The Evolution and Transmission Dynamics of Multidrug-Resistant Tuberculosis in an Isolated High-Plateau Population of Tibet, China

On the Tibetan Plateau, most tuberculosis is caused by indigenous Mycobacterium tuberculosis strains with a monophyletic structure and high-level drug resistance. This study investigated the emergence, evolution, and transmission dynamics of multidrug-resistant tuberculosis (MDR-TB) in Tibet. The whole-genome sequences of 576 clinical strains from Tibet were analyzed with the TB-profiler tool to identify drug-resistance mutations. The evolution of the drug resistance was then inferred based on maximum-likelihood phylogeny and dated trees that traced the serial acquisition of mutations conferring resistance to different drugs. Among the 576 clinical M. tuberculosis strains, 346 (60.1%) carried at least 1 resistance-conferring mutation and 231 (40.1%) were MDR-TB. Using a pairwise distance of 50 single nucleotide polymorphisms (SNPs), most strains (89.9%, 518/576) were phylogenetically separated into 50 long-term transmission clusters. Eleven large drug-resistant clusters contained 76.1% (176/231) of the local multidrug-resistant strains. A total of 85.2% of the isoniazid-resistant strains were highly transmitted with an average of 6.6 cases per cluster, of which most shared the mutation KatG Ser315Thr. A lower proportion (71.6%) of multidrug-resistant strains were transmitted, with an average cluster size of 2.9 cases. The isoniazid-resistant clusters appear to have undergone substantial bacterial population growth in the 1970s to 1990s and then subsequently accumulated multiple rifampicin-resistance mutations and caused the current local MDR-TB burden. These findings highlight the importance of detecting and curing isoniazid-resistant strains to prevent the emergence of endemic MDR-TB. IMPORTANCE Emerging isoniazid resistance in the 1970s allowed M. tuberculosis strains to spread and form into large multidrug-resistant tuberculosis clusters in the isolated plateau of Tibet, China. The epidemic was driven by the high risk of transmission as well as the potential of acquiring further drug resistance from isoniazid-resistant strains. Eleven large drug-resistant clusters consisted of the majority of local multidrug-resistant cases. Among the clusters, isoniazid resistance overwhelmingly evolved before all the other resistance types. A large bacterial population growth of isoniazid-resistant clusters occurred between 1970s and 1990s, which subsequently accumulated rifampicin-resistance-conferring mutations in parallel and accounted for the local multidrug-resistant tuberculosis burden. The results of our study indicate that it may be possible to restrict MDR-TB evolution and dissemination by prioritizing screening for isoniazid (INH)-resistant TB strains before they become MDR-TB and by adopting measures that can limit their transmission

Mycobacterium tuberculosis ecology in Venezuela: epidemiologic correlates of common spoligotypes and a large clonal cluster defined by MIRU-VNTR-24

<p>Abstract</p> <p>Background</p> <p>Tuberculosis remains an endemic public health problem, but the ecology of the TB strains prevalent, and their transmission, can vary by country and by region. We sought to investigate the prevalence of <it>Mycobacterium tuberculosis </it>strains in different regions of Venezuela. A previous study identified the most prevalent strains in Venezuela but did not show geographical distribution nor identify clonal genotypes. To better understand local strain ecology, we used spoligotyping to analyze 1298 <it>M. tuberculosis </it>strains isolated in Venezuela from 1997 to 2006, predominantly from two large urban centers and two geographically distinct indigenous areas, and then studied a subgroup with MIRU-VNTR 24 loci.</p> <p>Results</p> <p>The distribution of spoligotype families is similar to that previously reported for Venezuela and other South American countries: LAM 53%, T 10%, Haarlem 5%, S 1.9%, X 1.2%, Beijing 0.4%, and EAI 0.2%. The six most common shared types (SIT's 17, 93, 605, 42, 53, 20) accounted for 49% of the isolates and were the most common in almost all regions, but only a minority were clustered by MIRU-VNTR 24. One exception was the third most frequent overall, SIT 605, which is the most common spoligotype in the state of Carabobo but infrequent in other regions. MIRU-VNTR homogeneity suggests it is a clonal group of strains and was named the "Carabobo" genotype. Epidemiologic comparisons showed that patients with SIT 17 were younger and more likely to have had specimens positive for Acid Fast Bacilli on microscopy, and patients with SIT 53 were older and more commonly smear negative. Female TB patients tended to be younger than male patients. Patients from the high incidence, indigenous population in Delta Amacuro state were younger and had a nearly equal male:female distribution.</p> <p>Conclusion</p> <p>Six SIT's cause nearly half of the cases of tuberculosis in Venezuela and dominate in nearly all regions. Strains with SIT 17, the most common pattern overall may be more actively transmitted and SIT 53 strains may be less virulent and associated with reactivation of past infections in older patients. In contrast to other common spoligotypes, strains with SIT 605 form a clonal group centered in the state of Carabobo.</p

A Neuromedin U Receptor Acts with the Sensory System to Modulate Food Type-Dependent Effects on C. elegans Lifespan

Different food types modulate worm lifespan and involve the neuropeptide receptor NMUR-1, which acts with the sensory neurons in a bacterial lipopolysaccaharide structure-dependent manner

Mycobacterium tuberculosis clinical isolates carry mutational signatures of host immune environments

9 páginas, 4 figuras. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. Sequencing reads have been submitted to the European Nucleotide Archive (EMBL-EBI) under study accession PRJEB34582 and PRJEB34609. The analysis scripts used in this study are available online at GitHub (https://github.com/StopTB/Single_Colony_Project).Mycobacterium tuberculosis (Mtb) infection results in a spectrum of clinical and histopathologic manifestations. It has been proposed that the environmental and immune pressures associated with different contexts of infection have different consequences for the associated bacterial populations, affecting drug susceptibility and the emergence of resistance. However, there is little concrete evidence for this model. We prospectively collected sputum samples from 18 newly diagnosed and treatment-naïve patients with tuberculosis and sequenced 795 colony-derived Mtb isolates. Mutant accumulation rates varied considerably between different bacilli isolated from the same individual, and where high rates of mutation were observed, the mutational spectrum was consistent with reactive oxygen species-induced mutagenesis. Elevated bacterial mutation rates were identified in isolates from HIV-negative but not HIV-positive individuals, suggesting that they were immune-driven. These results support the model that mutagenesis of Mtb in vivo is modulated by the host environment, which could drive the emergence of variants associated with drug resistance in a host-dependent manner.This work was supported by the National Natural Science Foundation of China (91631301 and 81661128043 to Q.G., 81701975 to Q.L., and 31771416 to X.L.), the National Science and Technology Major Project of China (2017ZX10201302 to Q.G. and 2018ZX10714002-001-005 to Z.Z.), the Sanming Project of Medicine in Shenzhen (SZSM201611030 to Q.G.), European Research Council 638553-TB-AcCELERATE (to I.C.), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-220-1 to X.L.), and the CAS Light of West China Program (to X.L.). Y.F. is supported in part by NIH R01HG009524. Support was also received from NIH awards P01 AI132130 and AI142793 to S.M.F.Peer reviewe

The use of GeneXpert remnants for drug resistance profiling and molecular epidemiology of tuberculosis in Libreville, Gabon

International audienceMultidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis are major problems in global health. The GeneXpertMTB/RIF (Xpert) rapidly detects resistance to rifampicin (RIF-R), but detection of the additional resistance that defines MDR and XDR-TB, and for molecular epidemiology, specimen cultures and biosafe infrastructure are generally required. We sought to determine whether the remnants of sputa prepared for Xpert could be used directly to find mutations associated with drug resistance and for molecular epidemiology, and thus provide a precise characterization of MDR-TB cases in countries lacking BSL3 facilities for M. tuberculosis cultures. After sputa were processed and run on the Xpert instrument, the leftovers of the samples prepared for Xpert were used for PCR amplification and sequencing or line probe assay to detect mutations associated with resistance to additional drugs, and for molecular epidemiology with spoligotyping and selective MIRU-VNTR. Of 130 sputum samples from Gabon tested with Xpert, 124 yielded interpretable results, of which 21 were determined to be RIF-R (17%). Amplification and sequencing or line probe assay of the Xpert remnants confirmed 18/21 as MDR: 11/116 (9.5%) new and 7/8 (87%) previously treated TB patients. Spoligotyping and MIRU with hypervariable loci identified an MDR Beijing strain present in five samples. We conclude that the remnants of samples processed for Xpert in PCR reactions can be used to find mutations associated with the resistance to the additional drugs that define MDR and XDR-TB, and to study molecular epidemiology without the need for culturing or biosafe infrastructure

Low Child Survival Index in a Multi-Dimensionally Poor Amerindian Population in Venezuela

<div><p>Background</p><p>Warao Amerindians, who inhabit the Orinoco Delta, are the second largest indigenous group in Venezuela.  High Warao general mortality rates were mentioned in a limited study 21 years ago. However, there have been no comprehensive studies addressing child survival across the entire population.</p> <p>Objectives</p><p>To determine the Child Survival-Index (CSI) (ratio: still-living children/total-live births) in the Warao population, the principal causes of childhood death and the socio-demographic factors associated with childhood deaths.</p> <p>Methods</p><p>We conducted a cross-sectional epidemiological survey of 688 women from 97 communities in 7 different subregions of the Orinoco Delta. Data collected included socio-demographic characteristics and the reproductive history of each woman surveyed. The multidimensional poverty index (MPI) was used to classify the households as deprived across the three dimensions of the Human Development Index. Multivariable linear regression and Generalized Linear Model Procedures were used to identify socioeconomic and environmental characteristics statistically associated with the CSI.</p> <p>Findings</p><p>The average CSI was 73.8% ±26. The two most common causes of death were gastroenteritis/diarrhea (63%) and acute respiratory tract Infection/pneumonia (18%).  Deaths in children under five years accounted for 97.3% of childhood deaths, with 54% occurring in the neonatal period or first year of life.  Most of the women (95.5%) were classified as multidimensionally poor.  The general MPI in the sample was 0.56.   CSI was negatively correlated with MPI, maternal age, residence in a traditional dwelling and profession of the head of household other than nurse or teacher.</p> <p>Conclusions</p><p>The Warao have a low CSI which is correlated with MPI and maternal age.  Infectious diseases are responsible for 85% of childhood deaths.  The low socioeconomic development, lack of infrastructure and geographic and cultural isolation suggest that an integrated approach is urgently needed to improve the child survival and overall health of the Warao Amerindians. </p> </div

Deaths among Warao live-births by age groups.

<p>Deaths among Warao live-births by age groups.</p

Flow Diagram.

<p>Default technique used to select interviewed-women of our sample in the communities of the Orinoco Delta. </p