARDS, mainly through induction of excessive levels of cytokines (TNF)
    - - Strep pyogenes: protein F + teichoic acid on cell wall that bind to fibronectin
      - Other bacteria have pili (Stalks structurally conserved, whereas aas on tips vary (binding specificity))
        
        Strains of E. coli causing urinary tract infections uniquely express a specific P pilus (binds to a gal(α1–4)gal expressed on uroepithelial cells)
        
        N. gonorrhoeae pili (also are targets of host Ab response; variation in type of pili an imp mechanism by which N. gonorrhoeae escapes immune response)
    - - • Many species: quorum sensing (specific genes (virulence genes) expressed when [bacteria] high)--> allow bacteria growing in discrete host sites (abscess or consolidated pneumonia): overcome host defenses. ex S. aureus secretes autoinducer peptides;as bacteria grow to :arrow_up: [ ]--> autoinducer peptide :arrow_up:--> exotoxin production.
      - • form biofilms (organisms live within viscous layer of EC polysaccharides that adhere to host tissues / devices such as intravascular catheters and artificial joints); make bacteria inaccessible to immune effector mechanisms + :arrow_up: their resistance to drugs. ex bacterial endocarditis, artificial joint infections, and respiratory infections in people w/ CF
- - - - adult worms (Ascaris lumbricoides)
      - immature stages (Toxocara canis)
      - asexual larval forms (Echinococcus spp.).
    - - a burden of 10 hookworms-->mild or no clinical disease
      - 1000 hookworms consume enough blood-->severe anemia.
    - - • Roundworms (nematodes): nonsegmented
        
        Intestinal: Ascaris lumbricoides, Strongyloides stercoralis, and hookworms.
        
        invade into tissue: filariae and Trichinella spiralis
      - • Tapeworms (cestodes): head (scolex) and a ribbon of multiple flat segments (proglottids); adsorb nutrition through their tegument + don't have digestive tract; include fish, beef, and pork tapeworms, found in human intestine. The larvae that develop after ingestion of eggs of certain tapeworms can cause cystic disease within tissues (Echinoccus granulosus larvae cause hydatid cysts; pork tapeworm larvae produce cysts called cysticerci in many organs).
      - • Flukes (trematodes): leaf-shaped flatworms w/ prominent suckers used to attach to host; include liver and lung flukes and schistosomes.
  - - - Trichomonas vaginalis are sexually transmitted flagellated parasites that often colonize vagina + male urethra.
      - most prevalent intestinal protozoans: Entamoeba histolytica and Giardia lamblia, ingested as nonmotile cysts in contaminated food or water and become motile trophozoites that attach to intestinal epithelial cells.
      - Bloodborne protozoa (Plasmodium, Trypanosoma, Leishmania) transmitted by insect vectors, in which they replicate before being passed to new human hosts.
      - Toxoplasma gondii acquired either through contact w/ oocyst shedding kittens or by eating cyst-ridden, undercooked meat.
  - - - • Superficial: involve skin, hair, and nails; called dermatophytes. Infection of skin: tinea; (tinea pedis “athlete’s foot” + tinea capitis scalp ringworm); Certain invade subcut--> abscesses or granulomas sometimes called mycetomas.
      - • Deep fungal infections can spread systemically and invade tissues, destroying vital organs in immunocompromised hosts, but usually resolve or remain latent in otherwise normal hosts.
    - - • opportunistic (Candida, Aspergillus, Mucor, Cryptococcus) ubiquitous organisms that either colonize individuals or are encountered from environmental sources. In immunodeficient individuals, opportunistic fungi give rise to life-threatening invasive infections charac by tissue necrosis, hemorrhage, and vascular occlusion, w/ little or no inflammatory response
      - • Endemic: invasive species limited to particular geographic regions
  - - - Chlamydia trachomatis: most frequent infectious cause of female sterility (scarring + narrowing of fallopian tubes) + blindness (chronic inflam of conjunctiva that eventually causes scarring and opacification of the cornea).
      - Rickettsiae injure endothelial cells in which they grow--> a hemorrhagic vasculitis, often visible as a rash, but also may injure CNS, w/ potentially fatal outcome, as in Rocky Mountain spotted fever + epidemic typhus; transmitted by arthropod vectors (lice (in epidemic typhus), ticks (in Rocky Mountain spotted fever and ehrlichiosis), mites (in scrub typhus))
  - - - CMV infected cells: large eosinophilic nuclear inclusion + smaller basophilic cytoplasmic inclusions;
      - herpesviruses: a large nuclear inclusion surrounded by a clear halo
      - smallpox and rabies viruses: characteristic cytoplasmic inclusions.
      - many viruses (poliovirus) don't produce inclusions.
- - - - more than conventional testing
        
        PCR of CSF for HSV encephalitis: 80%, whereas viral culture <10%
        
        nucleic acid tests for genital Chlamydia detect 10-30% more than conventional culture
      - gonorrhea: sensitivity similar to culture
    - - diagnosis of gonorrhea, chlamydial infection, tuberculosis, herpes encephalitis
      - guide medical management of infections w/ HIV, HBV, HCV
- - - - Global warming: ex mosquitoes carrying Dengue fever, used to be confined to U.S.-Mexican border, now found in 28 states.
      - Deforestation of eastern US--> massive incr in deer + mice (carry ticks carrying Lyme disease, babesiosis, and ehrlichiosis)
- - - - Some secrete lytic Es--> destroy tissue + allow direct invasion.
        (S. aureus: hyaluronidase) Invasive microbes initially follow tissue planes of least resistance + drain to regional lymphatics.
        S. aureus may travel from a localized abscess to draining lymph nodes--> sometimes bacteremia + spread to deep organs (heart, bone).
      - Most viruses spread locally from cell to cell by replication + release of infectious virions, but others may propagate from cell to cell by causing fusion of host cells, or by transport within nerves (rabies virus and varicella-zoster virus).
      - spread in blood / lymph
        
        within host cells
        
        Leukocytes: herpesviruses, HIV, mycobacteria, Leishmania, and Toxoplasma.
        
        RBCs: parasites Plasmodium and Babesia
        
        free in EC fluid: Some viruses (poliovirus, HBV), most bacteria and fungi, some protozoa (African trypanosomes), and all helminths transported in blood
    - - stay confined to lumen of hollow viscera (Vibrio cholerae)
      - adhere to / proliferate exclusively in / on epithelial cells (papillomaviruses, dermatophytes)
  - - - Placental-fetal transmission: most likely when mother has primary infection during pregnancy; damage depends on the developmental stage of fetus. ex rubella during first trimester--> heart malformation, mental retardation, cataracts, or deafness in infant; little damage during third trimester.
      - passage of neonate through birth canal (gonococcal / chlamydial conjunctivitis) ex transmission of HIV mostly occurs during delivery. Antiretroviral treatment of pregnant women w/ HIV + treatment of newborn--> :arrow_down: rate of transmission from 25% to <2%.
      - maternal milk (CMV + HBV).
  - - - GI
        
        defenses
        
        Acidic gastric secretions
        
        volunteers do not become infected by Vibrio cholerae unless they are fed 10 to the power of 11 organisms, but neutralizing stomach acid reduces infectious dose by 10,000x
        
        -some agents (Shigella, Giardia cysts) relatively resistant--> <100 organisms can cause illness.
        
        Other normal defenses (1) mucus (2) lytic pancreatic Es + bile detergents (3) mucosal antimicrobial peptides (defensins) (4) normal flora
        
        (5) IgA made in MALT (These lymphoid aggregates covered by a single layer of specialized epithelial cells (M cells) imp for transport of Ags to MALT)
        Numerous gut pathogens use M cells to enter (poliovirus, enteropathic E coli, V. cholerae, Salmonella typhi, and Shigella flexneri)
        
        Infection occurs
        
        when local defenses weakened
        
        stalled peristalsis / mechanical obstruction.
        
        antibiotics altering normal flora (ex pseudomembranous colitis)
        
        low gastric acidity
        
        organisms develop strategies to overcome
        
        Viruses entering through intestinal tract (hepatitis A, rotavirus) lack envelopes (bc enveloped viruses inactivated by bile + digestive Es)
        
        bacteria
        
        S. aureus: grow in food (releases powerful enterotoxins)--> ingestion--> food poisoning w/o any bacterial multiplication
        
        V. cholerae + enterotoxigenic E. coli bind to epith + multiply in overlying mucous layer--> release exotoxins--> epithelial cells secrete large volumes of fluid--> watery diarrhea.
        
        Shigella, Salmonella, Campylobacter invade locally + damage mucosa, lamina propria--> ulceration, inflammation, and hemorrhage--> dysentery.
        
        Salmonella typhi passes from damaged mucosa through Peyer’s patches + mesenteric lymph nodes--> bloodstream--> systemic infection.
        
        Fungi: mainly in immunologically compromised persons
        Candida (normal GI flora): pre dilection for stratified squamous epith--> oral thrush / membranous esophagitis, but also may spread to stomach, lower GI, and other organs.
        
        protozoa: transmitted as cysts (resist stomach acid); In gut, cysts convert to motile trophozoites + attach to sugars on epith through lectins. What happens next differs
        
        E. histolytica kills host cells by contact-mediated cytolysis through a channelforming pore pr, w/ consequent ulceration + invasion of colonic mucosa.
        
        Giardia lamblia attaches to epith brush border
        
        cryptosporidia taken up by enterocytes, in which they form gametes + oocysts
        
        helminths cause disease when: present in large numbers / by reaching ectopic sites
        
        by obstructing the gut or invading and damaging the bile ducts (Ascaris lumbricoides).
        
        Hookworms: iron deficiency anemia by sucking blood from villi;
        Diphyllobothrium (fish tapeworm): anemia by depriving host of vit B12
        
        larvae of several helminths pass through gut briefly on their way to another organ;
        
        Trichinella spiralis larvae preferentially encyst in muscle,
        Echinococcus larvae grow in liver or lung.
      - urogenital
        
        urinary tract
        
        almost always invaded from exterior by urethra
        
        defense: regular flushing w/ urine (normally sterile, and successful pathogens (N. gonorrhoeae, E. coli) adhere to urinary epith)-->Obstruction of flow or reflux--> compromise normal defenses
        
        Anatomy
        
        women have 10x as many infections as in men bc length of urethra= 5 in women/ 20 cm in men.
        
        Urinary tract infections often spread in retrograde fashion from bladder to kidney--> acute + chronic pyelonephritis.
        
        puberty till menopause: vagina protected by a low pH (glycogen metabolism in normal epith by lactobacilli) Antibiotics can kill lactobacilli-->overgrowth of yeast--> vaginal candidiasis.
      - respiratory:
        
        size
        
        Large particles: trapped in mucociliary (nose + upper respiratory). --> transported to back of throat--> swallowed + cleared.
        
        <5 µm: directly to alveoli-->phagocytosed by alveolar MQs / neutrophils recruited by cytokines
        
        overcoming mechanisms
        
        Some viruses: attaching to + entering epith cells in lower respiratory tract + pharynx. ex influenza viruses have hemagglutinin prs on their surface--> bind to sialic acid on epith cells--> host cell engulfs virus
        
        Some pathogens avoid phagocytosis / destruction
        after phagocytosis. ex: M. tuberculosis escapes killing within phagolysosomes of MQs
        
        Certain bacteria (H. influenzae, Mycoplasma pneumoniae, B.
        pertussis)--> toxins--> impair ciliary activity.
        
        Some bacteria only in compromised hosts.
        
        S. pneumoniae + S. aureus: pneumonia subsequent to influenza, bc causes loss of protective ciliated epith
        
        P. jiroveci in patients with AIDS, Aspergillus spp. after chemotherapy
        
        damage to mucociliary
        
        Chronic: in smokers + people w/ CF
        
        acute: in intubated patients + those who aspirate gastric acid
    - - Skin: normal flora, including potential opportunists, S. aureus + Candida albicans
        
        Most penetrate through breaks
        
        burns (Pseudomonas aeruginosa)
        
        wounds (staphylococci)
        
        superficial pricks (fungal infections)
        
        diabetic and pressure-related foot sores (multibacterial infections)
        
        few traverse unbroken skin
        
        Schistosoma larvae from freshwater snails penetrate swimmers’ skin by releasing Es dissolving ECM
        
        Certain fungi (dermatophytes) infect intact stratum corneum, hair, and nails.
- - - - Collections of neutrophils--> localized liquefactive necrosis--> abscesses; necrotic tissue + inflam cells constitute pus, “pyogenic.” bacteria u. IC;
      - sizes of lesions vary
        
        tiny microabscesses formed by bacteria seeding from an infected heart valve
        
        distended, pus-filled fallopian tubes by N. gonorrhoeae,
        
        entire lobes of lung during pneumonia.
        
        diffuse involvement of meninges during H. influenzae
      - extent lesions' destructiveness depends on
        
        organism
        
        S. pneumoniae u. spares alveolar walls + even lobar streptococcal pneumonias u. resolve completely w/o permanent damage
        
        S. aureus + Klebsiella pneumoniae destroy alveolar walls and form abscesses that heal w/ scar formation.
        
        location
        
        untreated acute bacterial infection can destroy a joint in a few days.
        
        Bacterial pharyngitis resolves w/o sequelae,
  - - - development of malignant neoplasms
      - Focal cell damage in skin may--> epithelial cells detached--> blisters. some cause epithelial cells to prolif (venereal warts caused by HPV or umbilicated papules of molluscum contagiosum by poxviruses)
      - induce cells to fuse + form multinucleated cells called polykaryons (measles virus or herpesviruses)
      - Some viruses replicate in cells + make viral aggregates visible as inclusion bodies (HSV or adenovirus)
  - - - Clostridia often opportunistic pathogens introduced into muscle tissue by penetrating trauma or infection of bowel in a neutropenic host.
      - E. histolytica-->colonic ulcers + liver abscesses charac by extensive tissue destruction + liquefactive necrosis w/o a prominent inflammatory infiltrate.
      - By entirely different mechanisms, viruses--> widespread necrosis of host cells associated w/ inflam (ex destruction of temporal lobes of brain by HSV or liver by HBV)
  - - - schistosome eggs--> "pipestem” fibrosis of liver/ fibrosis of bladder wall
      - M. tuberculosis--> constrictive fibrous pericarditis.
      - Chronic HBV infection--> cirrhosis of liver, in which dense fibrous septa surround nodules of regenerating hepatocytes.
  - - - Ab--> severe EC bacteria infections + a few viral infections (rotavirus and enteroviruses).
      - T cell--> infections w/ IC pathogens, notably viruses and some parasites
      - complement components
        
        early--> infections by encapsulated bacteria, (S. pneumoniae)
        
        late--> Neisseria infections.
      - neutrophil function--> infections w/ S. aureus, some gram(-) bacteria, and fungi.
      - inherited deficiencies in mediators of innate + adaptive--> sometimes strikingly selective susceptibility to specific types of infections. ex
        
        mutations in signaling molecules downstream of several TLRs--> pyogenic bacterial diseases, partic S. pneumoniae.
        
        Impaired TLR3 responses--> childhood HSV encephalitis.
        
        Inherited defects in IL-17 immunity (such as mutations in STAT3, a TF needed for TH17 cell generation)--> chronic mucocutaneous candidiasis.
      - Diseases of organ systems other than immune system--> susceptible to specific microorganisms
        
        CF: respiratory infections caused by P. aeruginosa
        
        Lack of splenic function in sickle cell disease--> infection w/ encapsulated bacteria (S. pneumoniae)
        
        Burns destroy skin->infection w/ pathogen such as P aeruginosa
        
        malnutrition impairs immune defenses.
  - - - Granulomatous (a distinctive form of mononuclear u. evoked by infectious agents that resist eradication but nevertheless capable of stimulating strong T cell–mediated immunity): M. tuberculosis, Histoplasma capsulatum, schistosome eggs
      - plasma cells common in primary + secondary lesions of syphilis
      - lymphocytes in HBV