Diverse gut pathogens exploit the host engulfment pathway via a conserved mechanism.

Macrophages clear infections by engulfing and digesting pathogens within phagolysosomes. Pathogens escape this fate by engaging in a molecular arms race; they use WxxxE motif-containing "effector" proteins to subvert the host cells they invade and seek refuge within protective vacuoles. Here, we define the host component of the molecular arms race as an evolutionarily conserved polar "hot spot" on the PH domain of ELMO1 (Engulfment and Cell Motility protein 1), which is targeted by diverse WxxxE effectors. Using homology modeling and site-directed mutagenesis, we show that a lysine triad within the "patch" directly binds all WxxxE effectors tested: SifA (Salmonella), IpgB1 and IpgB2 (Shigella), and Map (enteropathogenic Escherichia coli). Using an integrated SifA-host protein-protein interaction network, in silico network perturbation, and functional studies, we show that the major consequences of preventing SifA-ELMO1 interaction are reduced Rac1 activity and microbial invasion. That multiple effectors of diverse structure, function, and sequence bind the same hot spot on ELMO1 suggests that the WxxxE effector(s)-ELMO1 interface is a convergence point of intrusion detection and/or host vulnerability. We conclude that the interface may represent the fault line in coevolved molecular adaptations between pathogens and the host, and its disruption may serve as a therapeutic strategy.

Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi.

The molecular mechanisms by which receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major signaling hubs in eukaryotes, independently relay signals across the plasma membrane have been extensively characterized. How these hubs cross-talk has been a long-standing question, but answers remain elusive. Using linear ion-trap mass spectrometry in combination with biochemical, cellular, and computational approaches, we unravel a mechanism of activation of heterotrimeric G proteins by RTKs and chart the key steps that mediate such activation. Upon growth factor stimulation, the guanine-nucleotide exchange modulator dissociates Gαi•ßγ trimers, scaffolds monomeric Gαi with RTKs, and facilitates the phosphorylation on two tyrosines located within the interdomain cleft of Gαi. Phosphorylation triggers the activation of Gαi and inhibits second messengers (cAMP). Tumor-associated mutants reveal how constitutive activation of this pathway impacts cell's decision to "go" vs. "grow." These insights define a tyrosine-based G protein signaling paradigm and reveal its importance in eukaryotes.

A long isoform of GIV/Girdin contains a PDZ-binding module that regulates localization and G-protein binding.

PDZ domains are one of the most abundant protein domains in eukaryotes and are frequently found on junction-localized scaffold proteins. Various signaling molecules bind to PDZ proteins via PDZ-binding motifs (PBM) and fine-tune cellular signaling. However, how such interaction affects protein function is difficult to predict and must be solved empirically. Here we describe a long isoform of the guanine nucleotide exchange factor GIV/Girdin (CCDC88A) that we named GIV-L, which is conserved throughout evolution, from invertebrates to vertebrates, and contains a PBM. Unlike GIV, which lacks PBM and is cytosolic, GIV-L localizes onto cell junctions and has a PDZ interactome (as shown through annotating Human Cell Map and BioID-proximity labeling studies), which impacts GIV-L's ability to bind and activate trimeric G-protein, Gαi, through its guanine-nucleotide exchange modulator (GEM) module. This GEM module is found exclusively in vertebrates. We propose that the two functional modules in GIV may have evolved sequentially: the ability to bind PDZ proteins via the PBM evolved earlier in invertebrates, whereas G-protein binding and activation may have evolved later only among vertebrates. Phenotypic studies in Caco-2 cells revealed that GIV and GIV-L may have antagonistic effects on cell growth, proliferation (cell cycle), and survival. Immunohistochemical analysis in human colon tissues showed that GIV expression increases with a concomitant decrease in GIV-L during cancer initiation. Taken together, these findings reveal how regulation in GIV/CCDC88A transcript helps to achieve protein modularity, which allows the protein to play opposing roles either as a tumor suppressor (GIV-L) or as an oncogene (GIV).

OsCyp2-P, an auxin-responsive cyclophilin, regulates Ca2+ calmodulin interaction for an ion-mediated stress response in rice.

OsCYP2-P is an active cyclophilin (having peptidyl-prolyl cis/trans-isomerase activity, PPIase) isolated from the wild rice Pokkali having a natural capacity to grow and yield seeds in coastal saline regions of India. Transcript abundance analysis in rice seedlings showed the gene is inducible by multiple stresses, including salinity, drought, high temperature, and heavy metals. To dissect the role of OsCYP2-P gene in stress response, we raised overexpression (OE) and knockdown (KD) transgenic rice plants with >2-3 folds higher and approximately 2-fold lower PPIase activity, respectively. Plants overexpressing this gene had more favorable physiological and biochemical parameters (K+ /Na+ ratio, electrolytic leakage, membrane damage, antioxidant enzymes) than wild type, and the reverse was observed in plants that were knocked down for this gene. We propose that OsCYP2-P contributes to stress tolerance via maintenance of ion homeostasis and thus prevents toxic cellular ion buildup and membrane damage. OE plants were found to have a higher harvest index and higher number of filled grains under salinity and drought stress than wild type. OsCYP2-P interacts with calmodulin, indicating it functions via the Ca-CaM pathway. Compared to the WT, the germinating OE seeds exhibited a substantially higher auxin level, and this hormone was below the detection limits in the WT and KD lines. These observations strongly indicate that OsCyp2-P affects the signaling and transport of auxin in rice.

Expression of a cyclophilin OsCyp2-P isolated from a salt-tolerant landrace of rice in tobacco alleviates stress via ion homeostasis and limiting ROS accumulation.

Cyclophilins are a set of ubiquitous proteins present in all subcellular compartments, involved in a wide variety of cellular processes. Comparative bioinformatics analysis of the rice and Arabidopsis genomes led us to identify novel putative cyclophilin gene family members in both the genomes not reported previously. We grouped cyclophilin members with similar molecular weight and subtypes together in the phylogenetic tree which indicated their co-evolution in rice and Arabidopsis. We also characterized a rice cyclophilin gene, OsCyp2-P (Os02g0121300), isolated from a salinity-tolerant landrace, Pokkali. Publicly available massively parallel signature sequencing (MPSS) and microarray data, besides our quantitative real time PCR (qRT-PCR) data suggest that transcript abundance of OsCyp2-P is regulated under different stress conditions in a developmental and organ specific manner. Ectopic expression of OsCyp2-P imparted multiple abiotic stress tolerance to transgenic tobacco plants as evidenced by higher root length, shoot length, chlorophyll content, and K(+)/Na(+) ratio under stress conditions. Transgenic plants also showed reduced lipid peroxidase content, electrolyte leakage, and superoxide content under stress conditions suggesting better ion homeostasis than WT plants. Localization studies confirmed that OsCyp2-P is localized in both cytosol and nucleus, indicating its possible interaction with several other proteins. The overall results suggest the explicit role of OsCyp2-P in bestowing multiple abiotic stress tolerance at the whole plant level. OsCyp2-P operates via reactive oxygen species (ROS) scavenging and ion homeostasis and thus is a promising candidate gene for enhancing multiple abiotic stress tolerance in crop plants.

Therapeutic potential of different commercially available synbiotic on acetaminophen-induced uremic rats.

BACKGROUND: Currently kidney disease appears a foremost problem across the world. Acetaminophen is a commonly used antipyretic agent, which in high doses, causes uremia and used for experimentally induction of kidney disease. Bacteriotherapy affords a promising approach to mitigate uremic toxins by ingestion of urease positive bacteria, probiotics and symbiotic able to catabolize uremic solutes within the gut. The present study evaluates the effect of seven commercial symbiotic on kidney disease. METHODS: Fifty-four albino male rats were randomly divided into nine groups. Control group (Group-I) received distilled water interperitoneally for 7 days. Positive control group (Group-II) received 500 mg/kg acetaminophen interperitoneally for 7 days. Commercially available seven symbiotic combinations at a dose of 10(9)cells/day for 3 weeks was administered to the tested groups (Group III-IX) after receiving 500 mg/kg/day acetaminophen interperitoneally for 7 days. Blood, kidney, liver and stool samples were collected after scarification for biochemical tests and DNA fragmentation assay of kidney tissue, kidney histological studies. Limited fecal analysis was conducted. RESULT: Blood urea nitrogen and toxicity indicators were increased, and antioxidant enzymes were decreased in Group-II. Blood urea nitrogen, toxicity indicators, glomerular necrosis, DNA damage of kidney tissue were reduced, and antioxidant enzymes were increased significantly in the treated Groups IV and IX (p < 0.05) in response to Group-II. Number of pathogenic bacteria decreased in synbiotic treated groups than Group I and II. CONCLUSION: The study demonstrated that some of commercial symbiotic combination can reduce the sever effect of kidney disease.

Implementing Kangaroo mother care in a resource-limited setting in rural Bangladesh.

AIM: This study evaluated stable and unstable low birthweight infants admitted to a Kangaroo mother care (KMC) unit at a resource-limited rural hospital in Bangladesh. METHODS: This was a descriptive consecutive patient series study of 423 low birthweight neonates <2500 g enrolled from July 2007 to December 2010. KMC was initiated as soon as possible after birth, regardless of health, and we monitored skin-to-skin contact, weight gain, exclusive breastfeeding, length of hospital stay and death rates. RESULTS: Mean birthweight was 1796 g, and mean gestational age was 34.9 weeks. Mean (median, 90th percentile) time of skin-to-skin initiation for stable and unstable neonates was 1.1 h (0.3-2.5) and 1.7 h (0.3-3.0), respectively. Adjusted mean daily skin-to-skin contact duration was significantly higher for unstable infants. About 99% of neonates were exclusively breastfed. The death rate was 8.3% (stable 1.9%, unstable 19%) at discharge. Neonatal mortality rate was 90 per 1000 live births (stable: 23 per 1000; unstable: 203 per 1000). CONCLUSION: Skin-to-skin duration was higher for unstable than stable low birthweight infants, and exclusive breastfeeding was almost universal at discharge. KMC was suitable for unstable infants and may be successfully implemented in resource-limited hospitals.

Insights into the Therapeutic Uses of Plant Derive Phytocompounds on Diabetic Nephropathy.

Diabetic nephropathy (DN) is one of the primary consequences of diabetes mellitus, affecting many people worldwide and is the main cause of death under the age of sixty. Reactive oxygen species (ROS) production rises during hyperglycemia and is crucial to the development of diabetic complications. Advanced glycation end products (AGEs) are produced excessively in a diabetic state and are accumulated in the kidney, where they change renal architecture and impair renal function. Another important targeted pathway for the formation of DN includes nuclear factor kappa-B (NF-kB), Nuclear factor E2-related factor 2 (Nrf2), NLR family pyrin domain containing 3 (NLRP3), protein kinase B/mammalian target of rapamycin (Akt/mTOR), and autophagy. About 40% of individuals with diabetes eventually acquire diabetic kidney disease and end-stage renal disease that needs hemodialysis, peritoneal dialysis, or kidney transplantation to survive. The current state of acceptable therapy for this kidney ailment is limited. The studies revealed that some naturally occurring bioactive substances might shield the kidney by controlling oxidative stress, renal fibrosis, inflammation, and autophagy. In order to provide new potential therapeutic lead bioactive compounds for contemporary drug discovery and clinical management of DN, this review was designed to examine the various mechanistic pathways by which conventional plants derive phytocompounds that are effective for the control and treatment of DN.

Aquaporins: a vital nexus in H2O2-gasotransmitter signaling.

Land plants have evolved with a complex mechanism of water uptake facilitated by the activity of aquaporins under normal and challenging environments. However, we lack a clear understanding of its interactions with reactive oxygen species, particularly hydrogen peroxide (H2O2) and the gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S), under oxidative stress. Here, we assess the crosstalk of aquaporin function, H2O2 homeostasis, and NO-H2S signaling in plants and provide a computational prediction of cysteine-based oxidative post-translational modifications (oxiPTMs) in plant aquaporins. We propose that aquaporin activity could be regulated by three major oxiPTMs, S-nitrosation, S-sulfenylation, and persulfidation, mediated by NO, H2O2, and H2S, respectively. Therefore, aquaporins might be key players in the gasotransmitter-mediated long-distance oxidative stress signals in plant cells.

Nanovehicles for melatonin: a new journey for agriculture.

The important role of melatonin in plant growth and metabolism together with recent advances in the potential use of nanomaterials have opened up interesting applications in agriculture. Various nanovehicles have been explored as melatonin carriers in animals, and it is now important to explore their application in plants. Recent findings have substantiated the use of silicon and chitosan nanoparticles (NPs) in targeting melatonin to plant tissues. Although melatonin is an amphipathic molecule, nanocarriers can accelerate its uptake and transport to various plant organs, thereby relieving stress and improving plant shelf-life in the post-harvest stages. We review the scope and biosafety concerns of various nanomaterials to devise novel methods for melatonin application in crops and post-harvest products.

Exploring Marine Alkaloids: A Natural Approach to Cancer Treatment.

Cancer is one of the most complicated and prevalent diseases in the world, and its incidence is growing worldwide. Natural products containing pharmacological activity are widely used in the pharmaceutical industry, especially in anticancer drugs, due to their diverse structures and distinctive functional groups that inspire new drug results by means of synthetic chemistry. Terrestrial medicinal plants have traditionally been the primary source for developing natural products (NPs). However, over the past thirty years, marine organisms such as invertebrates, plants, algae, and bacteria have revealed many new pharmaceutical compounds known as marine NPs. This field constantly evolves as a discipline in molecular targeted drug discovery, incorporating advanced screening tools that have revolutionised and become integral to modern antitumor research. This review discusses recent studies on new natural anticancer alkaloids obtained from marine organisms. The paper illustrates the structure and origin of marine alkaloids and demonstrates the cytotoxic action of new alkaloids from several structural families and their synthetic analogs. The most recent findings about the potential or development of some of them as novel medications, together with the status of our understanding of their current mechanisms of action, are also compiled.

Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors.

A long-standing question in the field of signal transduction is how distinct signaling pathways interact with each other to control cell behavior. Growth factor receptors and G protein-coupled receptors (GPCRs) are the two major signaling hubs in eukaryotes. Given that the mechanisms by which they signal independently have been extensively characterized, we investigated how they may cross-talk with each other. Using linear ion trap mass spectrometry and cell-based biophysical, biochemical, and phenotypic assays, we found at least three distinct ways in which epidermal growth factor affected canonical G protein signaling by the Gi-coupled GPCR CXCR4 through the phosphorylation of Gαi. Phosphomimicking mutations in two residues in the αE helix of Gαi (tyrosine-154/tyrosine-155) suppressed agonist-induced Gαi activation while promoting constitutive Gßγ signaling. Phosphomimicking mutations in the P loop (serine-44, serine-47, and threonine-48) suppressed Gi activation entirely, thus completely segregating growth factor and GPCR pathways. As expected, most of the phosphorylation events appeared to affect intrinsic properties of Gαi proteins, including conformational stability, nucleotide binding, and the ability to associate with and to release Gßγ. However, one phosphomimicking mutation, targeting the carboxyl-terminal residue tyrosine-320, promoted mislocalization of Gαi from the plasma membrane, a previously uncharacterized mechanism of suppressing GPCR signaling through G protein subcellular compartmentalization. Together, these findings elucidate not only how growth factor and chemokine signals cross-talk through the phosphorylation-dependent modulation of Gαi but also how such cross-talk may generate signal diversity.

Effect of newly isolated Lactobacillus ingluviei ADK10, from chicken intestinal tract on acetaminophen induced oxidative stress in Wistar rats.

The total antioxidative activity of L. ingluviei ADK10 isolated from chicken intestine intact cells and cell free culture supernatant (CFCS) was 54- 67.95%. The ability to scavenge a,a-Diphenyl-b-Picrylhydrazyl free radical ranged from 71 and 64% in intact cells and CFCS respectively. Total reducing activity of bacteria was equivalent to 290 microM/L of cysteine. Reducing glutathione activity was equivalent to 93.95 microg/mL. Oral administration of the strain at a dose of 10(9) cfu/kg body weight to acetaminophen induced oxidative stress in rats increased catalase, glutathione and superoxide dismutase activity in the blood, liver and kidney and lowered malondialdehyde level. The results indicate that L. ingluviei ADK10 has potential free radical scavenging activity for the treatment of oxidative stress related disease.

Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats.

Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control - receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats.

Bicyclic Peptide Library Screening for the Identification of Gαi Protein Modulators.

Noncanonical G protein activation and inactivation, particularly for the Gαi/s protein subfamilies, have long been a focus of chemical research. Combinatorial libraries were already effectively applied to identify modulators of the guanine-nucleotide exchange, as can be exemplified with peptides such as KB-752 and GPM-1c/d, the so-called guanine-nucleotide exchange modulators. In this study, we identified novel bicyclic peptides from a combinatorial library screening that show prominent properties as molecular switch-on/off modulators of Gαi signaling. Among the series of hits, the exceptional paradigm of GPM-3, a protein and state-specific bicyclic peptide, is the first chemically identified GAP (GTPase-activating protein) modulator with a high binding affinity for Gαi protein. Computational analyses identified and assessed the structure of the bicyclic peptides, novel ligand-protein interaction sites, and their subsequent impact on the nucleotide binding site. This approach can therefore lead the way for the development of efficient chemical biological probes targeting Gαi protein modulation within a cellular context.

Diverse Gut Pathogens Exploit the Host Engulfment Pathway via a Conserved Mechanism.

Macrophages clear infections by engulfing and digesting pathogens within phagolysosomes. Pathogens escape this fate by engaging in a molecular arms race; they use WxxxE motif-containing effector proteins to subvert the host cells they invade and seek refuge within protective vacuoles. Here we define the host component of the molecular arms race as an evolutionarily conserved polar hotspot on the PH-domain of ELMO1 (Engulfment and Cell Motility1), which is targeted by diverse WxxxE-effectors. Using homology modeling and site-directed mutagenesis, we show that a lysine triad within the patch directly binds all WxxxE-effectors tested: SifA (Salmonella), IpgB1 and IpgB2 (Shigella), and Map (enteropathogenic E. coli). Using an integrated SifA-host protein-protein interaction (PPI) network, in-silico network perturbation, and functional studies we show that the major consequences of preventing SifA-ELMO1 interaction are reduced Rac1 activity and microbial invasion. That multiple effectors of diverse structure, function, and sequence bind the same hotpot on ELMO1 suggests that the WxxxE-effector(s)-ELMO1 interface is a convergence point of intrusion detection and/or host vulnerability. We conclude that the interface may represent the fault line in co-evolved molecular adaptations between pathogens and the host and its disruption may serve as a therapeutic strategy.

Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model.

Chronic kidney diseases (CKD) caused by acute kidney injury (AKI) results rapid and reversible loss in renal function. A real-time, highly accurate, and sensitive acute kidney injury biomarker is urgently required in order to keep these patients alive and prevent end stage renal disease and related complications that include hypertension, fluid and electrolyte retention, metabolic acidosis, anemia, stroke etc. This study was designed to develop a specific and sensitive model for the early identification of renal damage in male albino rats. Using a single intraperitoneal dose of cisplatin (10 mg/kg body weight) to the rats, the various duration-dependent nephrotoxic activities were compared using multiple physiological, biochemical, genomic, and histopathological markers. We looked into when renal dysfunction would start occurring after receiving a single high dose of cisplatin while blood urea nitrogen (BUN) and serum creatinine (sCr) remained normal. Following a single cisplatin injection, various measurements were taken in plasma, urine, and/or kidney tissues of rats euthanized on days 1, 2, 3, 5, and 7. When the urine kidney injury molecule (KIM-1), interleukine 18 (IL-18), nephrin, neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (Cys C) levels are greatly raised on day 3 after cisplatin treatment, BUN and sCr levels remain normal. Nephrotoxicity of cisplatin is also indicated by the upregulated mRNA expression of KIM-1, IL-18, Cys C, and NGAL and downregulated expression of nephrin in kidney tissue at very initial stage. Protein expression of KIM-1, IL-18 and NGAL level of kidney tissues was upregulated indicated confirmatory results done by western blot. Utilising an array of kidney impairment indicators has emerged as an earlier, more effective, and more reliable technique to diagnose AKI when compared to the most sophisticated signs now available.

Regulation of DNA damage response by trimeric G-proteins.

Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•ßγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1's BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the "free" Gßγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.

A Multiomic Analysis Reveals How Breast Cancers Disseminated to the Bone Marrow Acquire Aggressive Phenotypes through Tumor-Stroma Tunnels.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network- analyses workflow to identify a comprehensive catalog of contact-induced changes. Induced genes and proteins in cancer cells, some borrowed and others tumor-intrinsic, were not recapitulated merely by conditioned media from MSCs. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatic approaches prioritized one of the 'borrowed' components, CCDC88A /GIV, a multi-modular metastasis-related protein which has recently been implicated in driving one of the hallmarks of cancers, i.e., growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced ∼20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

Leprosy and the adaptation of human toll-like receptor 1.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.