Tuberculosis is characterized by granuloma formation and caseous necrosis, but the factors causing tissue destruction are poorly understood. Matrix metalloproteinase (MMP)-9 (92-kDa gelatinase) secretion from monocytes is stimulated by Mycobacterium tuberculosis (M. tb) and associated with local tissue injury in tuberculosis patients. We demonstrate strong immunohistochemical MMP-9 staining in monocytic cells at the center of granuloma and adjacent to caseous necrosis in M. tb-infected patient lymph nodes. Minimal tissue inhibitor of MMPs-1 staining indicated that MMP-9 activity is unopposed. Because granulomas characteristically contain few mycobacteria, we investigated whether monocyte-monocyte cytokine networks amplify MMP-9 secretion. Conditioned medium from M. tb-infected primary human monocytes or THP-1 cells (CoMTB) stimulated MMP-9 gene expression and a >10-fold increase in MMP-9 secretion by monocytes at 3–4 days (p < 0.009, vs controls). Although CoMTB stimulated dose-dependent MMP-9 secretion, MMP-1 (52-kDa collagenase) was not induced. Anti-TNF-α Ab but not IL-1R antagonist pretreatment decreased CoMTB-induced MMP-9 secretion by 50% (p = 0.0001). Anti-TNF-α Ab also inhibited MMP-9 secretion from monocytic cells by 50%, 24 h after direct M. tb infection (p = 0.0002). Conversely, TNF-α directly stimulated dose-dependent MMP-9 secretion. Pertussis toxin inhibited CoMTB-induced MMP-9 secretion and enhanced the inhibitory effect of anti-TNF-α Ab (p = 0.05). Although chemokines bind to G protein-linked receptors, CXCL8, CXCL10, CCL2, and CCL5 did not stimulate monocyte MMP-9 secretion. However, the response to cholera toxin confirmed that G protein signaling pathways were intact. In summary, MMP-9 within tuberculous granuloma is associated with tissue destruction, and TNF-α, critical for antimycobacterial granuloma formation, is a key autocrine and paracrine regulator of MMP-9 secretion.

An investigation was performed after an outbreak of bartonellosis in a region of Peru nonendemic for this disorder. Symptoms of acute and chronic bartonellosis were recorded. Serological analysis was performed on 55% of the affected population (554 individuals), 77.5% of whom demonstrated previous infection with Bartonella bacilliformis. The attack rate of Oroya fever was 13.8% (123 cases); the case-fatality rate was 0.7%. The attack rate of verruga peruana was 17.6%. A new specific immunostain was developed and used to confirm the presence of B. bacilliformis in the biopsied skin lesions. Most seropositive individuals (56%) were asymptomatic. The symptoms that were associated with prior infection, as determined by Western blot, included fever (37.2% of the seropositive vs. 17.2% of the seronegative population; P<.001), bone and joint pain (27% vs. 9%; P<.001), headache (27% vs. 12.3%; P <.001), and skin lesions described as verruga peruana (26.8% vs. 4.9%; P<.001). Our findings suggest that infection with B. bacilliformis causes a broad spectrum of disease that is significantly milder in severity than that frequently reported.

Helicobacter pylori is an extremely diverse species. The characterization of strains isolated from individual patients should give insights into colonization and disease mechanisms and bacterial evolution. We studied H. pylori isolates from patients in the Japanese-Peruvian Polyclinic in Lima, Peru, by determining metronidazole susceptibility or resistance and by random amplified polymorphic DNA (RAPD) fingerprinting (a measure of overall genotype). Strains isolated from several biopsy specimens from each of 24 patients were studied. Both metronidazole-susceptible and -resistant strains were isolated from 13 patients, whereas strains of more than one RAPD type were isolated from only seven patients. We propose that the homogeneity in RAPD fingerprints for strains isolated from most persons reflects selection for particular H. pylori genotypes during chronic infection in individual hosts and the human diversity in traits that are important to this pathogen. Carriage of related metronidazole-resistant and -susceptible strains could reflect frequent metronidazole use in Peru and alternating selection for resistant and susceptible phenotypes during and after metronidazole therapy.

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