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      The IFNG rs1861494 Single Nucleotide Polymorphism Is Associated with Protection against Tuberculosis Disease in Argentina

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          Abstract

          Interferon gamma (IFNG) plays a key role during Mycobacterium tuberculosis ( Mtb) infection, and several polymorphisms located in its gene are associated with risk of tuberculosis in diverse populations. Nevertheless, the genetic resistance/susceptibility to tuberculosis in Argentina is unknown. The IFNG rs1861494 polymorphism (G→A) was reported to alter the binding of transcription factors to this region, influencing IFNG production. Using a case-control study, we found an association between the AA and AG genotypes and tuberculosis resistance (AA vs. GG: odds ratio (OR) = 0.235, p-value = 0.012; AG vs. GG: OR = 0.303, p-value = 0.044; AA vs. AG: OR = 0.776, p-value = 0.427; AA + AG vs. GG: OR = 0.270, p-value = 0.022). Moreover, Mtb-antigen stimulated peripheral blood mononuclear cells (PBMCs) from healthy donors and AA carriers secreted the highest amounts of IFNG in culture supernatants ( p-value = 0.034) and presented the greatest percentage of CD4 +IFNG + lymphocytes ( p-value = 0.035), in comparison with GG carriers. No association between the polymorphism and clinical parameters of tuberculosis severity was detected. However, our findings indicate that the rs1861494 single nucleotide polymorphism (SNP) could be considered as a biomarker of tuberculosis resistance in the Argentinean population.

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          Disseminated tuberculosis in interferon gamma gene-disrupted mice

          The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid- fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.
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            Immune control of tuberculosis by IFN-gamma-inducible LRG-47.

            Interferon-gamma (IFN-gamma) provides an essential component of immunity to tuberculosis by activating infected host macrophages to directly inhibit the replication of Mycobacterium tuberculosis (Mtb). IFN-gamma-inducible nitric oxide synthase 2 (NOS2) is considered a principal effector mechanism, although other pathways may also exist. Here, we identify one member of a newly emerging 47-kilodalton (p47) guanosine triphosphatase family, LRG-47, that acts independently of NOS2 to protect against disease. Mice lacking LRG-47 failed to control Mtb replication, unlike those missing the related p47 guanosine triphosphatases IRG-47 or IGTP. Defective bacterial killing in IFN-gamma-activated LRG-47-/- macrophages was associated with impaired maturation of Mtb-containing phagosomes, vesicles that otherwise recruited LRG-47 in wild-type cells. Thus, LRG-47 may serve as a critical vacuolar trafficking component used to dispose of intracellular pathogens like Mtb.
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              Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages.

              Control of tuberculosis worldwide depends on our understanding of human immune mechanisms, which combat the infection. Acquired T cell responses are critical for host defense against microbial pathogens, yet the mechanisms by which they act in humans remain unclear. We report that T cells, by the release of interferon-γ (IFN-γ), induce autophagy, phagosomal maturation, the production of antimicrobial peptides such as cathelicidin, and antimicrobial activity against Mycobacterium tuberculosis in human macrophages via a vitamin D-dependent pathway. IFN-γ induced the antimicrobial pathway in human macrophages cultured in vitamin D-sufficient sera, but not in sera from African-Americans that have lower amounts of vitamin D and who are more susceptible to tuberculosis. In vitro supplementation of vitamin D-deficient serum with 25-hydroxyvitamin D3 restored IFN-γ-induced antimicrobial peptide expression, autophagy, phagosome-lysosome fusion, and antimicrobial activity. These results suggest a mechanism in which vitamin D is required for acquired immunity to overcome the ability of intracellular pathogens to evade macrophage-mediated antimicrobial responses. The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                22 January 2018
                January 2018
                : 9
                : 1
                : 46
                Affiliations
                [1 ]Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Pabellón II, Universidad de Buenos Aires, 4°piso, Intendente Güiraldes 2160, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; rolandelliagus@ 123456gmail.com (A.R.); joaquinmpellegrini@ 123456gmail.com (J.M.P.); nicolasamiano@ 123456hotmail.com (N.O.A.); mariaceciliasantilli@ 123456gmail.com (M.C.S.); maria.paula.morelli@ 123456gmail.com (M.P.M.); florencia.castelloz@ 123456gmail.com (F.A.C.); nantateosian@ 123456gmail.com (N.L.T.)
                [2 ]Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, 4°piso, Intendente Güiraldes 2160, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina
                [3 ]División Tisioneumonología Hospital F.J. Muñiz, Uspallata 2272, (C1282AEN), Buenos Aires, Argentina; albertojlevi@ 123456gmail.com (A.L.); casconicolas@ 123456hotmail.com (N.C.); djpalmero@ 123456intramed.net (D.J.P.)
                Author notes
                [* ]Correspondence: vgarcia@ 123456qb.fcen.uba.ar (V.E.G.); Tel.: +011-5411-4576-3300 (ext. 203)
                Author information
                https://orcid.org/0000-0002-3505-8638
                https://orcid.org/0000-0001-7157-486X
                Article
                genes-09-00046
                10.3390/genes9010046
                5793197
                29361774
                796c1cfe-b389-4bca-a78a-1a87aa4bb87e
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 October 2017
                : 09 January 2018
                Categories
                Article

                interferon gamma,mycobacterium tuberculosis,single nucleotide polymorphism,rs1861494,tuberculosis

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