Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in about 1/100,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and 1/2,500 other individuals, is much more frequent in patients with tuberculosis than in ethnicity-adjusted controls (p = 8.37×10−8, odds ratio = 89.31 [95%CI: 14.7–1,725]). We also show that the frequency of P1104A in Europeans has decreased significantly, from about 9% to 4.2%, over the last 4,000 years, consistent with purging of this variant by endemic tuberculosis. Moreover, we show that catalytically inactive P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Finally, we show that catalytically competent TYK2 is critical for IL-23 but not IL-12 responses, whereas catalytically competent JAK2 is redundant for both. Homozygosity for the P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

BackgroundTuberculosis represents a serious public health problem and a significant diagnostic and therapeutic challenge worldwide. Molecular diagnostic techniques are crucial in the World Health Organization’s new tuberculosis control strategy.This study aims to evaluate the performance of GeneXpert MTB/RIF (Cepheid Sunnyvale, CA, United States) in diagnosis of extra-pulmonary tuberculosis then compare it’s performance in detecting Rifampicin resistance to GenoType MTBDRplus (HAIN Life Sciences, Nehren, Germany).MethodsSamples from pulmonary and/or extra-pulmonary origins were analysed in a 21 months retrospective study. Samples were sent to the bacteriology laboratory for Mycobacterium tuberculosis detection using conventional bacteriological and molecular methods (GeneXpert MTB/RIF and MTBDRplus). Sensitivity and specificity were calculated for the stained smear and GeneXpert according to culture (Gold Standard) as well as for GeneXpert MTB/RIF in both negative and positive microscopy tuberculosis cases. Data’s statistical analysis was performed with SPSS13.0 software.ResultsSeven hundred fourteen patients’ samples were analysed; the average age was 47.21 ± 19.98 years with a male predominance (66.4%). Out of 714 samples: 285 were from pulmonary and 429 were from extra-pulmonary origins. The positivity rates for microscopy, GeneXpert MTB/RIF and culture were 12.88, 20.59 and 15.82%, respectively. These rates were 18.9, 23.85 and 20.35% for pulmonary samples and 9.71, 18.41 and 12.82% for extra-pulmonary samples, respectively. The sensitivity and specificity of GeneXpert MTB/RIF were almost the same in both pulmonary and extra-pulmonary samples (78.2 and 90.4%) and (79,3 and 90.3%) respectively.Rifampicin resistance rate found by GeneXpert MTB/RIF was 0.84%. Comparison of Rifampicin resistance obtained by GeneXpert MTB/RIF and Genotype MTBDRplus, showed 100% agreement between the two techniques for studied samples.ConclusionsThis confirms GeneXpert MTB/RIF advantage for tuberculosis diagnosis, particularly extra-pulmonary tuberculosis with negatively stained smear. The performance of GeneXpert and Genotype MTBDRplus are similar in detection of Rifampicin resistance. However, variability of detection performance according to tuberculosis endemicity deserves more attention in the choice of screening techniques of Rifampicin resistance, hence the interest of conducting comparative studies of detection performance under low and medium endemicity on large samples of tuberculosis populations.

Increased prevalence of latent tuberculosis infection (LTBI) has been observed among high-risk populations such as healthcare workers (HCWs). The results may depend on the method of LTBI assessment, interferon-gamma release assay (IGRA) and/or tuberculin skin test (TST). Here, we investigated the prevalence and risk factors for LTBI assessed by both IGRAs and TST in HCWs living in Morocco, a country with intermediate tuberculosis (TB) endemicity and high BCG vaccination coverage. HCWs were recruited in two Moroccan hospitals, Rabat and Meknes. All the participants underwent testing for LTBI by both IGRA (QuantiFERON-TB Gold In-Tube, QFT-GIT) and TST. Different combinations of IGRA and TST results defined the LTBI status. Risk factors associated with LTBI were investigated using a mixed-effect logistic regression model. The prevalence of LTBI among 631 HCWs (age range 18–60 years) varied from 40.7% (95%CI 36.9–44.5%) with QFT-GIT to 52% (95%CI 48.2–56.0%) with TST using a 10 mm cut-off. The highest agreement between QFT-GIT and TST (κ = 0.50; 95%CI 0.43–0.56) was observed with the 10 mm cut-off for a positive TST. For a definition of LTBI status using a double positive result for both QFT-GIT and TST, significant associations were found with the following risk factors: being male (OR = 2.21; 95%CI 1.40–3.49; p = 0.0007), belonging to age groups 35–44 years (OR = 2.43; 95%CI 1.45–4.06; p = 0.0007) and even more 45–60 years (OR = 4.81; 95%CI 2.72–8.52; p = 7.10 −8 ), having a family history of TB (OR = 6.62; 95%CI 2.59–16.94; p = 8.10 −5 ), and working at a pulmonology unit (OR = 3.64; 95%CI 1.44–9.23; p = 0.006). Smoking was associated with LTBI status when defined by a positive QFT-GIT result (OR = 1.89; 95%CI 1.12–3.21; p = 0.02). A high prevalence of LTBI was observed among HCWs in two Moroccan hospitals. Male gender, increased age, family history of TB, and working at a pulmonology unit were consistent risk factors associated with LTBI.

Smoking is the leading cause of preventable death worldwide, it is responsible for 90% of bronchopulmonary cancers and is the main cause of chronic bronchitis and emphysema, two disorders which contribute to chronic obstructive pulmonary disease (COPD). We here report the case of a 58-year old not weaned chronic tabagic patient with a 2-month history of diffuse abdominal pain evolving in a context of alteration of the general state. Clinical examination showed generally poor health. Pleuropulmonary examination objectified reduction of vesicular breath sounds in the right hemithorax and diffuse abdominal susceptibility and massive left subclavicular lymphadenopathy. Thoraco-abdominal CT scan showed pleural, intra-abdominal and retroperitoneal tissue infiltration and diffuse bilateral lung emphysema (Figure). Bronchial fibroscopy objectified bud obstructing the orifice of the apical bronchus of the right upper lobar bronchus. Anatomopathologic study of bronchial biopsy and lymph node biopsy showed non-differentiated carcinoma. Evolution was marked by patient’s death after two weeks. This study aims to highlight fatal outcome due to these two complications due to tobacco use in the same patient in order to emphasize the importance of prevention awareness of the damages of tobacco use and on smoking cessation.

Here, we describe the annotated genome sequence of Mycobacterium tuberculosis MTB13_M. The organism was isolated from a sputum sample in Morocco.