Lung infections with Mycobacterium abscessus, a species of multidrug resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF) where they accelerate inflammatory lung damage leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.Nontuberculous mycobacteria (NTM; referring to mycobacterial species other than M. tuberculosis complex and M. leprae) are ubiquitous environmental organisms that can cause chronic pulmonary infections in susceptible individuals [1,2], particularly those with preexisting inflammatory lung diseases such as cystic fibrosis (CF) [3]. The major NTM infecting CF individuals around the world is Mycobacterium abscessus; a rapidly growing, intrinsically multidrug-resistant species, which can be impossible to treat despite prolonged combination antibiotic therapy [1,[3][4][5], leads to accelerated decline in lung function [6,7], and remains a contraindication to lung transplantation in many centers [3,8,9].Until recently, NTM infections were thought to be independently acquired by individuals through exposure to soil or water [10][11][12]. As expected, previous analyses from the 1990s and 2000s [13][14][15][16] showed that CF patients were infected with unique, genetically diverse strains of M. abscessus, presumably from environmental sources. We used whole genome sequencing at a single UK CF center and identified two clusters of patients (11 individuals in total) infected with identical or near-identical M. abscessus isolates, which social network analysis suggested were acquired within hospital via indirect transmission between patients Phylogenetic analysis of these sequences (using one isolate per patient), supplemented by published genomes from US, France, Brazil, Malaysia, China, and South Korea (Table S1), was performed and analysed in the context of the geographical provenance of isolates ( Figure 1; Figure S1). Within each subspecies, we found multiple examples of deep branches (indicating large genetic differences) between isolates from different individuals, consistent with independent acquisition of unrelated environmental bacteria. However, we also identified multiple clades of near-identical isolates from geographically diverse locations (Figure 1), suggesting widespread transmission of circulating clones within the global CF patient community.To investigate further the relatedness of isolates from different individuals, we a...

Toll-like receptors (TLRs) and members of their signalling pathway play an important role in the initiation of the innate immune response to a wide variety of pathogens1,2,3. The adaptor protein TIRAP mediates downstream signalling of 5,6. We report a case-control genetic association study of 6106 individuals from Gambia, Kenya, United Kingdom, and Vietnam, with invasive pneumococcal disease, bacteraemia, malaria and tuberculosis. Thirty-three SNPs were genotyped, including TIRAP S180L. Heterozygous carriage of this variant was found to associate independently with all four infectious diseases in the different study populations (P=0.003, OR=0.59, 95%CI 0.42-0.83 for IPD; P=0.003, OR=0.40, 95%CI 0.21-0.77 for bacteraemia; P=0.002, OR=0.47, 95%CI 0.28-0.76 for malaria; P=0.008, OR=0.23 95%CI 0.07-0.73 for tuberculosis). Substantial support for a protective effect of S180L heterozygosity against infectious diseases was observed when the study groups were combined (N=6106, OverallCorrespondence should be addressed on genetics to AVSH (adrian.hill@well.ox.ac.uk) In the UK population, heterozygosity at TIRAP S180L was associated with protection from invasive pneumococcal disease (3×2 χ 2 =8.72, P=0.013, Table 1). An excess of mutant homozygotes amongst IPD cases (Table 1) was also observed in this UK population. TIRAP S180L was then examined in a separate group of UK individuals with thoracic empyema and a second control group. Although no association was observed between genotype and susceptibility to thoracic empyema overall (n=584, 3×2 χ 2 =0.63, P=0.73), analysis of the small subgroup of individuals with pneumococcal empyema revealed a non-significant trend towards association (3×2 χ 2 =5.05, P=0.080; Table 1). Interestingly, an excess of mutant homozygotes was again observed amongst this second group of IPD cases (Table 1).We then studied TIRAP S180L in a second population with invasive bacterial disease, comprising Kenyan children with well-defined bacteraemia. Although the mutant allele was found to be less common in the Kenyan population than in UK individuals, the same pattern of association was observed. The TIRAP S180L heterozygotes were significantly more common amongst community controls (5.9%), compared to individuals with bacteraemia (2.4%) (2×2 χ 2 =9.05, P=0.003; Table 1). The heterozygote protective effect of the S180L locus was also significant within the subgroup of 164 Kenyan children with pneumococcal bacteraemia (F exact =0.024, Table 1), thus replicating the findings in the UK studies.In the Gambian malaria case-control study, TIRAP S180L heterozygosity demonstrated a significant protective effect against both general malaria (Wald=8.35, P=0.004, Table 1) and severe malaria (Wald=8.706, P=0.003, Table 1). This result was replicated in a second malaria case-control study, this time in a Vietnamese population whose design included only cases of severe malaria: TIRAP S180L heterozygotes were again found to be more prevalent Finally, the possible effect of the TIRAP S180L polymorphism on ...

Several stochastic simulation algorithms (SSAs) have recently been proposed for modelling reaction-diffusion processes in cellular and molecular biology. In this paper, two commonly used SSAs are studied. The first SSA is an on-lattice model described by the reaction-diffusion master equation. The second SSA is an off-lattice model based on the simulation of Brownian motion of individual molecules and their reactive collisions. In both cases, it is shown that the commonly used implementation of bimolecular reactions (i.e. the reactions of the form A + B --> C or A + A --> C) might lead to incorrect results. Improvements of both SSAs are suggested which overcome the difficulties highlighted. In particular, a formula is presented for the smallest possible compartment size (lattice spacing) which can be correctly implemented in the first model. This implementation uses a new formula for the rate of bimolecular reactions per compartment (lattice site).