Diagnostic values of the QuantiFERON-TB Gold In-tube assay carried out in China for diagnosing pulmonary tuberculosis.

BACKGROUND: Interferon-release assays (IGRAs) for diagnosing active pulmonary tuberculosis (PTB) are not yet fully validated, particularly in high TB-endemic areas as the People's Republic of China (PRC). The aim of this report was to assess the performance of the QuantiFERON-TB Gold In-tube (QFT-GIT) and tuberculin skin test (TST), in addition to microbiological results, as contributors for diagnosing active PTB in the PRC. METHODS/PRINCIPAL FINDINGS: A total of 300 PTB patients, 41 disease controls (DC) and 59 healthy community controls (HCC) were included prospectively between May 2010 and April 2011 from two provinces of the PRC (Heilongjiang and Zhejiang). The QFT-GIT and TST yielded an overall sensitivity for active TB of 80.9% and 86.2%, and a specificity of 36.6% and 26.8%, respectively. The province of origin and smear microscopy status did not significantly impact the diagnostic values for PTB. However, using the TST with a 10 mm cut-off point, a significantly higher proportion of LTBI was observed in the DC than the HCC (p=0.01). Discordant results between the QFT-GIT and TST were found among 1/3 of the PTB, HCC and DC. Two-thirds of the individuals presented TST-positive/QFT-GIT-negative discordant results. The TST-negative/QFT-GIT-positive result was not associated with age or bacillary load. Cumulative QFT-GIT and TST positive results increased the overall sensitivity (95.9%), but it was associated with a dramatic decrease of the overall specificity (24.8%) leading to a suboptimal PPV (80.1%) and a low NPV (61.1%). CONCLUSIONS/SIGNIFICANCE: The usefulness of the QFT-GIT to diagnose active TB in high TB-endemic countries remains doubtful because like the TST, the QFT-GIT cannot distinguish between LTBI and active TB. Used as single stand-alone tests, both the QFT-GIT and TST have very limited roles in the diagnosis of active PTB. However, the combined use of SM, the TST and QFT-GIT may allow for the exclusion of ATB.

A toolbox for tuberculosis (TB) diagnosis: an Indian multi-centric study (2006-2008); evaluation of serological assays based on PGL-Tb1 and ESAT-6/CFP10 antigens for TB diagnosis.

BACKGROUND: The aim of this multi-centric prospective study in India was to assess the accuracy of a serological test as an additional tool for diagnosing active tuberculosis (ATB). In particular, an assay based on ELISA using a phenolic glycolipid (PGL-Tb1) or a fusion protein (ESAT-6/CFP10) was compared to the tuberculin skin test (TST) and the microbiological results according to HIV status. METHODS: Individuals with and without ATB and HIV infection were enrolled. Serology and TST results were analyzed per se and in combination with the microbiological data. RESULTS: Among the 778 ATB patients, 102 were HIV-infected, 316 HIV-uninfected and 360 had an HIV-unknown status. Of the 945 non-ATB subjects, 559 were at low risk (community adults) and 386 at high risk of M. tuberculosis exposure. Among those with ATB, the sensitivity of ELISA-PGL-Tb1 for ATB was higher than that of ELISA-ESAT-6/CFP10, both in HIV-infected (72.3% versus 63.7%, p = 0.29) and HIV-uninfected/HIV-unknown groups (40.5% versus 28.6%; p<0.0001), whereas the specificity was around 91% for both tests. Sensitivity for ATB increased when the results of the two ELISA were combined, reaching 75.5% in the HIV-infected and 50.9% in the group of HIV-uninfected/HIV-unknown ATB, with a significant decrease of the global specificity (83.9%). Analyzing the ELISA results with the microbiological results, we observed that the sensitivity of both serology tests was independent of the ATB patients' smear microscopy (SM) status and grade. Combining the results of SM with both ELISA, the detection of ATB patients significantly increased (p<0.0001), particularly in those with extrapulmonary TB (up to 45.1%) or HIV infection (up to 83.3%). No significant association was observed between TST and serology results. CONCLUSIONS: In this prospective multi-centric study, the combination of two rapid tests, such as SM and serology, might be useful in detecting ATB, especially in HIV-infected patients.

A toolbox for tuberculosis (TB) diagnosis: an Indian multicentric study (2006-2008). Evaluation of QuantiFERON-TB gold in tube for TB diagnosis.

BACKGROUND: The aim of this multicentric prospective study in India was to assess the performance of the QuantiFERON TB-Gold in tube (QFT-GIT), Tuberculin Skin Test (TST) and microbiological results as additional tools for diagnosing active tuberculosis (TB) and latent infection (LTBI) according to Human Immunodeficiency Virus (HIV) status. METHODS: Individuals with and without active TB and HIV infection were enrolled between 2006-2008. QFT-GIT and TST results were analyzed per se and in combination with microbiological data. RESULTS: Among the 276 individuals (96 active pulmonary TB and 180 no active TB) tested by QFT-GIT, 18 indeterminate results (6.5%) were found, more significantly numerous in the HIV-infected (15/92; 16.3%) than the HIV-uninfected (3/184; 1.6%)(p<0.0001). QFT-GIT sensitivity for active TB was 82.3% and 92.9% respectively after including or excluding indeterminate results. Clinical sensitivity was significantly lower in the HIV-infected (68.4%) than the HIV-uninfected (91.4%) patients (p = 0.0059). LTBI was detected in 49.3% of subjects without active TB but varied according to TB exposure. When the TST and QFT-GIT were concomitantly performed, the respective sensitivity for active TB diagnosis was 95.0% and 85.0% in the HIV-uninfected (p = 0.60), and 66.7% and 51.5% in the HIV-infected patients (p = 0.32). QFT-GIT and TST respective specificity for active TB in the HIV-uninfected was 25.0% and 57.1% (p = 0.028), and 64.8% and 83.3% in the HIV-infected (p = 0.047). In those with active TB, QFT-GIT results were not associated with microbiological parameters (smear grade, liquid culture status, time-to-positivity of culture) or clinical suspicion of active TB score (provided by the clinicians at enrollment). Combining microbiological tests with both immunological tests significantly increased sensitivity for active TB diagnosis (p = 0.0002), especially in the HIV-infected individuals (p = 0.0016). CONCLUSION: QFT-GIT and TST have similar diagnostic value for active TB diagnosis. In HIV-infected patients, combining microbiological tests with both immunological tests significantly increases the sensitivity for active TB diagnosis.

A toolbox for tuberculosis diagnosis: an Indian multicentric study (2006-2008): microbiological results.

BACKGROUND: The aim of this multicentric prospective study in India was to assess the value of several microbiological tools that contribute to the diagnosis of tuberculosis (TB) according to HIV status. METHODS: Standard microbiological tools on individual specimens were analyzed. RESULTS: Among the 807 patients with active TB, 131 were HIV-infected, 316 HIV-uninfected and 360 had HIV-unknown status. Among the 980 non-active TB subjects, 559 were at low risk and 421 were at high risk of M. tuberculosis (Mtb) exposure. Sensitivity of smear microscopy (SM) was significantly lower in HIV-infected (42.2%) than HIV-uninfected (75.9%) (p = 0.0001) and HIV-unknown pulmonary TB patients (61.4%) (p = 0.004). Specificity was 94.5% in non-TB patients and 100% in health care workers (HCW) and healthy family contacts. Automated liquid culture has significantly higher diagnostic performances than solid culture, measured by sensitivity (74.7% vs. 55.9%) (p = 0.0001) and shorter median time to detection (TTD) (12.0 vs. 34.0 days) (p = 0.0001). Specificity was 100% in HCW and cured-TB patients, but was lower in non-TB patients (89%) due to isolation of Mycobacteria other than tuberculosis (MOTT). TTD by both methods was related to AFB score. Contamination rate was low (1.4%). AccuProbe hybridization technique detected Mtb in almost all culture-positive specimens, but MOTT were found in 4.7% with a significantly higher frequency in HIV-infected (15%) than HIV-uninfected TB patients (0.5%) (p = 0.0007). Pre-test classification significantly increased the diagnostic value of all microbiological tests in pulmonary TB patients (p<0.0001) but to a lesser degree in extrapulmonary TB patients. CONCLUSIONS: Conventional microbiological tools led to results similar to those already described in India special features for HIV-infected TB patients included lower detection by SM and culture. New microbiological assays, such as the automated liquid culture system, showed increased accuracy and speed of detection.

Diagnosing latent tuberculosis infection in the HIV era.

Tuberculin skin testing (TST) and Interferon-gamma (IFNγ)release assays (IGRAs) are presently the only available assays for the detection of Mycobacterium tuberculosis infected individuals. IGRAs might progressively replace TST, as numerous published reports establish their higher specificity and similar sensitivity when tested in BCG vaccinated, immunocompetent individuals or in populations who may have been in contact with atypical mycobacteria. However, few published reports have commented on their role in TB diagnosis in immunocompromised individuals (HIV, immunosuppressive therapy, cancer...). It is the purpose of this report to review IGRAs published studies in HIV individuals in endemic and non endemic area for tuberculosis (TB). IGRAs were tested in the presence or absence of active TB but correlated to duration of exposure. In newly diagnosed active TB, IGRAs demonstrated a similar sensitivity to TST. In TB non infected individuals, TST and IGRAs also gave similar values when categorization of individuals was correlated to the risk of infection. A higher number of positive IGRAs was observed in individuals from TB endemic areas, in similar proportions to immunocompetent individuals. Comparison between the two IGRAs: QuantiFERON-TB Gold(®) (QF-TB, Cellestis, Australia) and T-SPOT-TB(®) (Oxford Immunotec, UK), and against TST, in the same HIV population demonstrates a higher sensitivity of T-SPOT-TB and TST than QF-TB. Indeterminate results, which correspond to the absence of a positive T-cell IFNγ response towards phytohemaglutinin (PHA), is a key point when comparing both IGRAs. This PHA control is indicative of the level of immunosuppression observed in the tested individual. QF-TB seems to present, in HIV populations, more indeterminate results than T-SPOT-TB. The calibration and/or concentration of PBMC on nitrocellulose membrane for the T-SPOT-TB, as compared to a whole blood assay, might explain this difference, with less indeterminate results with the T-SPOT-TB assay. Neither assay is able to differentiate active TB from latent TB infection (LTBI). Several laboratories have tried new antigenic epitopes to solve this issue. It is of importance that these studies need to be repeated on a larger scale by others to validate their results. Two blood assays might add information characterising the evolution from LTBI to active TB: either by losing protective immunity, as demonstrated by the whole blood killing assay, or by evaluating the kinetics of the antibodies synthesized against M. tuberculosis specific antigens. In conclusion, longitudinal studies are still needed to validate IGRAs and other assays and to define their respective predictive values.

Intermediate maturation of Mycobacterium tuberculosis LAM-activated human dendritic cells.

Contrasting observations raise the question of the role of mycobacterial derived products as compared with the whole bacterium Mycobacterium tuberculosis on maturation and function of human dendritic cells (DCs). DC-SIGN has been identified as the key DC receptor for M. tuberculosis through its interaction with the mannosylated lipoarabinomannan (ManLAM). Although ManLAM is a major mycobacterial component released from infected antigen-presenting cells, there is no formal evidence yet for an effect of ManLAM per se on DC maturation and function. DCs activated with purified ManLAM displayed an intermediate maturation phenotype as compared with lipopolysaccharide fully matured DCs with reduced expression of MHC class I and class II molecules, CD83 and CD86 and of the chemokine receptor CCR7. They were sensitive to autologous natural killer (NK) lysis, thus behaving like immature DCs. However, ManLAM-activated DCs lost phagocytic activity and triggered priming of naive T-cells, confirming their intermediate maturation. Partial maturation of ManLAM-activated DCs was overcome by triggering the CD40/CD40L pathway as a second signal, which completed maturation phenotypically and abolished autologous NK lysis susceptibility. Altogether, these data provide evidence that ManLAM may induce a partial maturation phenotype on non-infected bystander DCs during infection suggesting that ManLAM released from infected cells might impair adaptive immune response towards M. tuberculosis.

B-cell immune responses in HIV positive and HIV negative patients with tuberculosis evaluated with an ELISA using a glycolipid antigen.

The diagnostic value of the PGL-Tb1 enzyme-linked immunosorbent assays (ELISA) was established following a survey study using sera from 220 Tuberculosis patients (including 69 HIV coinfected) and 324 controls. A higher percentage (76.8%) of the HIV-seropositive compared to the HIV-seronegative (58.9%) TB patients were ELISA positive (p=0.02) with a specificity of 94%. In HIV-positive TB patients, ELISA sensitivity was identical for all sites of disease and antibody levels were not affected by the CD4+ counts, PPD results, age or bacterial yield. Combining data for both the smear microscopy and ELISA maximized sensitivity. The kinetics of anti-PGL-Tb1 antibody was evaluated in cohort studies using sera collected before, during and after treatment for clinical TB for 79 TB patients (including 39 HIV coinfected). Statistically significant ELISA signals were observed in 51.3% of HIV-seropositive TB patients prior to the diagnosis of clinical TB and elevated antibody levels persisting 18 months after the end of antituberculous chemotherapy. Asymptomatic development of antibody also occurred in 22.7% of a cohort of 44 HIV-positive patients with a high risk of tuberculosis, but no correlation was found between persisting elevated antibody levels and progression to active disease. This antibody response in absence of disease, might reflect the control of an incipient tuberculosis infection by antituberculous prophylaxis or through an improved protective immune response associated with antiretroviral therapy.

Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients.

OBJECTIVES: To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV-tuberculosis (TB) coinfected patients. DESIGN: Prospective, multicenter study of 19 consecutive untreated HIV-TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS- if no IRS occurred within 3 months after HAART initiation. METHODS: Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-gamma quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence. RESULTS: Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-gamma-producing cells increased sharply during IRS (median, 2970 spot forming cells/10 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6- but no 85B-specific responses. IRS- patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-gamma, IP10 and monokine-induced by IFN-gamma] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-alpha, IL-6, IL-1beta, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation. CONCLUSION: An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.

DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis.

BACKGROUND: Interplays between Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) in human and host professional phagocytes, namely macrophages (Mphis) 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 Mphis express DC-SIGN. By contrast, the lectin is barely detected in alveolar Mphis 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 Mphis 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 Mphis 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 Mphis in vivo. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN-expressing alveolar Mphis 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 Mphis, 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 Mphis may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host.

Deciphering the molecular bases of Mycobacterium tuberculosis binding to the lectin DC-SIGN reveals an underestimated complexity.

Interactions between dendritic cells and Mycobacterium tuberculosis, the aetiological agent of tuberculosis in humans, are thought to be central to anti-mycobacterial immunity. We have previously shown that M. tuberculosis binds to human monocyte-derived dendritic cells mostly through the C-type lectin DC-SIGN (dendritic-cell-specific intercellular molecule-3-grabbing non-integrin)/CD209, and we have suggested that DC-SIGN may discriminate between mycobacterial species through recognition of the mannose-capping residues on the lipoglycan lipoarabinomannan of the bacterial envelope. Here, using a variety of fast- and slow-growing Mycobacterium species, we provide further evidence that mycobacteria recognition by DC-SIGN may be restricted to species of the M. tuberculosis complex. Fine analyses of the lipoarabinomannan molecules purified from these species show that the structure and amount of these molecules alone cannot account for such a preferential recognition. We propose that M. tuberculosis recognition by DC-SIGN relies on both a potential difference of accessibility of lipoarabinomannan in its envelope and, more probably, on the binding of additional ligands, possibly including lipomannan, mannose-capped arabinomannan, as well as the mannosylated 19 kDa and 45 kDa [Apa (alanine/proline-rich antigen)] glycoproteins. Altogether, our results reveal that the molecular basis of M. tuberculosis binding to DC-SIGN is more complicated than previously thought and provides further insight into the mechanisms of M. tuberculosis recognition by the immune system.

DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells.

Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mphis), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis-derived material was detected in CD14(-)HLA-DR(+)DC-SIGN(+) cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN-mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.

Comparison of A60 and three glycolipid antigens in an ELISA test for tuberculosis.

OBJECTIVES: To compare the diagnostic usefulness in tuberculosis of the serodiagnostic enzyme-linked immunosorbent assay (ELISA) kit A60 (Anda Biologicals, Strasbourg, France) and of our domestic ELISA based on three purified cell wall glycolipid antigens. METHODS: The presence and concentrations of IgG and IgM anti-A60 antibodies and anti-LOS, anti-DAT and anti-PGLTb1 antibodies against the glycolipid antigens were determined by ELISA in 50 HIV-seronegative and 46 HIV-seropositive patients, with documented active tuberculosis. The specificity of these ELISAs was determined with use of sera from 50 healthy blood donors, 29 patients with non-mycobacterial pulmonary diseases and 24 HIV-positive patients with disseminated Mycobacterium avium infection. RESULTS: With a calculated cut-off for each antigen and immunoglobulin that gave a specificity higher than or equal to 98%, the cumulative ELISA results showed that only 36.5% of the patients with tuberculosis had a positive response in the A60 test, as compared with 84.4% who showed a response to the three glycolipid antigens (p<0.001). This striking difference persisted when the cumulative sensitivities were calculated according to the HIV status of the patients and the localization of tuberculosis. The anti-A60 antibody (IgG and IgM) levels and the degree of sensitivity of the ELISA for detection of A60 antigen were always lower in HIV-positive patients with pulmonary and extrapulmonary tuberculosis than in HIV-negative patients with tuberculosis. The sensitivity of A60 ELISA was further decreased in HIV-positive patients with low CD4+ lymphocytes counts, in contrast to the results with the three glycolipid antigens. CONCLUSIONS: These results show the limitations of the A60 ELISA, and confirm the potencies of the glycolipid antigens in serodiagnosis of tuberculosis in HIV-positive and HIV-negative patients.

The colonization of cartilage by "Trypanosoma cruzi" associated with inflammatory reaction

Objetivo: Avaliar no modelo murino o nível de colonizaçao de cartilagens costais e articulares, assim como os ligamentos pelo Trypanosoma cruzi. Métodos: Estudo histopatológico e histoquímico das cartilagens, ligamentos e musculatura esquelética em camundongos atímicos e eutímicos na fase aguda da doença de Chagas experimental. Resultados: Foi observado que em camundongos jovens, infectados com duas amostras polares de T. cruzi, as cartilagens, os ligamentos, a musculatura esquelética e a medula óssea apresentavam-se altamente colonizados pelo parasito. A colonizaçao do pericôndrio e ligamentos muitas vezes está associada com uma reaçao inflamatória em que predomina um infiltrado mononuclear. A idade é um fator importante na colonizaçao da cartilagem pelo parasito, sendo rara em camundongos adultos. A miosite observada no miocárdio e músculos esqueléticos de camundongos, que apresentam a resposta T-dependente intacta, muitas vezes mostra uma paralisia de membros posteriores. Neste caso, observamos certa freqüência de calcificaçao da fibra muscular demonstrada por testes histoquímicos. Camundongos atímicos (Nude) nao têm miosite nem calcificaçao, porém apresentam carga parasitária em níveis extraordinários na musculatura lisa e estriada. Conclusoes: Os fenômenos de paralisia na fase aguda aparecem com freqüência associados com calcificaçoes observadas na musculatura esquelética e a uma intensa miosite. Os resultados mostraram que estes aspectos da patologia da doença de Chagas experimental estao relacionados com a resposta T-dependente, pois camundongos atímicos nunca apresentaram o quadro acima descrito, apesar da intensa carga parasitária nos tecidos musculares. Cepas polares, quer sejam miotrópica ou reticulotrópicas, estao envolvidas com os fenômenos de paralisia. Os condrócitos sao colonizados pelo T. cruzi, assim como o pericôndrio, o que desencadeia um processo inflamatório local

Preliminary evidence of natural resistance to Mycobacterium bovis (BCG) in lepromatous leprosy

An assay system has been developed based on radiometric quantification of 3H uracil incorporation into viable BCG in the absence or presence of blood monocytes in cultures from untreated lepromatous (LL) or tuberculoid (TT) leprosy patients. 3H Uracil incorporation into BCG was inhibited when the bacilli were cultivated in the presence of blood-derived macrophages in culture for four days, and that inhibition was always greater with macrophages harvested from LL patients compared to TT patients. The reasons for such an observed difference in humans are discussed according to our knowledge obtained in murine models of mycobacterial infections.