Search

Mycobacterium tuberculosis (MTb) is the leading cause of death in the setting of AIDS. MTb enhances the pathogenicity and accelerates the course of HIV disease and, furthermore, infection with HIV-1 increases the risk of reactivation or reinfection with MTb. In this study, we show that host-specific recall responses to one pathogen, MTb, has a direct effect upon the regulation of a second pathogen, HIV-1. Using cells from immunocompetent former tuberculosis (TB) patients who displayed either a persistently positive (responsive) or negative (anergic), delayed-type hypersensitivity (DTH) reaction to intradermal injection of purified protein derivative (PPD), we investigated the effect of recall Ags to MTb upon the replication of HIV-1 primary isolates in vitro. We show that HIV-1 replication of a T cell-tropic isolate was significantly impaired in MTb-stimulated PBMC from PPD-anergic donors. Furthermore, these donors displayed a significant increase in CD8+ T cells and IL-10 levels and lower levels of IL-2 and TNF-α relative to PPD-responsive donors in response to PPD stimulation. Strikingly, CD8+ T cell depletion and blocking of IL-10 significantly increased HIV-1 replication in these PPD-anergic donors, indicating that an immunosuppressive response to MTb recall Ags inhibits HIV-1 replication in PPD-anergic individuals. Therefore, immunotherapeutic approaches aimed at recapitulating Ag-specific MTb anergy in vivo could result in novel and effective approaches to inhibit HIV-1 disease progression in MTb/HIV-1 coinfection.

International audience; BACKGROUND: Little is known about post-infectious pulmonary sequelae in countries like Cambodia where tuberculosis is hyper-endemic and childhood pulmonary infections are highly frequent. We describe the characteristics of hospitalized Cambodian patients presenting with community-acquired acute lower respiratory infections (ALRI) on post-infectious pulmonary sequelae (ALRIPS). METHODS: Between 2007 and 2010, inpatients ≥15 years with ALRI were prospectively recruited. Clinical, biological, radiological and microbiological data were collected. Chest radiographs were re-interpreted by experts to compare patients with ALRIPS, on previously healthy lungs (ALRIHL) and active pulmonary tuberculosis (TB). Patients without chest radiograph abnormality or with abnormality suggestive as other chronic respiratory diseases were excluded from this analysis. RESULTS: Among the 2351 inpatients with community-acquired ALRI, 1800 were eligible: 426 (18%) ALRIPS, 878 (37%) ALRIHL and 496 (21%) TB. ALRIPS patients had less frequent fever than other ALRI (p

International audience; Only a small fraction of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12-13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p < 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10(-5) and 9.2 × 10(-5), respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10(-8); odds ratio of PTB for AA versus AG/GG = 3.09 [1.99-4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3' region of TOX, and further functional explorations will focus on CD4 T lymphocytes.

International audience; OBJECTIVE: To assess the incidence and risk factors for severe liver toxicity in human immunodeficiency virus (HIV) infected patients on anti-tuberculosis treatment and the impact of patients' characteristics and concomitant medications instituted during the first week of antituberculosis treatment. METHODS: HIV-infected patients referred to six French hospitals between 1 January 1992 and 31 December 2004, with confirmed or 'presumptive' tuberculosis (TB). Liver toxicity was studied during the first 2 months of TB treatment. RESULTS: During the 12 years of the study period, 144 patients were enrolled. Severe liver toxicity developed in 15 (10.7%). The median time to development of liver toxicity was 14 days. In the univariate analysis, high baseline bilirubin levels (P = 0.004), CD4 cell counts between 50 and 100 cells/mm3 (P = 0.022) and the use of fluconazole (P = 0.0005) were associated with liver toxicity. In the multivariate analysis, independent risk factors were abnormal baseline alanine aminotransferase (ALT) (P = 0.028) and bilirubin levels (P = 0.033) and the use of fluconazole (P = 0.008). CONCLUSION: Severe liver toxicity is frequent, and occurs early in the course of anti-tuberculosis treatment. ALT and bilirubin levels should be closely monitored during the first month of treatment, especially in patients with high baseline ALT or bilirubin levels. We suggest caution when prescribing fluconazole and anti-tuberculosis drugs concomitantly, although this needs to be confirmed and further investigated.

International audience; OBJECTIVE: To assess the incidence and risk factors for severe liver toxicity in human immunodeficiency virus (HIV) infected patients on anti-tuberculosis treatment and the impact of patients' characteristics and concomitant medications instituted during the first week of antituberculosis treatment. METHODS: HIV-infected patients referred to six French hospitals between 1 January 1992 and 31 December 2004, with confirmed or 'presumptive' tuberculosis (TB). Liver toxicity was studied during the first 2 months of TB treatment. RESULTS: During the 12 years of the study period, 144 patients were enrolled. Severe liver toxicity developed in 15 (10.7%). The median time to development of liver toxicity was 14 days. In the univariate analysis, high baseline bilirubin levels (P = 0.004), CD4 cell counts between 50 and 100 cells/mm3 (P = 0.022) and the use of fluconazole (P = 0.0005) were associated with liver toxicity. In the multivariate analysis, independent risk factors were abnormal baseline alanine aminotransferase (ALT) (P = 0.028) and bilirubin levels (P = 0.033) and the use of fluconazole (P = 0.008). CONCLUSION: Severe liver toxicity is frequent, and occurs early in the course of anti-tuberculosis treatment. ALT and bilirubin levels should be closely monitored during the first month of treatment, especially in patients with high baseline ALT or bilirubin levels. We suggest caution when prescribing fluconazole and anti-tuberculosis drugs concomitantly, although this needs to be confirmed and further investigated.

International audience; OBJECTIVE: To assess the incidence and risk factors for severe liver toxicity in human immunodeficiency virus (HIV) infected patients on anti-tuberculosis treatment and the impact of patients' characteristics and concomitant medications instituted during the first week of antituberculosis treatment. METHODS: HIV-infected patients referred to six French hospitals between 1 January 1992 and 31 December 2004, with confirmed or 'presumptive' tuberculosis (TB). Liver toxicity was studied during the first 2 months of TB treatment. RESULTS: During the 12 years of the study period, 144 patients were enrolled. Severe liver toxicity developed in 15 (10.7%). The median time to development of liver toxicity was 14 days. In the univariate analysis, high baseline bilirubin levels (P = 0.004), CD4 cell counts between 50 and 100 cells/mm3 (P = 0.022) and the use of fluconazole (P = 0.0005) were associated with liver toxicity. In the multivariate analysis, independent risk factors were abnormal baseline alanine aminotransferase (ALT) (P = 0.028) and bilirubin levels (P = 0.033) and the use of fluconazole (P = 0.008). CONCLUSION: Severe liver toxicity is frequent, and occurs early in the course of anti-tuberculosis treatment. ALT and bilirubin levels should be closely monitored during the first month of treatment, especially in patients with high baseline ALT or bilirubin levels. We suggest caution when prescribing fluconazole and anti-tuberculosis drugs concomitantly, although this needs to be confirmed and further investigated.

Background Interplays between Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) in human and host professional phagocytes, namely macrophages (Mφs) and dendritic cells (DCs), are central to immune protection against TB and to TB pathogenesis. We and others have recently shown that the C-type lectin dendritic cell–specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209) mediates important interactions between mycobacteria and human monocyte-derived DCs (MoDCs) in vitro. Methods and Findings In order to explore the possible role of DC-SIGN in M. tuberculosis infection in vivo, we have analysed DC-SIGN expression in broncho-alveolar lavage (BAL) cells from patients with TB (n = 40) or with other non-mycobacterial lung pathologies, namely asthma (n = 14) and sarcoidosis (n = 11), as well as from control individuals (n = 9). We show that in patients with TB, up to 70% of alveolar Mφs express DC-SIGN. By contrast, the lectin is barely detected in alveolar Mφs from all other individuals. Flow cytometry, RT-PCR, and enzyme-linked immunosorbent assay analyses of BAL-derived fluids and cells indicated that M. tuberculosis infection induces DC-SIGN expression in alveolar Mφs by a mechanism that is independent of Toll-like receptor-4, interleukin (IL)-4, and IL-13. This mechanism most likely relies on the secretion of soluble host and/or mycobacterial factors that have yet to be identified, as both infected and uninfected bystander Mφs were found to express DC-SIGN in the presence of M. tuberculosis. Immunohistochemical examination of lung biopsy samples from patients with TB showed that the bacilli concentrate in pulmonary regions enriched in DC-SIGN-expressing alveolar Mφs in vivo. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN–expressing alveolar Mφs constitute preferential target cells for M. tuberculosis, as compared to their DC-SIGN− counterparts. In contrast with what has been reported previously in MoDCs in vitro, ex vivo DC-SIGN ligation by mycobacterial products failed to induce IL-10 secretion by alveolar Mφs, and IL-10 was not detected in BALs from patients with TB. Conclusion Altogether, our results provide further evidence for an important role of DC-SIGN during TB in humans. DC-SIGN induction in alveolar Mφs may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host., Alveolar macrophages from patients with TB express higher levels of DC-SIGN compared with controls. Ex-vivo infection induced DC-SIGN in infected and bystander cells, which made the latter more susceptible.