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Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.

ABSTRACT: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-?). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-?, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-?R2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN-?-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-?R2 deficiency respond poorly to IFN-?, in some cases as poorly as the cells of P1. Naive CD4(+) T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-?, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-?R2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-?R2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-?R2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN-? in these individuals.

SUBMITTER: Kong XF

PROVIDER: S-EPMC3554203 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.

Kong Xiao-Fei XF Vogt Guillaume G Itan Yuval Y Macura-Biegun Anna A Szaflarska Anna A Kowalczyk Danuta D Chapgier Ariane A Abhyankar Avinash A Furthner Dieter D Djambas Khayat Claudia C Okada Satoshi S Bryant Vanessa L VL Bogunovic Dusan D Kreins Alexandra A Moncada-Vélez Marcela M Migaud Mélanie M Al-Ajaji Sulaiman S Al-Muhsen Saleh S Holland Steven M SM Abel Laurent L Picard Capucine C Chaussabel Damien D Bustamante Jacinta J Casanova Jean-Laurent JL Boisson-Dupuis Stéphanie S

Human molecular genetics 20121116 4

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-γ). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-γ, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-γR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for b ...[more]

PMID: 23161749

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Project description:The worldwide increase in the frequency of multidrug-resistant and extensively drug-resistant cases of tuberculosis is mainly due to therapeutic noncompliance associated with a lengthy treatment regimen. Depending on the drug susceptibility profile, the treatment duration can extend from 6?months to 2?years. This protracted regimen is attributed to a supposedly nonreplicating and metabolically inert subset of the Mycobacterium tuberculosis population, called "persisters." The mechanism underlying stochastic generation and enrichment of persisters is not fully known. We have previously reported that the utilization of host cholesterol is essential for mycobacterial persistence. In this study, we have demonstrated that cholesterol-induced activation of a RNase toxin (VapC12) inhibits translation by targeting proT tRNA in M. tuberculosis This results in cholesterol-specific growth modulation that increases the frequency of generation of the persisters in a heterogeneous M. tuberculosis population. Also, a null mutant strain of this toxin (?vapC12) demonstrated an enhanced growth phenotype in a guinea pig model of M. tuberculosis infection, depicting its role in disease persistence. Thus, we have identified a novel strategy through which cholesterol-specific activation of a toxin-antitoxin module in M. tuberculosis enhances persister formation during infection. The current findings provide an opportunity to target persisters, a new paradigm facilitating tuberculosis drug development.IMPORTANCE The current TB treatment regimen involves a combination of drugs administered for an extended duration that could last for 6?months to 2?years. This could lead to noncompliance and the emergence of newer drug resistance strains. It is widely perceived that the major culprits are the so-called nonreplicating and metabolically inactive "persister" bacteria. The importance of cholesterol utilization during the persistence stage of M. tuberculosis infection and its potential role in the generation of persisters is very intriguing. We explored the mechanism involved in the cholesterol-mediated generation of persisters in mycobacteria. In this study, we have identified a toxin-antitoxin (TA) system essential for the generation of persisters during M. tuberculosis infection. This study verified that M. tuberculosis strain devoid of the VapBC12 TA system failed to persist and showed a hypervirulent phenotype in a guinea pig infection model. Our studies indicate that the M. tuberculosis VapBC12 TA system acts as a molecular switch regulating persister generation during infection. VapBC12 TA system as a drug target offers opportunities to develop shorter and more effective treatment regimens against tuberculosis.

Dataset Information

Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.

Publications

Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.

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