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Download Path pages 357-381 Gram-Positive Bacterial Infections
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Path pages 357-381 Gram-Positive Bacterial Infections Staphylococcus epidermidis – causes opportunistic infections in catheterized patients, patients w/prosthetic cardiac valves, and drug addicts Staphylococcus saprophyticus – common cause of UTI in young women Staphylococcus aureus – pyogenic gram-positive cocci that forms clusters; cause skin lesions, abscesses, sepsis, osteomyelitis, pneumonia, endocarditis, food poisoning, and toxic shock syndrome (TSS) o Virulence factors: surface proteins involved in adherence, secreted enzymes that degrade proteins, and secreted toxins that damage host cells Surface receptors include fibrinogen (clumping factor), fibronectin, and vitronectin; used as bridge to bind to host endothelial cells Those infecting prosthetic valves and catheters have polysaccharide capsule that allows them to attach to artificial materials and resist host cell phagocytosis Lipase degrades lipids on skin surface (expression correlated w/ability to form skin abscesses) Protein A binds Fc portion of Ig, allowing organism to escape antibody-mediated killing o Hemolytic toxins: α-toxin (pore-forming protein that intercalates into PM of host cells and depolarizes them), β-toxin (sphingomyelinase), δ-toxin (detergent-like peptide), γ-toxin (lyses RBCs), and leukocidin (lyses phagocytic cells) Exfoliative A and B toxins – serine proteases that cleave protein desmoglein 1 (part of desmosomes that hold epidermal cells tightly together); causes keratinocytes to detach, resulting in loss of barrier function that leads to secondary skin infections Bullous impetigo – exfoliation locally at site of infection SSS – secreted toxin causes disseminated loss of superficial epidermis o Superantigens cause food poisoning and TSS; bind to conserved portions of MHC molecules and relatively conserved portions of T-cell receptor β chains, stimulating T lymphocytes, leading to release of large amounts of cytokines (TNF and IL-1), resembling septic shock TSS happens when hyperabsorbent tampons become colonized during use; characterized by hypotension, renal failure, coagulopathy, liver disease, respiratory distress, generalized erythematous rash, and soft tissue necrosis at site of infection Superantigens also cause vomiting by affecting CNS or enteric nervous system o Causes pyogenic inflammation distinctive for local destructiveness o Skin infections usually centered around hair follicles Furuncle (boil) – focal suppurative inflammation of skin and SQ tissue, most frequently in moist, hairy areas; develops into growin and deepening abscess that eventually thins and ruptures skin Carbuncle – deeper suppurative infection that spreads laterally beneath deep SQ fascia and burrows superficially to erupt in multiple adjacent skin sinuses Typically appear on upper back and posterior neck Hidradenitis – chronic suppurative inflammation of apocrine glands, most often in axilla Paronychia – infections of nail bed; very painful Felons – infections on palmar side of fingertips; very painful o Lung infections have PMN infiltrate similar to pneumococcus; cause more tissue destruction Usually occur in people w/hematogenous source (infected thrombus) or predisposing condition such as influenza o Ritter disease – also called scaled-skin syndrome (SSS); most frequently occurs in children w/infections in nasopharynx or skin; sunburn-like rash over entire body and evolves into fragile bullae Desquamation of epidermis occurs at level of granulosa layer o Community-acquired MRSA produces potent membrane damaging toxin, which kills WBCs Streptococcus pyogenes – β-hemolytic group A strep that causes pharyngitis, scarlet fever, erysipelas, impetigo, TSS, rheumatic fever, and glomerulonephritis o Secrete phage-encoded pyrogenic exotoxin that causes fever and rash in scarlet fever o Poststreptococcal acute rheumatic fever caused by anti-streptococcal M protein antibodies and T cells that cross-react w/cardiac proteins o o Cause rapidly progressive necrotizing fasciitis Erysipelas – most common among middle-aged persons in warm climates; caused by exotoxins from superficial infection; rapidly spreading erythematous cutaneous swelling Rash has sharp, well-demarcated, serpiginous border; may form butterfly distribution on face Diffuse, edematous, neutrophilic inflammatory reaction in dermis and epidermis extending into SQ tissues Microabscesses may be formed, but tissue necrosis minor o Pharyngitis – major antecedent of poststreptococcal glomerulonephritis; edema, epiglottic swelling, and punctate abscesses of tonsillar crypts, sometimes accompanied by cervical lymphadenopathy Peritonsillar or retropharyngeal abscess formation can encroach on airways o Scarlet fever – most common in age 3-15; punctate erythematous rash more prominent over trunk and inner aspects of arms and legs Small area around mouth remains unaffected to produce circumoral pallor Inflammation of skin leads to hyperkeratosis and scaling during defervescence Streptococcus agalactiae – β-hemolytic group B strep that colonizes female genital tract and causes sepsis and meningitis in neonates and chorioamnionitis in pregnancy Streptococcus pneumoniae – α-hemolytic strep; common cause of community-acquired lobar pneumonia and meningitis in adults o Pneumolysin – cytosolic bacterial protein released on disruption of S. pneumoniae; inserts into host cell membranes and lyses them, increasing tissue damage; activates classical pathway of complement, reducing complement available for opsonization of bacteria Viridans group of streptococci – several species of α-hemolytic and non-hemolytic streptococci that are normal oral flora; common cause of endocarditis Streptococcus mutans – major cause of dental caries; metabolizes sucrose to lactic acid (causes demineralization of tooth enamel) and secreting high-molecular-weight glucans that promote aggregation and plaque formation Enterococci – gram-positive cocci that grow in chains; often resistant to commonly used antibiotics and are significant cause of endocarditis and UTI o Antiphagocytic capsule; produce enzymes that cleave host tissues; relatively low-virulence o Emerging resistance to antibiotics (including vanco) Streptococcus pathogenesis o M protein – surface protein that prevents bacteria from being phagocytosed; produced by S. pyogenes, S. agalactiae, and S. pneumoniae o Complement C5a peptidase – degrades complement C5a; produced by S. pyogenes, S. agalactiae, and S. pneumoniae o Infections characterized by diffuse interstitial neutrophilic infiltrates w/minimal destruction of host tissues; skin lesions less likely to cause formation of discrete abscesses than staph Corynebacterium diphtheria – causes diphtheria; rod w/clubbed ends; passed through aerosols or skin exudate o Can be carried asymptomatically, cause skin lesions in neglected wounds, or cause life-threatening syndrome that includes formation of tough pharyngeal membrane and toxin-mediated damage to heart, nerves, and other organs o Produces phage-encoded A-B toxin that blocks host cell protein synthesis A fragment catalyzes covalent transfer of ADP-ribose to EF-2, inhibiting it (normally necessary for translation of mRNA into protein) Single molecule of diphtheria toxin can kill a cell by ADP-ribosylating more than a million EF-2s o Immunization w/diphtheria toxoid (formalin-fixed toxin) doesn’t prevent colonization, but protects from lethal effects of toxin o Inhaled bacteria proliferate at site of attachment on mucosa of nasopharynx, oropharynx, larynx, or trachea; form satellite lesions in esophagus and lower airways Release of exotoxin causes necrosis of epithelium and dense fibrinosuppurative exudate Coagulation of exudate on ulcerated necrotic surface creates tough, dark gray membrane Neutrophilic infiltration in underlying tissues intense; marked vascular congestion, interstitial edema, and fibrin exudation When membrane sloughs off its inflamed vascularized bed, bleeding and asphyxiation occur With control of infection, membrane coughed up or removed by enzymatic digestion, and inflammatory reaction subsides o Generalized hyperplasia of spleen and lymph nodes as result of entry of soluble exotoxin into blood o Exotoxin may cause fatty change of myocardium w/isolated myofiber necrosis, polyneuritis w/degeneration of myelin sheaths and axis cylinders, and (less common) fatty change and focal necroses of parenchymal cells in liver, kidneys, and adrenals Listeria monocytogenes – facultative intracellular bacillus that causes severe food-borne infections o Pregnant women, neonates, elderly, and immunosuppressed particularly susceptible to severe infection o Causes amnionitis that may result in abortion, stillbirth, or neonatal sepsis o In neonates and immunosuppressed, can cause disseminated disease (granulomatosis infantiseptica) and exudative meningitis o Internalins on surface that bind E-cadherin on host epithelial cells and induce internalization of bacterium; inside cell, bacteria escape phagolysosome by pore-forming protein (listeriolysin O) and 2 phospholipases o ACTA – bacterial surface protein; binds to host cytoskeletal proteins and induces actin polymerization that propels bacteria into adjacent uninfected host cells o Resting macrophages (internalize bacteria through C3 activated on bacterial surface) fail to kill bacteria o Macrophages activated by IFN-γ (produced by NK cells and T cells) phagocytose and kill bacteria o Focal abscesses alternate w/grayish or yellow nodules representing necrotic amorphous basophilic tissue debris; can occur in any organ o In infections of longer duration, macrophages appear in large numbers; granulomas rare o Infants born w/sepsis have popular red rash over extremities and listerial abscesses in placenta; smear of meconium shows bacteria o Bacillus anthracis – anthrax; large, spore-forming rods; can infect from contaminated soil; large boxcarshaped gram-positive extracellular bacteria in chains o Typically acquired through exposure to animals or animal products (wool, hides) o Produces potent toxins and polyglutamyl capsule that is antiphagocytic o Toxin has A and B subunits; B subunit (protective antigen) is what antibodies attack to protect host B subunit binds to cell-surface protein, and host protease clips off fragment of B subunit Remaining fragment self-associates to form heptamer 2 alternate A subunits: edema factor (EF) and lethal factor (LF) 3 A subunits bind to B heptamer; whole complex endocytosed into host cell Low pH of endosome causes conformational change in B heptamer, which forms selective channel in endosome membrane through which EF and LF move into cytoplasm, where EF binds to Ca and calmodulin to form adenylate cyclase Active EF converts ATP to cAMP, stimulating efflux of water from cell, causing interstitial edema LF – protease that destroys MAPKKs (regulate activity of MAPKs, which regulate cell growth and differentiation) o Lesions typified by necrosis and exudative inflammation w/infiltration of neutrophils and macrophages o Cutaneous anthrax – 95% of naturally occurring infections; painless pruritic papule that develops into vesicle in 2 days; as vesicle enlarges, edema forms around it; regional lymphadenopathy develops After vesicle ruptures, remaining ulcer becomes covered w/characteristic black eschar; dries and falls off as person recovers Bacteremia rare o Inhalation anthrax – when spores inhaled; organism carried by phagocytes to lymph nodes where spores germinate, and release of toxins causes hemorrhagic mediastinitis After prodromal illness of 1-6 days (fever, cough, and chest or abdominal pain), abrupt onset of increased fever, hypoxia, and sweating Frequently meningitis develops from bacteremia Leads to shock and death in 1-2 days Causes numerous foci of hemorrhage in mediastinum w/hemorrhagic enlarged hilar and peribronchial lymph nodes Perihilar interstitial pneumonia w/infiltration of macrophages/neutrophils; pulmonary vasculitis Mediastinal lymph nodes show lymphocytosis, macrophages w/phagocytosed apoptotic lymphocytes, and fibrin-rich edema B. anthracis present in alveolar capillaries and venules; to lesser degree in alveolar space In fatal cases, bacteria found in spleen, liver, intestines, kidneys, adrenals, and meninges o GI anthrax – contracted by eating undercooked meat contaminated w/bacteria; person has nausea, abdominal pain, and vomiting followed by severe, bloody diarrhea; mortality over 50% Nocardia – slender aerobic bacteria that grow in branched chain filaments; form thin aerial filaments resembling hyphae in vitro; stain w/acid-fast; elicit suppurative response and central liquefaction w/surrounding granulation and fibrosis; no granulomas o Found in soil; cause opportunistic infection in immunocompromised o Nocardia asteroids – respiratory infections; 20% of infections involve CNS after dissemination from lungs Most patients have defects in T cell-mediated immunity (prolonged steroid use, HIV) or DM Causes fever, weight loss, and cough o Nocardia brasiliensis – infects skin; range of manifestations Gram-Negative Bacterial Infections Neisseria – diplococci flattened on adjoining sides (shape of coffee bean); aerobic; grow best on enriched media (chocolate agar); generate antigenic variation; adhere to & invade non-ciliated epithelial cells at site of entry o OPA genes located on outer membrane of bacteria; increase binding of bacteria to epithelial cells and promote entry; each gene has several repeats frequently duplicated or deleted o N. meningitides – bacterial meningitis in children <2 years; common colonizer of oropharynx (10% of population); spread by respiratory route; each colonization lasts several months Immune response leads to elimination in most people Invade respiratory epithelial cells and travel to basolateral side of cells to enter blood; in blood, capsule of bacteria inhibits opsonization and destruction of bacteria by complement proteins Increased rates of serious infection in those w/inherited defects in C5-C9 proteins that form membrane attack complex Has up to 12 OPA genes o N. gonorrhoeae – infection in men causes urethritis; in women, infection asymptomatic; untreated can lead to PID (can cause infertility or ectopic pregnancy) Usually manifests locally in genital or cervical mucosa, pharynx, or anorectum Disseminated infections can occur; more likely in those lacking complement proteins; usually causes septic arthritis w/rash of hemorrhagic papules and pustules Neonatal infection causes blindness and rarely sepsis; eye infection preventable by silver nitrate or antibiotics in newborn’s eyes Adherence to epithelial cells initially mediated by long pili (bind to CD46 (complementregulatory protein on all nucleated cells)); gene has coding sequence for 10-15 variants (only one juxtaposed to promoter; recombination mixes them around) Has 3-4 genes for OPA proteins Bordetella pertussis – whooping cough; coccobacillus; paroxysms of violent coughing followed by loud inspiratory whoop; vaccine effective in preventing, but antigenic divergence causing less immunity o Diagnosis best made by PCR o Colonizes brush border of bronchial epithelium and invades macrophages o Coordinated expression of virulence factors regulated by bvg gene locus BVGS – transmembrane protein that senses signals that induce expression of virulence factors; when activated, phosphorylates BVGA (regulates transcription of mRNA for adhesins and toxins) Filamentous hemagglutinin adhesion binds to carbs on surface of respiratory epithelial cells and CR3 (Mac-1) integrins on macrophages Pertussis toxin – exotoxin composed of 5 proteins; ADP-ribosylates and inactivates guanine nucleotide-binding proteins (no longer transduce signals from host PM receptors); paralyzes cilia o Causes laryngotracheobronchitis that can have bronchial mucosal erosion, hyperemia, and copious mucopurulent exudate; unless superinfected, lung alveoli open and intact Peripheral lymphocytosis, hypercellularity and enlargement of mucosal lymph follicles and peribronchial lymph nodes Pseudomonas aeruginosa – opportunistic aerobic bacillus of cystic fibrosis, severe burns, or neutropenia pts o Resistant to antibiotics; often infects extensive skin burns (can be source of sepsis) o Common cause of hospital-acquired infections o Can cause corneal keratitis in contact wearers, endocarditis and osteomyelitis in IV drug abusers, otitis externa (swimmer’s ear), and severe otitis externa in diabetics o Has pili and adherence proteins that bind to epithelial cells and lung mucin; express endotoxin that causes sepsis o In lungs of people w/cystic fibrosis, secrete mucoid exopolysaccharide (alginate) forming slimy biofilm that protects bacteria from antibodies, complement, phagocytes, and antibiotics o Secrete exotoxin A (inhibits protein synthesis by ADP-ribosylating EF-2), exoenzyme S (ADP-ribosylates RAS and other proteins that regulate cell growth and metabolism), phospholipase C (lyses RBCs and degrades pulmonary surfactant), and elastase (degrades IgGs and ECM proteins) Enzymes important in tissue invasion and destruction of cornea in keratitis o Produces iron-containing compounds extremely toxic to endothelial cells; cause vascular lesions o Causes necrotizing pneumonia distributed through terminal airways in fleur-de-lis pattern; pale necrotic centers and red, hemorrhagic peripheral areas Masses of organisms cloud tissue w/bluish haze concentrating in walls of blood vessels where host cells undergo coagulative necrosis Vasculitis w/thrombosis and hemorrhage o Bronchial obstruction by mucus plugging and subsequent infection complications of cystic fibrosis Chronic infection may result in bronchiectasis and pulmonary fibrosis, despite antibiotics o In skin burns, proliferates wildly, penetrating deeply into veins and spreading hematogenously Ecthyma gangrenosum – well-demarcated necrotic and hemorrhagic oval skin lesions Disseminated intravascular coagulation DIC) – frequent complication of bacteremia Yersinia – proliferate in lymphoid tissue; complex of genes (Yop virulon) that enables it to kill host phagocytes o Yop virulon encodes proteins that assemble into type III secretion system (hollow syringe-like structure that projects from bacterial surface, binds to host cells, and injects bacterial toxins called Yops into cell) YopE, YopH, and YopT block phagocytosis by inactivating molecules that regulate actin polymerization YopJ inhibits singaling pathways activated by LPS, blocking production of inflammatory cytokines o Y. pestis – facultative intracellular bacterium transmitted from rodents to humans by fleabites or less often from human to human by aerosols; causes plague (black death) Forms biofilm that obstructs gut of infected flea; flea must regurgitate before it feeds, infecting rodent or human it is biting Causes lymph node enlargement (buboes), pneumonia, or sepsis w/striking neutrophilia Destructive histologic features: Massive proliferation of organisms Early appearance of protein-rich and polysaccharide-rich effusions w/few inflammatory cells but marked tissue swelling Necrosis of tissues and blood vessels w/hemorrhage and thrombosis Neutrophilic infiltrates that accumulate near necrotic areas as healing begins Bubonic plague – fleabite usually on legs, marked by small pustule or ulcer; draining lymph nodes enlarge and become soft, pulpy, and plum colored; lymph nodes may infarct or rupture through skin Pneumonic plague – severe confluent hemorrhagic and necrotizing bronchopneumonia often w/fibrinous pleuritis Septicemic plague – lymph nodes and organs throughout body rich in mononuclear phagocytes; develop foci of necrosis Fulminant bacteremias induce DIC w/widespread hemorrhages and thrombi o Y. enterocolitica – cause fecal-orally transmitted ileitis o Y. pseudotuberculosis – causes fecal-orally transmitted mesenteric lymphadenitis Hemophilus ducreyi – chancroid; acute STD; ulcerative infection most common in lower socioeconomic groups and those w/regular contact w/prostitutes o o o One of most common causes of genital ulcers in Africa and SE Asia; cofactor in transmission of HIV Must be cultured in special conditions and PCR-based tests not widely available, so underdiagnosed 4-7 days after inoculation, person develops tender erythematous papule involving external genitalia; over next several days, surface of primary lesion erodes to produce irregular ulcer (more apt to be painful in males than females); ulcer not indurated; multiple lesions may be present Base of ulcer covered by shaggy, yellow-gray exudate Regional lymph nodes (esp. inguinal) enlarged and tender in 1-2 weeks from inoculation In untreated cases, inflamed enlarged nodes (buboes) may erode overlying skin to produce chronic, draining ulcers o Ulcer contains superficial zone of neutrophilic debris and fibrin w/underlying zone of granulation tissue containing areas of necrosis and thrombosed vessels Dense lymphoplasmacytic inflammatory infiltrate present beneath layer of granulation tissue o Coccobacilli; sometimes demonstrable in Gram or silver stains; often obscured by other bacteria that colonize ulcer base Klebsiella granulomatis – causes granuloma inguinale (donovanosis); chronic inflammatory disease; STD o Encapsulated coccobacillus (Donovan bodies) o Untreated cases characterized by extensive scarring, often associated w/lymphatic obstruction and lymphedema (elephantiasis) of external genitalia o Culture difficult and PCR assays still in development; Dx made by smears or biopsy of ulcer o Begins as raised popular lesion on moist stratified squamous epithelium of genitalia or rarely oral mucosa or pharynx Lesion eventually ulcerates and develops abundant granulation tissue, manifested grossly as protuberant, soft, painless mass As lesion enlarges, borders become raised and indurated Disfiguring scars sometimes associated w/urethral, vulvar, or anal strictures Regional lymph nodes typically spared or show nonspecific reactive changes o Active lesions – epithelial hyperplasia at borders of ulcer; mixture of neutrophils and mononuclear inflammatory cells present at base of ulcer and beneath surrounding epithelium Stained by Giemsa stain; found in macrophages Silver stains may be used Mycobacteria Mycobacterium tuberculosis – slender, aerobic rod; cell wall of mycolic acid (acid-fast); weakly Gram+ o Responsible for most cases of TB; reservoir is human w/active TB o Infection w/HIV makes people susceptible to rapidly progressive TB o Increased risk w/diabetes mellitus, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression o Most infections acquired by person-to-person aerosol transmission o In most people, primary TB asymptomatic (may cause fever and pleural effusion); only sign of infection is tiny fibrocalcific nodule at site of infection; viable organisms remain dormant in lesion for decades and, if immune defenses lowered, infection reactivates o Typically leads to development of delayed hypersensitivity to M. tuberculosis antigens (shown by Mantoux, which uses tuberculin); Mantoux tests positive 2-4 weeks after infection False negatives occur in certain viral infections, sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression, and overwhelming active TB disease False positives result from infection by atypical mycobacteria or prior vaccination w/BCG (attenuated strain of M. bovis used as vaccine in some countries) o Pathogenesis depends on cell-mediated immunity, which confers resistance to bacteria and results in development of hypersensitivity to mycobacterial antigens Pathologic manifestations (caseating granulomas and cavitation) result of hypersensitivity that develops in concert w/protective host immune response o Macrophages – primary cells infected by TB; early in infection, bacilli replicate essentially unchecked, stimulating macrophages to contain proliferation of bacteria o o Pathogenesis – bacteria enters macrophages by endocytosis mediated by mannose receptor (bind lipoarabinomannan) and complement receptors (bind opsonized mycobacteria) Bacteria replicate in phagosome by blocking fusion of phagosome and lysosome by inhibiting Ca2+ signals and recruitment and assembly of proteins that mediate phagolysosome fusion Replication results in bacteremia and seeding of multiple sites; most asymptomatic still Polymorphisms in NRAMP1 gene (transmembrane protein in endosomes and lysosomes that pumps divalent cations out of lysosome; inhibits microbial growth by limiting availability of ions) cause disease to progress due to absence of effective immune response 3 weeks later, TH1 activate macrophages to become bactericidal; response initiated by mycobacterial antigens entering lymph nodes and being displayed to T cells Differentiation of TH1 cells depends on IL-12 produced by APCs that saw invader M. tuberculosis makes ligands for TLR2, promoting production of IL-12 by DCs Mature TH1 cells produce IFN-γ (critical mediator that enables macrophages to contain infection); IFN-γ stimulates formation of phagolysosome in infected macrophages, exposing bacteria to acidic environment, and stimulates expression of inducible NO synthase; NO capable of destroying several mycobacterial constituents TH1 response orchestrates formation of granulomas and caseous necrosis Macrophages activated by IFN-γ differentiate into epithelioid histiocytes that characterize granulomatous response; may fuse to form giant cells In many, halts tissue infection before significant tissue destruction or illness Activated macrophages secrete TNF, which promotes recruitment of more monocytes NK-T cells that recognize mycobacterial lipid antigens bound to CD1 on APCs or T cells that express γδ T-cell receptor also make IFN-γ Clinical Features Primary TB – develops in previously unexposed person; only 5% develop clinically sig. disease Immunosuppressed may lose immunity so can have primary TB more than once Progressive disease has lower and middle lobe consolidation, hilar adenopathy, and pleural effusion Lymphohematogenous dissemination leads to tuberculous meningitis and miliary TB Inhaled bacilli implant in distal airspaces of lower part of upper lob or upper part of lower lobe, usually close to pleura Ghon focus – gray-white inflammation w/consolidation; center usually undergoes caseous necrosis Ghon complex – combo of parenchymal lung lesion and nodal involvement; undergoes progressive fibrosis then calcification w/resolution Sites of active involvement have granulomatous inflammation w/caseating and noncaseating tubercles Granulomas usually enclosed in fibroblastic rim punctuated by lymphocytes; multinucleate giant cells present in granulomas Secondary TB – previously sensitized host; most commonly reactivation of latent infection Can result from exogenous reinfection in waning host immunity or w/overwhelming Usually involves apex of lungs Preexistence of hypersensitivity causes fast response Regional lymph nodes less prominently involved than primary Cavitation readily occurs; erosion of cavities into airway source of infection Systemic symptoms related to cytokines released by activated macrophages Fever low grade; night sweats occur Some degree of hemoptysis present in half cases Pleuritic pain results from extension to pleural surfaces Initial lesion small focus of consolidation near apical pleura; central caseation and peripheral fibrosis; undergoes progressive fibrous encapsulation to fibrocalcific scars Localized TB may heal w/fibrosis spontaneously or after therapy o o o Diagnosis – conventional culture takes 10 weeks; liquid media provides answer in 2 weeks Multidrug resistance more common; treat w/multiple drugs Use of highly active antiretroviral therapy (HAART) reduces risk of TB in people w/HIV (CD4 count indicates risk); lower CD4 count presents w/Sx resembling progressive primary TB o Extent of immunodeficiency determines frequency of extrapulmonary involvement HIV has increased false-negative sputum smears; cavitation and bronchial damage less, resulting in less bacilli expelled; also have no granulomas o Progressive pulmonary TB – in elderly and immunosuppressed; apical lesion expands into adjacent lung and erodes into bronchi and vessels, evacuating caseous center, creating ragged irregular cavity poorly walled off by fibrous tissue; erosion of blood vessels causes hemoptysis Cavities may persist or become fibrotic, even after elimination of inflammation o Miliary pulmonary disease – organism draining through lymphatics enter venous blood and circulate back to lung; lesions are foci of yellow-white consolidation scattered through lung parenchyma Lesions may expand and coalesce, resulting in consolidation of large regions or lobes With progressive pulmonary TB, pleural cavity involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop o Endobronchial, endotracheal, and laryngeal TB – develops by spread through lymph or expectorated infectious material; mucosal lining studded w/minute granulomatous lesions o Systemic miliary TB – bacteria disseminate through systemic arterial system; miliary TB most prominent in liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis o Isolated TB – may appear in any organ or tissue seeded hematogenously Pott disease – when vertebrae affected; paraspinal cold abscesses may track tissue planes and present as abdominal or pelvic mass Can cause Addison’s disease in adrenals o Lymphadenitis – most frequent presentation of extrapulmonary TB, usually in cervical region (scrofula) If HIV neg, local and unifocal; if HIV pos, multifocal and systemic o Intestinal TB – contracted by drinking contaminated milk; can be caused by swallowing coughed up infective material in those w/advanced pulmonary disease Mycobacterium bovis – oropharyngeal and intestinal TB contracted by drinking contaminated milk; aerobic rod Mycobacterium avium and M. intracellulare – separate species, but infections so similar, they are referred to as M. avium-intracellulare complex (MAC); common in soild, water, dust, and domestic animals o Clinical significance uncommon except in AIDS patients, who get widely disseminated infections and organisms proliferating in lungs and GI system (among other organs) o Patients feverish w/drenching night sweats and weight loss o In rare case of person w/o HIV, organisms infect lung, causing productive cough and sometimes fever o Hallmark is abundant acid-fast bacilli in macrophages; depending on severity of immune deficiency, infection can be widely disseminated throughout mononuclear phagocyte system (enlargement of lymph nodes, liver, and spleen) or localized to lungs o Granulomas, lymphocytes, and tissue destruction rare Mycobacterium leprae – leprosy (Hansen’s disease); slowly progressive infection that affects skin and peripheral nerves; transmitted person to person via aerosols from asymptomatic lesions in upper respiratory tract o Inhaled bacteria taken up by alveolar macrophages and disseminate through blood o Replicates only in relatively cool tissues of skin and extremities o Low communicability o Acid-fast obligate intracellular organism that grows poorly in culture (propagated in armadillo) o Virulence based on properties of cell wall; similar enough to M. tuberculosis that immunization w/BCG confers some protection against M. leprae infection o Cell-mediated immunity reflected by delayed-type hypersensitivity reactions to dermal injections of bacterial extract (lepromin) o Patterns of disease – pattern determined by TH response Tuberculoid leprosy – less severe; dry scaly skin lesions that lack sensation; often asymmetric involvement of large peripheral nerves TH1 response associated w/production of IL-2 and IFN-γ Localized flat red skin lesions that enlarge and develop irregular shapes w/indurated, elevated, hyperpigmented margins and depressed pale centers (central healing) Neuronal involvement dominates; nerves enclosed in granulomatous inflammatory reactions and if small are destroyed; leads to skin anesthesias and muscle atrophy, rendering person liable to trauma of affected part, leading to development of ulcer Facial nerve involvement leads to paralysis of eyelids w/keratitis and corneal ulcerations Bacilli almost never found on microscopic exam (paucibacillary leprosy) Lepromatous (anergic) leprosy – more severe; symmetric skin thickening and nodules; unresponsiveness of host immune system; cooler areas of skin more affected than warmer areas Widespread invasion into Schwann cells and endoneural and perineural macrophages damages PNS; in advanced cases, bacteria in sputum and blood Weak TH1 response and relative increase in TH2 response; result is weak cell-mediated immunity and inability to control bacteria Antibodies produced against M. leprae antigens; may form immune complexes w/free antigens that lead to erythema nodosum, vasculitis, and glomerulonephritis Involves skin, peripheral nerves, anterior chamber of eye, upper airways, testes, hands, and feet; lesions contain large aggregates of lipid-laden macrophages (lepra cells) filled w/masses (globi) of acid-fast bacilli (multibacillary) Macular, popular, or nodular lesions form; w/progression, nodular lesions coalesce to yield distinctive leonine facies Lesions in nose may cause bacilli-laden discharge and persistent inflammation Lymph nodes contain aggregates of bacteria-filled foamy macrophages in paracortical (T-cell) areas and reactive germinal centers In advanced disease, aggregates of macrophages present in splenic red pulp and liver Testes extensively involved, leading to destruction of seminiferous tubules Borderline leprosy – intermediate form of disease Spirochetes Gram-negative, corkscrew-shaped bacteria w/axial periplasmic flagella wound around helical protoplasm o Membrane called outer sheath; masks bacterial antigens from host immune response Treponema pallidum subsp. pallidum – causes syphilis; microaerophilic spirochete o Bacteria too slender to be seen in Gram stain; visualized by silver stains, dark-field exam, and immunofluorescence o Transplacental transmission occurs readily, resulting in congenital syphilis Happens most frequently during primary or secondary syphilis (spirochetes most numerous) Intrauterine death and perinatal death occur in 25% of untreated cases Early (infantile) – nasal discharge and congestion (snuffles) in first few months of life Desquamating or bullous rash leads to sloughing of skin, esp. hands, feet, mouth, anus Osteochondritis and periostitis affect all bones Destruction of vomer collapses bridge of nose (saddle nose) Periostitis of tibia leads to excessive new bone growth and anterior bowing (saber shin) Epiphyses widened as cartilage overgrows; cartilage in displaced islands in metaphysis Liver – diffuse fibrosis permeates lobules to isolate hepatic cells in nests; characteristic lymphoplasmacytic infiltrate and vascular changes Gummas occasionally found in liver Lungs – diffuse interstitial fibrosis Tardive (late) congenital syphilis – distinctive triad (interstitial keratitis, Hutchinson teeth, and 8th-nerve deafness) Ocular changes include choroiditis and abnormal retinal pigmentation Hutchinson teeth = small incisors shaped like screwdriver or peg (notches in enamel) 8th nerve deafness and optic nerve atrophy develop secondary to meningovascular syphilis o 3 stages: o Primary syphilis: 3 weeks after exposure; single firm nontender raised chancre at site of treponemal invasion on penis, cervix, vaginal wall, or anus; chancre heals in 3-6 weeks; treponemes spread throughout body by hematologic and lymphatic dissemination even before chancre appearance; erodes to clean-based shallow ulcer Contiguous induration creates button-like mass directly adjacent to eroded skin (hard) Chancre contains intense infiltrate of plasma cells w/scattered macrophages, lymphocytes; progresses to intimal fibrosis Regional nodes usually enlarged due to nonspecific lymphadenitis, plasma cell-rich infiltrates, or granulomas Secondary syphilis: 2-10 weeks after primary chancre; due to spread and proliferation of spirochetes in skin and mucocutaneous tissues; skin lesions on palms, soles, oral cavity (redbrown macules); moist areas of skin have condylomata lata (broad-based elevated plaques) Silvery superficial erosions form on any mucous membranes; contain spirochetes Lymphadenopathy, mild fever, malaise, and weight loss common Sx last several weeks, then person enters latent phase of disease Superficial lesions may recur during early latent phase Lesions have plasma cell infiltrate and obliterative endarteritis; inflammation less intense than primary Tertiary syphilis: rare where adequate medical care available; usually after latent period 5 yrs+ Cardiovascular syphilis, neurosyphilis, and benign tertiary syphilis; alone or in combo Cardiovascular – aortitis leads to slowly progressive dilation of aortic root and arch (aortic valve insufficiency and aneurysms of proximal aorta) o Caused by endarteritis of vasa vasorum of proximal aorta (occlusion results in scarring of media of proximal aortic wall, causing loss of elasticity) o Narrowing of coronary artery ostia caused by subintimal scarring w/resulting myocardial ischemia Neurosyphilis – chronic meningovascular disease, tabes dorsalis, or general paresis (brain parenchymal disease) o Asymptomatic: 1/3 of cases; CSF has pleocytosis, elevated protein levels, or decreased glucose; antibodies stimulated by spirochetes o Gummas – white-gray and rubbery; can resemble tubercles or tumor-like mass Centers of coagulated, necrotic material and margins composed of plump, palisading macrophages and fibroblasts surrounded by mononuclear leukocytes (esp. plasma cells) Not many spirochetes in these Benign – formation of gummas (nodular lesions from delayed hypersensitivity to bacteria) in various sites (mostly bone, skin, and mucous membranes of upper airway o Local pain, tenderness, swelling, sometimes stress fractures o Nodular lesions or rarely ulcerative lesions Serology – mainstay of diagnosis; microscopy and PCR useful Nontreponemal antibody tests – measure antibody to cardiolipin (phospholipid present in host tissues and T. pallidum); antibodies detected in rapid plasma regain and VDRL tests Positive 4-6 weeks after infection Nearly always positive in secondary, but negative in tertiary syphilis VDRL and rapid plasma region tests used as screeing and to monitor response to therapy; become negative after successful Tx of infection False pos VDRL test associated w/certain acute infections, collagen vascular diseases, drug addiction, pregnancy, hypergammaglobulinemia, and lepromatous leprosy Treponemal antibody tests – measure antibodies to T. pallidum; fluorescent antibody absorption test and microhemagglutination assay for antibodies Become positive 4-6 weeks from infection; remain positive indefinitely (even after Tx) Not recommended as primary screening because more expensive than nontreponemal More specific than nontreponemal, but false positives can occur Serologic response may be delayed, absent, or exaggerated (false-positive) in those w/syphilis and HIV; in most cases, tests still useful in diagnosis and management o Proliferative endarteritis occurs in all stages o TH1 cells infiltrate chancre (activation of macrophages to kill bacteria) Antibody response doesn’t eliminate infection Outer membrane of spirochete prevents antibody binding Immune response ultimately inadequate (spirochetes disseminate, persist, and cause later) o Antibiotic Tx in pts w/high bacterial load can cause massive release of endotoxins, resulting in cytokine storm that manifests w/high fever, rigors, hypotension, and leukopenia (Jarisch-Herxheimer reaction) Seen in other spirochetal diseases as well; can be mistaken for drug allergy Borrelia recurrentis – causes relapsing fever (epidemic relapsing fever); louse-transmitted disease o Endemic relapsing fever caused by several Borrelia species transmitted from small animals to humans by soft-bodied ticks o 1-2 week incubation period after bite as spirochetes multiply in blood o Clinical infection heralded by shaking chills, fever, headache, and fatigue, followed by DIC and multiorgan failure o Spirochetes temporarily cleared from blood by anti-Borrelia antibodies (target variable major protein on bacteria surface) o After few days, bacteria w/different surface antigen emerge and reach high densities in blood; Sx return until body makes antibodies to these; vicious cycle continues; can eventually become less until Sx gone o Diagnosis made by finding spirochetes in blood smears obtained during febrile periods o Spleen enlarged and contains focal necrosis and miliary collections of WBCs and numerous borreliae Congestion and hypercellularity of red pulp, which contains macropahges w/erythrophagocytosis o Liver may be enlarged and congested w/prominent Kupffer cells and septic foci o Scattered hemorrhages resulting from DIC may be found in serosal and mucosal surfaces, skin, & viscera o Pulmonary bacteria superinfection common complication Borrelia burgdorferi – Lyme disease; transmitted from rodents by deer ticks; serology main method of Dx o Stage 1 – spirochetes multiply and spread in dermis at site of bite, causing expanding area of redness w/pale center (erythema chronicum migrans); may be accompanied by fever and lymphadenopathy Disappears in 4-12 weeks o Stage 2 – early disseminated stage; spirochetes spread hematogenously throughout body and cause secondary skin lesions, lymphadenopathy, migratory joint and muscle pain, cardiac arrhythmias, and meningitis associated w/cranial nerve involvement o Stage 3 – late disseminated stage; 2-3 years after initial bite; chronic arthritis sometimes w/severe damage to large joints and polyneuropathy and encephalitis o Much of pathology secondary to immune response against bacteria and accompanying inflammation Binding of bacterial lipoproteins to TLR2 on macrophages; in response, macrophages release IL-6 and TNF and generate NO, reducing infection Adaptive immune response mediated by CD4+ T cells and B cells Antibodies drive complement-mediated killing of bacteria; spirochetes escape antibody response through antigenic variation B. burgdorferi has plasmid w/single promoter sequence and multiple coding sequences for antigenic surface protein (V1sE) o Skin lesions characterized by edema and lymphocytic-plasma cell infiltrate o Early disease – synovium resembles early RA (villous hypertrophy, lining-cell hyperplasia, and abundant lymphocytes and plasma cells in subsynovium) o Lyme arthritis – arteritis; produce onion-skin-like lesions resembling those in lupus o Lyme meningitis – CSF hypercellular due to marked lymphplasmacytic infiltrate; contains anti-spirochete IgGs Anaerobic Bacteria Abscesses usually mixed anaerobic and facultative aerobic bacteria o o Usually caused by commensal bacteria from adjacent sites Head and neck abscesses – Prevotella and Porphyromonas species (both Gram negative) Facultative S. aureus and S. pyogenes o Fusobacterium necrophorum – oral commensal; causes Lemierre syndrome (infection of lateral pharyngeal space and septic jugular vein thrombosis o Abdominal – Gram+ Peptostreptococcus and Clostridium species; Gram- Bacteriodes fragilis and E. coli o Genital tract infections in women – Gram- bacilli (Prevotella in Bartholin cysts) often mixed w/E. coli or Strep agalactiae o Contain discolored, foul-smelling pus often poorly walled off; pathologically resemble those of pyogenic infections; mixed Gram+ and – rods and Gram+ cocci w/neutrophils Clostridium species – Gram+ bacilli; anaerobic; produce spores present in soil o C. perfringens, C. septicum, and other species cause cellulitis and myonecrosis of traumatic and surgical wounds (gas gangrene), uterine myonecrosis associated w/illegal abortions, mild food poisoning, and infection of small bowel associated w/ischemia or neutropenia that leads to severe sepsis Cellulitis – originates in wounds; thin discolored exudate, foul oder, and relatively quick and wide tissue destruction; amount of necrosis disproportionate to number of neutrophils and Gram+ bacteria present; granulation tissue at borders; treatable by debridement & antibiotics Gas gangrene – edema and enzymatic necrosis of involved muscle cells 1-3 days after injury Swelling of affected region, forming large bullous vesicles that rupture Gas bubbles caused by bacterial fermentation As infection progresses, inflamed muscles become soft, blue-black, friable, and semifluid because of massive proteolytic action of released bacterial enzymes Severe myonecrosis, extensive hemolysis, and marked vascular injury w/thrombosis C. perfringens associated w/dusk-colored wedge-whaped infarcts in small bowel, particularly in neutropenic people; bacteria disseminates hematogenously; formation of gas bubbles o C. tetani – causes tetanus; proliferates in puncture wounds and umbilical stump of newborn infants and releases potent neurotoxin (tetanospasmin) that causes convulsive contractions Tetanus toxoid (formalin-fixed neurotoxin) is part of DPT immunization Toxin causes spastic paralysis by blocking release of GABA o C. botulinum – in inadequately sterilized canned foods; releases potent neurotoxin that blocks synaptic release of ACh and causes severe paralysis of respiratory and skeletal muscles (botulism) Toxin bind gangliosides on motor neurons and is transported into cell; in cytoplasm, A fragment cleaves synaptobrevin (mediates fusion of neurotransmitter-containing vesicles w/membrane) o C. difficile – overgrows other intestinal flora in antibiotic-treated people, releases toxins, and causes pseudomembranous colitis Produces toxin A (enterotoxin that stimulates chemokine production and attracts leukocytes) and toxin B (cytotoxin that causes distinctive cytoplathic effects in cultured cells Both toxins are glucosyl transferases; part of pathogenicity island absent from non-pathogenic strains of C. difficile o Cellulitis and myonecrosis Dx by culture; pseudomembranous colitis by toxin assays; botulism by both o Tissue death essential for growth of C. perfringens; release collagenase and hyaluronidase that degrade ECM proteins and contribute to bacterial invasiveness; secretes 14 toxins α-toxin – phospholipase C that degrades lecithin (major component of PM) and destroys RBCs, platelets, and muscle cells, causing myonecrosis Has sphingomyelinase activity that contributes to nerve sheath damage Ingestion of contaminated food causes brief diarrhea; spores survive cooking; organism proliferates in cooling food Enterotoxin forms pores in epithelial PM, lysing cells and disrupting tight junctions Obligate Intracellular Bacteria Chlamydia trachomatis – small gram- bacterium o Exists in 2 forms during life cycle Infectious form (elementary body or EB) – metabolically inactive spore-like structure Taken up by host cells by receptor-mediated endocytosis Bacteria prevent fusion of endosome and lysosome; inside endosome, EB differentiates into reticulate body Reticulate body – metabolically active form; using energy sources and amino acids from host cell, replicates and forms new EBs o Different serotypes cause different infections Urogenital infections and inclusion conjunctivitis – serotypes D-K Lymphogranuloma venereum – serotypes L1-L3 Ocular infection of children (trachoma) – serotypes A-C o Genital infection – most common bacterial STD in world Current CDC recommendations call for Tx of both N. gonrrhoeae and C. trachomatis in patients diagnosed w/either because coinfection of both common Can be asymptomatic in either gender, leading to spreading Urethritis can be diagnosed by culture of bacteria in human cell lines; amplified nucleic acid tests performed on genital swabs or urine specimens more sensitive (replaced cultures) Mucopurulent discharge containing predominance of neutrophils; organisms not seen in smear o Lymphogranuloma venereum – chronic ulcerative disease; initially manifests as small papule on genital mucosa or nearby skin; 2-6 weeks later, growth of organism and host response in draining lymph nodes produce swollen, tender lymph nodes that can coalesce and rupture If not treated, can cause fibrosis and strictures in anogenital tract Lesions contain mixed granulomatous and neutrophilic inflammatory response Chlamydial inclusions seen in cytoplasm of epithelial cells or inflammatory cells Stellate abscesses – lymph nodes w/granulomatous inflammatory reaction associated w/irregularly shaped foci of necrosis and neutrophilic infiltration Later, nonspecific chronic inflammatory infiltrates and extensive fibrosis Fibrosis may cause local lymphatic obstruction, lymphedema, and strictures Active lesions – Dx made by demonstration of organism in biopsy or smears of exudate Chronic cases – Dx rests w/demonstration of antibodies to chlamydial serotype Rickettsiales – vector-borne obligate intracellular bacteria that cause epidemic typhus (Rickettsia prowazekki), scrub typhus (Orienta tsutsugamushi), and spotted fevers (Rickettsia rickettsia and others) o Gram-, rod-shaped bacteria; stain poorly w/Gram stain o Epidemic typhus – transmitted from person to person by body lice o Scrub typhus – transmitted by chiggers; mite-borne infection; usually milder version of typhus fever; may be prominent inflammatory lymphadenopathy o Rocky Mountain spotted fever (RMSF) – transmitted to human by dog ticks; transmitted after several hours of tick feeding or when tick crushed during removal from skin Hemorrhagic rash over entire body (including palms and soles); eschar at site of bite uncommon Vascular lesions that underlie rash lead to acute necrosis, fibrin extravasation, and occasionally thrombosis of small blood vessels, including arterioles Severe – foci of necrotic skin appear (fingers, toes, elbows, ears, scrotum) Perivascular inflammatory response in brain, skeletal muscle, lungs, kidneys, testes, and heart Those in brain can involve larger vessels and produce microinfarcts Noncardiogenic pulmonary edema causing adult respiratory distress syndrome is major cause of death w/RMSF o Ehrlichiosis – tick-transmitted disease; bacteria predominantly infect neutrophils (Anaplasma phagocytophilum and Ehrlichia ewingii) or macrophages (Ehrlichia chaffeensis) Characteristic cytoplasmic inclusions (morulae) – shaped like mulberries; masses of bacteria; seen in WBCs Characterized by abrupt onset of fever, headache, and malaise May progress to respiratory insufficiency, renal failure, and shock; rash occurs in 40% of people w/E. chaffeensis Diagnosed clinically and confirmed by serology o Those that cause typhus and spotted fevers infect vascular endothelial cells, esp. in lungs and brain o o Enter endothelial cells by endocytosis, escape from endosome into cytoplasm before fusion w/lysosome; proliferate in cytoplasm and either lyse cell (typhus) or spread from cell to cell through actin-mobilized motion (spotted fever) Severe manifestations primarily due to vascular leakage secondary to endothelial cell damage; causes hypovolemic shock w/peripheral edema, pulmonary edema, renal failure, and CNS manifestations including coma Innate immune response mounted by NK cells, which produce IFN-γ, reducing bacterial proliferation Subsequent CTL responses critical for elimination IFN-γ and TNF from activated NK and T cells stimulate production of NO CTLs lyse infected cells Dx by immunostaining of organisms or detection of antirickettsial antibodies in serum Typhus fever – rash and small hemorrhages due to vascular lesions; in severe cases, necrosis of skin and gangrene of tips of fingers, nose, earlobes, scrotum, penis, and vulva Irregular ecchymotic hemorrhages may be found internally, principally in brain, heart, testes, serosal membrane, lungs, and kidneys Endothelial swelling in capillaries, arterioles, and venules may narrow lumens of vessels Cuff of mononuclear inflammatory cells usually surrounds affected vessel Vascular lumens sometimes thrombosed; leads to gangrenous necrosis of skin (minority) Necrosis unusual In brain, characteristic typhus nodules composed of focal microglial proliferations w/infiltrate of mixed T lymphocytes and macrophages