Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence ...suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.
(Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent ...advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release assay (IGRA) negative adolescents provided 45% protection against sustained Mtb infection defined by IGRA conversion; and the protein-subunit vaccine M72/AS01
provided 50% protection against progression from Mtb infection to tuberculosis disease in IGRA-positive adults. These findings provide encouraging evidence for pre-exposure and post-exposure approaches to vaccination against tuberculosis, both of which may be necessary to rapidly interrupt the cycle of Mtb transmission and sustain long-term impact on global tuberculosis control. New trials are needed to demonstrate efficacy of M72/AS01
with greater precision, in a wider age range, in diverse epidemic settings, and in populations that include Mtb-uninfected and HIV-infected persons. Modeling the impact of mass campaigns with M72/AS01
and other fast-follower vaccine candidates will be crucial to make the use case and demonstrate public health value for TB endemic countries. The size and scope of the next generation of efficacy trials, and the need to expand and accelerate the existing clinical development pipeline, will require public and private consortium funding and concerted political will.
Although several lines of evidence suggest that variation in human inflammation is genetically controlled, the genes which regulate these responses are largely unknown. TLRs (Toll-like receptors) ...mediate recognition of microbes, regulate activation of the innate immune response and influence the formation of adaptive immunity. Cellular and molecular studies over the past several years have identified a number of common TLR polymorphisms that modify the cellular immune response and production of cytokines in vitro. In addition, human genetic studies suggest that some of these polymorphisms are associated with susceptibility to a spectrum of diseases. In this review, we summarize studies of common TLR polymorphisms and how this work is beginning to illuminate the influence of human variation on inflammation and disease susceptibility.
Exposure to
Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish ...larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to
Mycobacterium marinum. A hypersusceptible mutant maps to the
lta4h locus encoding
leukotriene A
4 hydrolase
, which catalyzes the final step in the synthesis of leukotriene B
4 (LTB
4), a potent chemoattractant and proinflammatory eicosanoid.
lta4h mutations confer hypersusceptibility independent of LTB
4 reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for
LTA4H polymorphisms that have previously been correlated with differential LTB
4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
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► Mutations in zebrafish
lta4h result in hypersusceptibility to mycobacterial infection ► LTA4H activity orchestrates the balance of pro- and anti-inflammatory eicosanoids ► Excess Lipoxin A4 production inhibits TNF induction during infection ► In humans, heterozygosity at the
LTA4H locus protects from tuberculosis and leprosy
Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium ...marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
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► Conserved eicosanoids are regulated by LTA4H activity and impact inflammatory state ► Genotype-directed modulation of TNF improves outcomes in a zebrafish tuberculosis model ► Drug therapies tailored to lta4h genotype improve infection outcome in zebrafish ► In humans, LTA4H genotype associates with responsiveness to therapy for TB meningitis
A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.
Interrupting transmission events is critical to tuberculosis control. Cough-generated aerosol cultures predict tuberculosis transmission better than microbiological or clinical markers. We ...hypothesize that highly infectious individuals with pulmonary tuberculosis (positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals. We performed a prospective, longitudinal study using cough aerosol sampling system. We enrolled 142 participants with treatment-naïve pulmonary tuberculosis in Kenya and assessed the association of clinical, microbiologic, and immunologic characteristics with Mycobacterium tuberculosis aerosolization and transmission in 129 household members. Contacts of the forty-three aerosol culture-positive participants (30%) are more likely to have a positive interferon-gamma release assay (85% vs 53%, P = 0.006) and higher median IFNγ level (P < 0.001, 4.28 IU/ml (1.77-5.91) vs. 0.71 (0.01-3.56)) compared to aerosol culture-negative individuals. We find that higher bacillary burden, younger age, larger mean upper arm circumference, and host inflammatory profiles, including elevated serum C-reactive protein and lower plasma TNF levels, associate with positive cough aerosol cultures. Notably, we find pre-treatment whole blood transcriptional profiles associate with aerosol culture status, independent of bacillary load. These findings suggest that tuberculosis infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may identify highly infectious persons.Using cough-generated aerosol cultures, authors probe the inflammatory markers and epidemiological characteristics of individuals with pulmonary tuberculosis, in association with infection state.
Vascular dysfunction is a major complication of metabolic disorders such as diabetes and obesity. The current studies were undertaken to determine whether inflammatory responses are activated in the ...vasculature of mice with diet-induced obesity, and if so, whether Toll-Like Receptor-4 (TLR4), a key mediator of innate immunity, contributes to these responses. Mice lacking TLR4 (TLR4(-/-)) and wild-type (WT) controls were fed either a low fat (LF) control diet or a diet high in saturated fat (HF) for 8 weeks. In response to HF feeding, both genotypes displayed similar increases of body weight, body fat content, and serum insulin and free fatty acid (FFA) levels compared with mice on a LF diet. In lysates of thoracic aorta from WT mice maintained on a HF diet, markers of vascular inflammation both upstream (IKKbeta activity) and downstream of the transcriptional regulator, NF-kappaB (ICAM protein and IL-6 mRNA expression), were increased and this effect was associated with cellular insulin resistance and impaired insulin stimulation of eNOS. In contrast, vascular inflammation and impaired insulin responsiveness were not evident in aortic samples taken from TLR4(-/-) mice fed the same HF diet, despite comparable increases of body fat mass. Incubation of either aortic explants from WT mice or cultured human microvascular endothelial cells with the saturated FFA, palmitate (100 micromol/L), similarly activated IKKbeta, inhibited insulin signal transduction and blocked insulin-stimulated NO production. Each of these effects was subsequently shown to be dependent on both TLR4 and NF-kappaB activation. These findings identify the TLR4 signaling pathway as a key mediator of the deleterious effects of palmitate on endothelial NO signaling, and are the first to document a key role for TLR4 in the mechanism whereby diet-induced obesity induces vascular inflammation and insulin resistance.
Despite high exposure to Mycobacterium tuberculosis, a small proportion of South African goldminers resist TB infection. We determined, among long-service gold miners i) the proportion who were TB ...uninfected and ii) epidemiological factors associated with being uninfected.
We enrolled HIV-negative gold miners aged 33-60 years with ≥15 years' service and no history of TB or silicosis. Miners were defined as TB uninfected if i) QuantiFERON-TB Gold Plus (QFT-Plus) negative or ii) in a stricter definition, QFT-Plus-negative and zero-response on TST and as resisters if they were of Black/African ethnicity and negative on both tests. Logistic regression was used to identify epidemiological factors associated with being TB uninfected.
Of 307 participants with a QFT-Plus result, median age was 48 years (interquartile range IQR 44-53), median time working underground was 24 years (IQR 18-28), 303 (99%) were male and 91 (30%) were QFT-Plus-negative. The odds of being TB uninfected was 52% lower for unskilled workers (adjusted odds ratio aOR 0.48; 95% confidence interval CI 0.27-0.85; p = 0.013). Among 281 participants of Black/African ethnicity, 71 (25%) were QFT-Plus negative. Miners with a BMI ≥30 were less likely to be TB uninfected (OR 0.38; 95% CI 0.18-0.80). Using the stricter definition, 44.3% (136/307) of all miners were classified as either TB uninfected (35; 26%) or infected, (101; 74%) and the associations remained similar. Among Black/African miners; 123 were classified as either TB uninfected (23; 19%) or infected (100; 81%) using the stricter definition. No epidemiological factors for being TB uninfected were identified.
Despite high cumulative exposure, a small proportion of miners appear to be resistant to TB infection and are without distinguishing epidemiological characteristics.
Although behavioral risk factors are strongly associated with urinary tract infection (UTI) risk, the role of genetics in acquiring this disease is poorly understood.
To test the hypothesis that ...polymorphisms in Toll-like receptor (TLR) pathway genes are associated with susceptibility to UTIs, we conducted a population-based case-control study of women ages 18-49 years. We examined DNA variants in 9 TLR pathway genes in 431 recurrent cystitis (rUTI) cases, 400 pyelonephritis cases, and 430 controls with no history of UTIs. In the Caucasian subgroup of 987 women, polymorphism TLR4_A896G was associated with protection from rUTI, but not pyelonephritis, with an odds ratio (OR) of 0.54 and a 95% confidence interval (CI) of 0.31 to 0.96. Polymorphism TLR5_C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of rUTI (OR(95%CI): 1.81 (1.00-3.08)), but not pyelonephritis. Polymorphism TLR1_G1805T was associated with protection from pyelonephritis (OR(95%CI): 0.53 (0.29-0.96)).
These results provide the first evidence of associations of TLR5 and TLR1 variants with altered risks of acquiring rUTI and pyelonephritis, respectively. Although these data suggest that TLR polymorphisms are associated with adult susceptibility to UTIs, the statistical significance was modest and will require further study including validation with independent cohorts.
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