Micro Ch 23
Mycobacteria: Tuberculosis and Leprosy
Key Concepts
 Pathogen: Mycobacterium tuberculosis – slow-growing obligate aerobe; acid-fast staining results from mycolic
acid linked to cell wall
 Encounter: infects 1/3 of world’s population; only 10% of those infected develop clinical disease
 Entry: acquired by inhaling aerosolized droplet nuclei
 Spread and multiplication: illness that begins soon after initial infection (primary disease) or can remain latent
for years before reactivating and causing illness (endogenous reactivation)
 Damage: cellular immune response that controls infection (still positive tuberculin skin test); may elicit host
immune response responsible for pathologic features of disease; active TB most often causes pulmonary disease
associated w/fever, weight loss, and drenching night sweats
 Diagnosis: TB diagnosed by microscopy and culture of sputum
 Treatment and Prevention: treated w/combo antimicrobial therapy
 Mycobacterium leprae – slow-growing, acid-fast bacillus; causative agent of leprosy; causes illness that ranges
between 2 polar forms: tuberculoid (strong immune response w/few organisms) and lepromatous (minimal
immune response w/immense numbers of organisms)
Mycobacteria in General
 Live in soil and acquired from environment
 Many harmless; some live on human body w/o causing disease (M. smegmatis)
 Acid-fast (retain basic dyes when treated w/acidic solution), resistant to drying, grow slowly compared w/most
other bacteria
o Acid-fast property comes from mycobacterial envelope, which contains waxes of long-chain branched
hydrocarbons; most abundant wax mycolic acid (covalently linked to cell wall)
o Neither Gram+ nor Gram-; fuschin stain, then treated w/acid (removes stain from all other cells) and
counterstained w/blue for contrasting background (acid fast procedure)
o Slender red rods; use fluorochrome dyes now instead of fuschin
 M. bovis causes TB of intestine or tonsils from ingestion of contaminated milk
Mycobacterium tuberculosis
 Waxy coat makes resistant to phagocytes; resistant to drying and chemicals; survives outside and inside body
 Killed by pasteurization (heating to 60° C for 30 minutes)
 Growth on solid media may take up to 6 weeks; can take 2 weeks w/liquid broth media
 Risk factors include illicit drug use, excess alcohol use, homelessness, and HIV infection
 Lung initial site of infection; droplet nuclei can remain suspended for hours and when inhaled can reach terminal
air passages; air in room occupied by person w/TB can remain infectious even after person leaves room
 Prolonged exposure and multiple aerosol inocula required to establish infection
 Infection rarely occurs outdoors because UV kills M. tuberculosis
 Host inflammatory response to TB creates open lung lesions (pulmonary cavities); coughing spreads to air
o Contagiousness correlates w/number of acid-fast bacilli visible by sputum microscopy; acid-fast smear +
are more contagious than acid-fast smear – w/culture +
 Primary infection – droplet nuclei reach alveoli where multiplication begins; usually involves middle lung zone
(where airflow greatest)
o Bacteria ingested by alveolar macrophages  bacteria multiplies and destroys macrophages (facultative
intracellular pathogen)  bacteria ingested by macrophages  infected macrophages carried by
lymphatics to regional lymph nodes  bacteria disseminate (lymphohematogenous dissemination) 
organisms preferentially colonize lymph nodes, vertebral bodies, meninges, and lung apices
o Ghon complex – area of lung inflammation associated w/enlarged hilar lymph nodes
o Cellular immunity and tissue hypersensitivity appear 3-8 weeks after infection; marked by positive
tuberculin skin test; response controls infection in most; no Sx develop
o If immune response doesn’t control, progressive primary TB develops; primary focus directly progresses
to worsening pneumonia; very young may develop tuberculous meningitis
 In those w/immunity from previous exposure, organisms destroyed before significant multiplication occurs









o Nearly all TB in previously infected patients is result of endogenous reactivation, not reinfection
Endogenous reactivation (secondary TB) – occurs w/in 2 years after initial infection; caused by any impairment
of cellular immune system
o Subtle depression of immune system from stress or hormonal factors may go undetected
o Malnutrition, corticosteroids, malignancy, and end-stage renal disease also cause
o Most important reactivation risk is HIV
o Some HLA haplotypes have higher risk (genetic predisposition)
o Physical disturbance (lung surgery) can disturb pulmonary foci and cause active TB
o Lesions slowly become necrotic, undergo caseous necrosis, and merge into larger lesions
 Caseous lesions liquefy and discharge contents into bronchi, creating well-aerated cavity in
which mycobacteria proliferate
 Discharge of caseous material distributes organisms to other sites of lung, which can lead to
tuberculous pneumonia
o Bacteria-laden contents of caseous lesions coughed up and become infectious droplet nuclei
TB requires cellular immune response; antibodies have no role
o In lysosomes, mycobacteria prevent acidification and thus increase survival
o Everyone has CD4+ T cells that can recognize mycobacterial antigens if processed and presented by
macrophages in context of MHC class II proteins; lymphocytes activated and proliferate, producing
lymphokines that attract, retain, and activate macrophages at site of antigen exposure
o Activated macrophages accumulate lytic enzymes and reactive metabolites that can cause necrosis
o When population of activated lymphocytes reaches certain size, cutaneous delayed-type
hypersensitivity to tuberculin becomes manifest (3-8 weeks)
Classical tissue hypersensitivity response involves organization of macrophages, Langhans giant clels, and
lymphocytes resulting in formation of granulomas (tubercles)
o Tubercles signify containment of infection, healing w/fibrosis, encapsulation, and scar formation
o Center of tubercles becomes necrotic (incomplete necrosis, resulting in semisolid caseous material)
o Caseous necrosis unstable (esp. in lungs) where it liquefies and discharges through bronchial tree
o Proteolytic processing of killed bacteria leads to continued immunological stimulation
Miliary tuberculosis – immunocompromised w/primary infection that invades bloodstream and disseminates
o Tubercles in many organs (liver, spleen, kidneys, brain, and meninges); caseation and cavitation less
frequent than secondary TB
IL-1 and TNF-α produced by macrophages contribute to Sx (fever, weight loss, and night sweats)
o Increased production of IL-10 may suppress immune response and promote disease progression
o Net effects are caseous necrosis and fibrosis w/calcification
Purified protein derivative (PPD) – has tuberculin in it; positive reaction (induration of skin several days after
inoculation) results from infiltration by mononuclear phagocytes and T cells (delayed-type hypersensitivity)
o Depending on site of reaction, can cause accumulation of exudate in pleural cavities (effusion) or sudden
inflammation of meninges; few tubercle bacilli present in pleural fluid or CSF during reactions, but still
able to cause considerable inflammation; also + if pt received bacilli Calmette Guérin (BCG) vaccine
o Newly + test after previous – test (tuberculin conversion) indicates recent tuberculous infection;
indication for chemoprophylaxis
o 15% of individuals w/active TB have – tuberculin tests but + skin tests for other things they have had
 Soon after effective anti-TB therapy initiated, tuberculin test becomes + as health improves
o Many immunocompromised have negative tuberculin tests (lack reactivity to other skin tests too)
o False-positive can be caused by exposure to atypical mycobacteria (small diameter of induration)
IFN-γ regulates cellular immune response to TB; assays can measure production of IFN-γ in response to antigens
specific for M. tuberculosis
o Specificity for diagnosing latent TB infection; antigens used not present in non-tuberculous
mycobacteria or BCG vaccine strains
Ptt disease – TB affecting vertebral bodies; presents as chronic back pain; failure to Dx and Tx can cause
permanent destruction of vertebrae and permanent disability
Asymptomatic infection usually diagnosed by PPD; active disease diagnosed by acid-fast staining and culture of
sputum or affected tissues (usually sputa collected on three separate days); early morning sputa has best result

Radiometric culture techniques – accelerate diagnosis by early detection of radioactive CO2 released by
organisms metabolizing 14C-labeled palmitic acid (provides results in 7-14 days); test sensitivity too
 Drugs for treating TB include isoniazid (INH), rifampin, pyrazinamide (PZA), and ethambutol
o Those w/pulmonary TB become noncontagious in 2 weeks of therapy if organisms sensitive to drugs
o Requires multiple drugs for cure because of propensity to develop resistance
o Multidrug-resistent TB (MDR TB) – TB resistant to INH and rifampin
 Primary resistant strain – already resistant to drugs
 Secondary resistant strain – comes about when person doesn’t finish antibiotic treatment
o XDR TB – strains resistant to INH, rifampin, and second-line agents (fluoroquinolones and
aminoglycosides)
 BCG vaccine = strain of M. bovis made relatively avirulent (attenuated) by multiple passages in culture
o Test for effectiveness by positive PPD
o Long-term persistence depends on person’s age at vaccination (earlier = less durable)
Mycobacteria and AIDS
 Nearly all persons coinfected w/HIV and M. tuberculosis develop active TB unless either effectively treated
 Pts w/AIDS predisposed to reactivation of remote infection and rapid progression of recently acquired infection
 AIDS pts w/TB likely to develop widespread extrapulmonary disease as depletion CD4+ T cells impairs cellmediated immunity
 Patients w/advanced AIDS susceptible to Mycobacterium avium complex (MAC), which is found in water and soil
o Harmless in immunocompetent; can cause chronic pneumonia in those w/underlying lung disease
o Frequently colonizes GI tract of pts w/advanced AIDS before invading deeper tissues and causing
disseminated disease; have fever, malaise, and wasting; can have diarrhea and abdominal pain from
involvement of liver, spleen, and retroperitoneal lymph nodes
o Effective Tx requires prolonged administration of multiple drugs
Mycobacterium leprae
 Causes leprosy; much less contagious than TB; acquisition requires prolonged contact w/infectious cases
o Pts shed bacteria in their nasal secretions; airborne transmission
 Can’t be grown in vitro; also called Hansen disease; grows very slowly on footpads of mice; can infect armadillos;
some genes can be expressed in E. coli
 Survives and multiplies in macrophages; phenolic glycolipid (surface lipid) provides defense against oxidative
killing; macrophages must be activated by CD4+ T cells
 Bacilli grow best at low temperatures, so multiply most rapidly in skin
 Treat w/dapsone, rifampin, and clofazimine
 Tuberculoid leprosy – red blotchy lesions w/localized anesthesia on face, trunk, and extremities
o Bacilli cause thickening in nerve sheaths; thickened nerves palpable through skin (characteristic)
o Demonstrate delayed-type hypersensitivity to lepromin prepared from infected tissues
o Analogous to secondary TB (invokes cell-mediated immune response and tissue hypersensitivity)
o Prognosis better than lepromatous leprosy; in some cases self-limited disease
 Lepromatous leprosy – little or no delayed-type hypersensitivity to lepromin; lack of cellular immunity
associated w/enormous numbers of bacilli in skin and superficial nerves
o Both skin and nerves involved
o Loss of local sensation leads to inadvertent traumatic lesions of face and extremities that may become
secondarily infected (disfigurement)
o Sometimes not clear why host immune system is so low