Download Path pages 357-381 Gram-Positive Bacterial Infections

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
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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
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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
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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
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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
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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
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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
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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
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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