Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection.

To determine the mechanisms that mediate resistance to Mycobacterium tuberculosis (M. tuberculosis) infection in household contacts (HHCs) of patients with tuberculosis (TB), we followed 452 latent TB infection-negative (LTBI-) HHCs for 2 years. Those who remained LTBI- throughout the study were identified as nonconverters. At baseline, nonconverters had a higher percentage of CD14+ and CD3-CD56+CD27+CCR7+ memory-like natural killer (NK) cells. Using a whole-transcriptome and metabolomic approach, we identified deoxycorticosterone acetate as a metabolite with elevated concentrations in the plasma of nonconverters, and further studies showed that this metabolite enhanced glycolytic ATP flux in macrophages and restricted M. tuberculosis growth by enhancing antimicrobial peptide production through the expression of the surface receptor sialic acid binding Ig-like lectin-14. Another metabolite, 4-hydroxypyridine, from the plasma of nonconverters significantly enhanced the expansion of memory-like NK cells. Our findings demonstrate that increased levels of specific metabolites can regulate innate resistance against M. tuberculosis infection in HHCs of patients with TB who never develop LTBI or active TB.

Defective expansion and function of memory like natural killer cells in HIV+ individuals with latent tuberculosis infection.

PURPOSE: Tuberculosis (TB) is the leading cause of infectious disease related mortality, and only 10% of the infected individuals develop active disease. The likelihood of progression of latent tuberculosis infection (LTBI) to active TB disease is high in HIV infected individuals. Identification of HIV+ individuals at risk would allow treating targeted population, facilitating completion of therapy for LTBI and prevention of TB development. NK cells have an important role in T cell independent immunity against TB, but the exact role of NK cell subsets in LTBI and HIV is not well characterized. METHODS: In this study, we compared the expansion and function of memory like NK cells from HIV-LTBI+ individuals and treatment naïve HIV+LTBI+ patients in response to Mtb antigens ESAT-6 and CFP-10. RESULTS: In freshly isolated PBMCs, percentages of CD3-CD56+ NK cells were similar in HIV+LTBI+ patients and healthy HIV-LTBI+ individuals. However, percentages of CD3-CD56+CD16+ NK cells were higher in healthy HIV-LTBI+ individuals compared to HIV+LTBI+ patients. HIV infection also inhibited the expansion of memory like NK cells, production of IL-32α, IL-15 and IFN-γ in response to Mtb antigens in LTBI+ individuals. CONCLUSION: We studied phenotypic, functional subsets and activation of memory like-NK cells during HIV infection and LTBI. We observed that HIV+LTBI+ patients demonstrated suboptimal NK cell and monocyte interactions in response to Mtb, leading to reduced IL-15, IFN-γ and granzyme B and increased CCL5 production. Our study highlights the effect of HIV and LTBI on modulation of NK cell activity to understand their role in development of interventions to prevent progression to TB in high risk individuals.

Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk.

In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the "0" time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progressors stimulated with early secretory antigenic target 6 (ESAT-6) and 10 kDa culture filtrate antigen (CFP-10) produced less IL-1α. Thyroid hormones inhibited Mycobacterium tuberculosis (Mtb) growth in macrophages in an IL-1α-dependent manner. Mtb-infected Thra1PV/+ (mutant thyroid hormone receptor) mice had increased mortality and reduced IL-1α production. Our findings suggest that young HHCs who exhibit decreased production of thyroid hormones are at high risk of developing active TB disease.

A Study on the Impact of Genetic Polymorphisms of Cytokines TNFα, IFNγ and IL10 in South Indian Leprosy Patients.

BACKGROUND: Leprosy (Hansen's disease) is a chronic, debilitating disease predominantly of the peripheral nervous system characterized by the impairment of peripheral nerves and subsequent sensory loss caused by Mycobacterium leprae. The pro- and antiinflammatory cytokine genes play a major role in nerve damage in leprosy. AIMS AND OBJECTIVES: The objective of the present study is to ascertain the association of cytokine gene polymorphisms TNFα - 308G/A (rs 1800629), IFNγ +874A/T (rs 2430561), and IL10 - 1082G/A rs 1800896 in causation with leprosy. MATERIALS AND METHODS: The present study comprised 365 leprosy patients and 185 control subjects. The polymorphisms in TNFα-308, IFNγ+874, and IL10-1082 genes were typed using the amplification refractory mutation system polymerase chain reaction method (ARMS PCR). RESULTS: The present study found significant association between IL10-1082 GA heterozygote (P < 0.02) and IFNγ+874 AA (P < 0.001) genotype and leprosy. TNFα-308GA could not establish any association with the disease. CONCLUSION: The identification of genetic variations in pro- and antiinflammatory cytokines that are susceptible to leprosy would assist in better understanding of the pathogenesis of leprosy and perhaps lead to new approaches for diagnosis and treatment.

Correction: IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis.

[This corrects the article DOI: 10.1371/journal.ppat.1008140.].

Defective Antigen Presentation Leads to Upregulation of PD1 and IL-10 in HIV-TB Co-Infection.

Human immunodeficiency virus-tuberculosis (HIV-TB) co-infection poses a challenge to the immunologists in developing new diagnostic and therapeutic tools. Mechanisms behind the breakdown of the immune defense of the co-infected individual are poorly known. Numerous studies in HIV alone have revealed the role of PD1, TAP, and IL-10, but not in co-infection. The interaction of the 2 distinct bugs, which is resulting in domination over the host immune system, is still a lacuna. Hence, we aimed to portray functions of IL-10, TAP, and PD1 molecules in HIV-TB co-infection. Co-culture cells challenged with γ-irradiated M.Tb under various conditions resulted in high interleukin (IL)-10 secretion and high percentage of PD1 expression on CD8 T cells, which might be due to defective antigen presentation of TAP on dendritic cells and macrophages. Herein our observations provide an insight into the escape mechanisms by M.Tb in HIV-infected individuals from the host immune responses leading to TB co-infection.

Toll-like receptor 2 polymorphisms and their effect on the immune response to ESAT-6, Pam3CSK4 TLR2 agonist in pulmonary tuberculosis patients and household contacts.

Toll-like receptors (TLRs) play a pivotal role in organizing the effective immune response through inducing the pro-inflammatory cytokines for control of tuberculosis infection and TLR polymorphisms are associated with altered cytokine levels have been described. Therefore, the main aim of the present study was to confirm whether TLR2 (C2029T, G2258A) polymorphisms effects the cytokine production in PTB patients and Household contacts (HHC), healthy controls (HC). The polymorphisms were performed by amplification refractory mutation system-polymerase chain reaction (ARMS) & Restriction Fragment Length Polymorphism (RFLP) in 336 subjects. Cytokine levels were estimated in Pam3CSK4, antigen ESAT-6 stimulated culture supernatants by Enzyme-Linked Immunosorbent Assay. Under the over-dominant model GA genotype of G2258A SNP and CT genotype of the co-dominant model in C2029T SNP showed a susceptible effect in patients, whereas in HHC, CT genotype showed a protective effect. A significant decreased TNF-α, IL-12 and increased IL-1ß levels were observed after Pam3CSK4, antigen ESAT-6stimulation; our results showed the following associations: TLR2 G2258A SNP of GA with decreased TNF-α; TLR2 C2029T SNP of CT, TT with decreased IL-12 and increased IL-1ß levels. Regression analysis demonstrated that age, BCG, gender and T allele were significantly associated with TB. Pre-mRNA secondary structure of the A, T alleles are more stable than G, C alleles. Altogether, we suggest that cytokine levels, 2029T allele, TLR2 polymorphisms were considered as predictive markers for identification of high-risk individuals in TB.

IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis.

Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.

Down regulation of RANTES in pleural site is associated with inhibition of antigen specific response in tuberculosis.

Tuberculosis is the most common infectious reason for death and a major cause of pleural effusion globally. To understand the role of chemokines in trafficking of cells during TB pleurisy, we studied the responses to MTB, Ag85A in cells from pleural fluids and peripheral blood. Patients with TB pleural effusions, malignant effusions and asymptomatic healthy controls were enrolled. High expression (p < 0.05) of IP-10, MCP-1, MIG, IL-8, IFN-γ and IL-23 were observed in pleural fluids of TB patients compared to their plasma where expression of RANTES was significantly higher (p < 0.05). On specific stimulation of PFMCs with Ag85A, expression of RANTES was significantly lower in TB compared to NTB patients. We also observed increased expression of T regs and PD1 on CD8+T cells in PFMC of TB patients. Though some of the inflammatory chemokine/cytokines were up-regulated in pleura of TB patients, antigenic stimulation failed to induce them indicating poor antigenic responses at the site. Low expression of RANTES might be a reason for decreased trafficking of cells to the site and dissemination of infection into pleural site. The pattern of RANTES expression in pleural fluid vs serum is interesting. The observations necessitate further studies to investigate the levels of RANTES for its potential biological relevance in TB immunity and its use as a biomarker for diagnosis of pleural TB.

Transforming Growth Factor-ß Suppresses Interleukin (IL)-2 and IL-1ß Production in HIV-Tuberculosis Co-Infection.

Interleukin (IL)-1ß and IL-2 play important roles in protective immune responses against Mycobacterium tuberculosis (Mtb) infection. Information on the factors that regulate the production of these cytokines in the context of human immunodeficiency virus and latent tuberculosis infection (LTBI) or active tuberculosis (TB) disease is limited. In this study, we compared the production of these cytokines by peripheral blood mononuclear cells (PBMCs) from HIV- and HIV+ individuals with latent and active Tuberculosis infection in response to Mtb Antigen 85A. PBMCs from HIV+ LTBI+ and HIV+ active TB patients produced low IL-1ß, IL-2 but high transforming growth factor beta (TGF-ß) compared to healthy controls. CD4+ T cells from HIV patients expressed low retinoic acid-related orphan receptor gamma (RORγ), and high suppressors of cytokine signaling-3 (SOCS-3). Active TB infection in HIV+ individuals further inhibited antigen-specific IL-1ß and IL-2 production compared with those with LTBI. Neutralization of TGF-ß restored IL-1ß and IL-2 levels and lowered SOCS-3 production by CD4+ T cells. We hypothesize that high TGF-ß in HIV patients could be a reason for defective Mtb-specific IL-1ß, IL-2 production and activation of latent TB in HIV. Coupling anti-TGF-ß antibodies with antiretroviral therapy treatment might increase T cell function to boost the immune system for effective clearance of Mtb.

Identifying and mapping TB hot spots in an urban slum by integratingGeographic positioning system and the local postman - A pilot study.

SETTING: Mahavir DOT Centre, Hyderabad, Telangana, India INTRODUCTION: Urban slums are characterized by crowding, poverty. In such setting due to lack of infection control the transmission of tuberculosis is known to rise, thereby creating a "Hot" spot. Distribution of residences in such areas does not necessarily follow postal codes, making it difficult for health workers to locate TB patients unless accompanied by the STLS. OBJECTIVE: To investigate the utility of integrating the help of local postman and geographic positioning system (GPS) to identify and create map of hot spots in an area under a regional DOT centre. MATERIALS & METHODS: Retrospective and prospective demographic data of TB patients enrolled during 12 years (1999-2011) was analysed from the TB register at a ward where number of cases continued to increase despite active implementation of DOTS strategy. Non-Spatial data was generated with the local postman identifying individual house addresses. The corresponding co-ordinates were recorded with GPS and uploaded in Google Earth to identify the locations. Area map was created by software (AutoCAD, Map R3, MapInfo Pro 7.5 Trial Version and MS office Tools). Residences of Index patients were marked in different colours year wise on the map. RESULTS: Maps displayed in the DOT centre area helped in identifying HOT SPOT and visualization of the clustering of TB cases in the area. Time interval between subsequent infections (3 months-5 years) could be calculated in the locality, within household, neighbourhood and random contacts. Average distances (<1 m) between houses indicated the probable source of infection. Risk factors included crowding, poor ventilation and sanitation contributed to TB transmission in HOT spot area. CONCLUSION: Integrating local postman and information technology to identify HOT SPOT in RNTCP, will help in early intervention by health personnel to arrest TB transmission.

Association of increased risk of asthma with elevated arginase & interleukin-13 levels in serum & rs2781666 G/T genotype of arginase I.

BACKGROUND & OBJECTIVES: High expression of arginase gene and its elevated level in serum and bronchial lavage reported in animal models indicated an association with the pathogenesis of asthma. This study was undertaken to assess the serum arginase activity in symptomatic asthma patients and healthy controls and to correlate it with cytokine levels [interleukin (IL)-4 and IL-13] and arginase I (ARG1) gene polymorphism. METHODS: Asthma was confirmed by lung function test according to the GINA guidelines in patients attending Allergy and Pulmonology Clinic, Bhagwan Mahavir Hospital and Research Centre, Hyderabad, India, a tertiary care centre, during 2013-2015. Serum arginase was analyzed using a biochemical assay, total IgE and cytokine levels by enzyme-linked immunosorbent assay and genotyping of ARG1 for single-nucleotide polymorphisms (SNPs) rs2781666 and rs60389358 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: There was a significant two-fold elevation in the arginase activity in asthmatics as compared to healthy controls which correlated with disease severity. Non-atopic asthmatics showed elevated activity of arginase compared to atopics, indicating its possible role in intrinsic asthma. Levels of serum IL-13 and IL-4 were significantly high in asthma group which correlated with disease severity that was assessed by spirometry. A positive correlation was observed between arginase activity and IL-13 concentration. Genetic analysis of ARG1 SNPs revealed that rs2781666 G/T genotype, T allele and C-T haplotype (rs60389358 and rs2781666) were associated with susceptibility to asthma. INTERPRETATION & CONCLUSIONS: This study indicated that high arginase activity and IL-13 concentration in the serum and ARG1 rs2781666 G/T genotype might increase the risk of asthma in susceptible population. Further studies need to be done with a large sample to confirm these findings.

PPE17 (Rv1168c) protein of Mycobacterium tuberculosis detects individuals with latent TB infection.

Latent tuberculosis infection (LTBI) is a clinically distinct category of Mycobacterium tuberculosis (Mtb) infection that needs to be diagnosed at the initial stage. We have reported earlier that one of the Mtb proline-proline-glutamic acid (PPE) proteins, PPE17 (Rv1168c) is associated with stronger B-cell and T-cell responses and could be used to diagnose different clinical categories of active TB patients with higher specificity and sensitivity than PPD and ESAT-6. Based on these observations we further tested the potential of PPE17 for the diagnosis of LTBI. We tested 198 sera samples collected from LTBI individuals (n = 61), QFT-negative (n = 58) and active TB patients (n = 79). Individuals were defined as LTBI by QuantiFERON-TB Gold In-Tube test (QFT-GIT) positive results, while active TB patients were confirmed based on the guidelines of the Revised National TB Control Programme of India. The antibody responses against PPE17, ESAT-6:CFP-10 and PPD were compared in these subjects by enzyme-linked immunosorbent assay. We observed that LTBI individuals show a higher sero-reactivity to PPE17 as compared to currently used latent TB diagnostic antigens like ESAT-6, CFP-10 and PPD. The LTBI and active TB patients display almost similar sensitivity. Interestingly, PPE17 could discriminate LTBI positive subjects from the QFT-negative subjects (P < 0.001). Our study hints that PPE17 may be used as a novel serodiagnostic marker to screen the latently infected subjects and may also be used as a complimentary tool to the QFT-GIT.

Alcohol enhances type 1 interferon-α production and mortality in young mice infected with Mycobacterium tuberculosis.

In the current study, we used a mouse model and human blood samples to determine the effects of chronic alcohol consumption on immune responses during Mycobacterium tuberculosis (Mtb) infection. Alcohol increased the mortality of young mice but not old mice with Mtb infection. CD11b+Ly6G+ cells are the major source of IFN-α in the lungs of Mtb-infected alcohol-fed young mice, and IFN-α enhances macrophage necroptosis in the lungs. Treatment with an anti-IFNAR-1 antibody enhanced the survival of Mtb-infected alcohol-fed young mice. In response to Mtb, peripheral blood mononuclear cells (PBMCs) from alcoholic young healthy individuals with latent tuberculosis infection (LTBI) produced significantly higher amounts of IFN-α than those from non-alcoholic young healthy LTBI+ individuals and alcoholic and non-alcoholic old healthy LTBI+ individuals. Our study demonstrates that alcohol enhances IFN-α production by CD11b+Ly6G+ cells in the lungs of young Mtb-infected mice, which leads to macrophage necroptosis and increased mortality. Our findings also suggest that young alcoholic LTBI+ individuals have a higher risk of developing active TB infection.

IL-17 and IL-22 production in HIV+ individuals with latent and active tuberculosis.

BACKGROUND: IL-17 and IL-22 cytokines play an important role in protective immune responses against Mycobacterium tuberculosis (Mtb) infection. Information on the production of these cytokines and the factors that regulate their production in the context of human immunodeficiency virus (HIV) and latent tuberculosis infection (LTBI) or active tuberculosis disease (ATB) is limited. In the current study, we compared the production of these two cytokines by PBMC of HIV-LTBI+ and HIV + LTBI+ individuals in response to Mtb antigens CFP-10 (culture filtrate protein) and ESAT-6 (Early Secretory Antigenic Target). We also determined the mechanisms involved in their production. METHODS: We cultured Peripheral Blood Mononuclear Cells (PBMCs) from HIV- individuals and HIV+ patients with latent tuberculosis and active disease with CFP-10 and ESAT-6. Production of IL-17, IL-22 and PD1 (Programmed Death 1), ICOS (Inducible T-cell Costimulator), IL-23R and FoxP3 (Forkhead box P3) expression on CD4+ T cells was measured. RESULTS: In response to Mtb antigens CFP-10 and ESAT-6, freshly isolated PBMCs from HIV+ LTBI+ and HIV+ active TB patients produced less IL-17 and IL-22 and more IL-10, expressed less IL-23R, and more PD1 and expanded to more FoxP3+ cells. Active TB infection in HIV+ individuals further inhibited antigen specific IL-17 and IL-22 production compared to those with LTBI. Neutralization of PD1 restored IL-23R expression, IL-17 and IL-22 levels and lowered IL-10 production and reduced expansion of FoxP3 T cells. CONCLUSIONS: In the current study we found that increased PD1 expression in HIV + LTBI+ and HIV+ active TB patients inhibits IL-17, IL-22 production and IL-23R expression in response to Mtb antigens CFP-10 and ESAT-6.

Defective MyD88 and IRAK4 but not TLR-2 expression in HIV+ individuals with latent tuberculosis infection.

HIV infection markedly increases the likelihood of latent tuberculosis infection progressing to active TB. Information on expression of TLR-2, myeloid differentiation factor (MyD88), IL-1R- associated kinase-4 (IRAK4) and nuclear factor kappa B (NF-kB) in HIV+LTBI+ and HIV+ patients with active TB disease is limited. We found significantly higher percentages of CD14+TLR2+ cells in PBMCs of HIV+LTBI+ patients compared to HIV-LTBI+ individuals. γ-irradiated Mtb was unable to induce MyD88, IRAK4 expression and IL-1ß, MCP-1, IP-10 production in HIV+LTBI+ patients. Pleural fluids from HIV+TB+ patients had low IL-1ß, MCP-1, IP-10 and high IL-10, TNF-α production. γ-irradiated Mtb stimulated CD14+ cells from HIV+TB+ patients had low IL-1ß, MCP-1, IP-10 production and MyD88, IRAK4 and similar NF-kB expression compared to those from of HIV-TB+ patients. Our results suggest defective MyD88, IRAK4 but not NF-kB inhibit IL-1ß, MCP-1 and IP-10 production by CD14+ cells of HIV+ individuals with LTBI and active TB disease in peripheral blood and at the site of disease.

Interleukin-21 Regulates Natural Killer Cell Responses During Mycobacterium tuberculosis Infection.

Background: In the current study, we determined the effects of interleukin (IL)-21 on human natural killer (NK) cells and monocyte responses during Mycobacterium tuberculosis (Mtb) infection. Methods: We found that Mtb stimulated CD4+ and NK T cells from healthy individuals with latent tuberculosis infection (LTBI+) are major sources of IL-21. CD4+ cells from tuberculosis patients secreted less IL-21 than did CD4+ cells from healthy LTBI+ individuals. Interleukin-21 had no direct effect on Mtb-stimulated monocytes. Results: Interleukin-21-activated NK cells produced interferon (IFN)-γ, perforin, granzyme B, and granulysin; lysed Mtb-infected monocytes; and reduced Mtb growth. Interleukin-21-activated NK cells also enhanced IL-1ß, IL-18, and CCL4/macrophage-inflammatory protein (MIP)-1ß production and reduced IL-10 production by Mtb-stimulated monocytes. Recombinant IL-21 (1) inhibited Mtb growth, (2) enhanced IFN-γ, IL-1ß, IL-18, and MIP-1ß, and (3) reduced IL-10 expression in the lungs of Mtb-infected Rag2 knockout mice. Conclusions: These findings suggest that activated T cells enhance NK cell responses to lyse Mtb-infected human monocytes and restrict Mtb growth in monocytes through IL-21 production. Interleukin-21-activated NK cells also enhance the immune response by augmenting IL-1ß, IL-18, and MIP-1ß production and reducing IL-10 production by monocytes in response to an intracellular pathogen.

Geographical distribution of complement receptor type 1 variants and their associated disease risk.

BACKGROUND: Pathogens exert selective pressure which may lead to substantial changes in host immune responses. The human complement receptor type 1 (CR1) is an innate immune recognition glycoprotein that regulates the activation of the complement pathway and removes opsonized immune complexes. CR1 genetic variants in exon 29 have been associated with expression levels, C1q or C3b binding and increased susceptibility to several infectious diseases. Five distinct CR1 nucleotide substitutions determine the Knops blood group phenotypes, namely Kna/b, McCa/b, Sl1/Sl2, Sl4/Sl5 and KCAM+/-. METHODS: CR1 variants were genotyped by direct sequencing in a cohort of 441 healthy individuals from Brazil, Vietnam, India, Republic of Congo and Ghana. RESULTS: The distribution of the CR1 alleles, genotypes and haplotypes differed significantly among geographical settings (p≤0.001). CR1 variants rs17047660A/G (McCa/b) and rs17047661A/G (Sl1/Sl2) were exclusively observed to be polymorphic in African populations compared to the groups from Asia and South-America, strongly suggesting that these two SNPs may be subjected to selection. This is further substantiated by a high linkage disequilibrium between the two variants in the Congolese and Ghanaian populations. A total of nine CR1 haplotypes were observed. The CR1*AGAATA haplotype was found more frequently among the Brazilian and Vietnamese study groups; the CR1*AGAATG haplotype was frequent in the Indian and Vietnamese populations, while the CR1*AGAGTG haplotype was frequent among Congolese and Ghanaian individuals. CONCLUSION: The African populations included in this study might have a selective advantage conferred to immune genes involved in pathogen recognition and signaling, possibly contributing to disease susceptibility or resistance.

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection.

In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice.