Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection.

During mycobacterial infections, pathogenic mycobacteria manipulate both host immune and stromal cells to establish and maintain a productive infection. In humans, non-human primates, and zebrafish models of infection, pathogenic mycobacteria produce and modify the specialized lipid trehalose 6,6'-dimycolate (TDM) in the bacterial cell envelope to drive host angiogenesis toward the site of forming granulomas, leading to enhanced bacterial growth. Here, we use the zebrafish-Mycobacterium marinum infection model to define the signaling basis of the host angiogenic response. Through intravital imaging and cell-restricted peptide-mediated inhibition, we identify macrophage-specific activation of NFAT signaling as essential to TDM-mediated angiogenesis in vivo. Exposure of cultured human cells to Mycobacterium tuberculosis results in robust induction of VEGFA, which is dependent on a signaling pathway downstream of host TDM detection and culminates in NFATC2 activation. As granuloma-associated angiogenesis is known to serve bacterial-beneficial roles, these findings identify potential host targets to improve tuberculosis disease outcomes.

An ancestral mycobacterial effector promotes dissemination of infection.

The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.

Reaching the unreachable: providing STI control services to female sex workers via mobile team outreach.

BACKGROUND: As part of a community-randomized trial of a multicomponent intervention to prevent sexually transmitted infections, we created Mobile Teams (MTs) in ten intervention cities across Peru to improve outreach to female sex workers (FSW) for strengthened STI prevention services. METHODS: Throughout 20 two-month cycles, MTs provided counseling; condoms; screening and specific treatment for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), and vaginal Trichomonas vaginalis (TV) infections; and periodic presumptive metronidazole treatment for vaginal infections. RESULTS: MTs had 48,207 separate encounters with 24,814 FSW; numbers of sex work venues and of FSW reached increased steadily over several cycles. Approximately 50% of FSW reached per cycle were new. Reported condom use with last client increased from 73% to 93%. Presumptive metronidazole treatment was accepted 83% of times offered. Over 38 months, CT prevalence declined from 15.4% to 8.2%, and TV prevalence from 7.3% to 2.6%. Among participants in ≥ 9 cycles, CT prevalence decreased from 12.9% to 6.0% (p <0.001); TV from 4.6% to 1.5% (p <0.001); and NG from 0.8% to 0.4% (p = 0.07). CONCLUSIONS: Mobile outreach to FSW reached many FSW not utilizing government clinics. Self-reported condom use substantially increased; CT and TV prevalences declined significantly. The community-randomized trial, reported separately, demonstrated significantly greater reductions in composite prevalence of CT, NG, TV, or high-titer syphilis serology in FSW in these ten intervention cities than in ten matched control cities.

Demographic, behavioral, and clinical characteristics of men with nongonococcal urethritis differ by etiology: a case-comparison study.

BACKGROUND: Nongonococcal urethritis (NGU) is common, yet up to 50% of cases have no defined etiology. The extent to which risk profiles and clinical presentations of pathogen-associated and idiopathic cases differ is largely unknown. METHODS: Urethral swabs and urine specimens were collected from 370 NGU treatment trial participants who sought care at a sexually transmitted disease clinic in Seattle, WA from 2007 to 2009 and had a visible urethral discharge and/or microscopic evidence of urethral inflammation assessed by Gram-stain (≥5 polymorphonuclear leukocytes per high-powered field [PMNs/HPF]). Neisseria gonorrhoeae, Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV), and Ureaplasma urealyticum (UU) were detected in urine, using nucleic acid amplification tests. Cases negative for all assessed pathogens were considered idiopathic. Bivariate and multivariate analyses identified clinical, sociodemographic, and behavioral factors associated with detection of specific pathogens. RESULTS: After excluding 3 participants with gonococcal infection, pathogens were detected in only 50.7% of the 367 eligible cases: CT in 22.3%, MG in 12.5%, TV in 2.5%, and UU in 24.0%, with multiple pathogens detected in 9.5%. In all, 3.5% of cases were negative for CT, MG, and TV but lacked speciated ureaplasma results. The remaining cases (45.8%) were considered idiopathic. Pathogen detection was associated with young age, black race, risky sexual behaviors, cloudy or purulent discharge, and visible discharge plus≥5 PMNs/HPF. In contrast, idiopathic cases were more likely to report prior NGU, were older and less likely to be black, or have an abnormal urethral discharge on examination, compared to all other cases. These cases were not associated with any high risk behaviors. CONCLUSIONS: NGU is a heterogeneous condition. Pathogen detection was associated with a variety of traditional risk factors and clinical features; whereas, idiopathic cases tended to be diagnosed among lower-risk men.