Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infections in human

• Applicants: Professor Dr. Nico Lachmann; Professor Dr. Aurelio A. Teleman
• Subject Area: Immunology ; Human Genetics ; Clinical Immunology and Allergology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505651847

Infectious diseases remain a devastating public health burden worldwide. Life-threatening bacterial diseases can result from single-gene inborn errors of immunity (IEI). Mendelian susceptibility to mycobacterial disease (MSMD) is a group of IEI characterized by severe infections caused by weakly virulent mycobacteria in otherwise healthy patients. MSMD patients are also vulnerable to tuberculosis and other diseases caused by intra-macrophagic pathogens. Eighteen of the 19 known MSMD-causing genes control the induction and/or the response to interferon gamma (IFN-g), which is the macrophage-activating factor. We hypothesize that these patients suffer from novel single-gene IEI, probably affecting IFN-g mediated immunity. This project capitalizes on a unique collection of 1,200 patients with MSMD. However, the genetic etiology of many MSMD patients remains unknown, with available whole exome sequencing (WES) data. We will search for novel IEI in these patients and validate their disease-causing effects following three specific aims: i) recruitment of MSMD patients (worldwide) and genome-wide (GW) computational approaches to select novel MSMD-causing candidate genes, ii) validation at the molecular and cellular levels of the products of novel MSMD-causing genes and mutant variants, and their connection with those of known genetic etiologies of MSMD, iii) study of myelopoiesis of MSMD-causing genes and variants using in vitro hematopoietic differentiation of iPSCs. Our project is supported by strong preliminary data, with our identification of four exciting candidate etiologies; with autosomal recessive IRF1, TNF, and CCR2 deficiencies; and one X-linked recessive MCTS1 deficiency. While IRF1, CCR2 and TNF deficiencies were predicted to underlie MSMD based on the mouse model, the discovery of MCTS1 deficiency is most surprising. The four disorders affect the myeloid lineage. We have also already generated iPSCs from one IRF1-deficient patient. The unique expertise of the three groups will synergistically tackle the problems of hematopoietic cells (in particular myeloid cells) and MSMD through the in-depth characterization of rare germline mutations occurring in natura in patients with MSMD diagnosis. This integrated program combining WES analyses with in-depth functional studies including by iPSC technology is achievable and highly innovative in the fields of medicine, genetics, immunology, and infection. This project will provide new biological insights into the pathogenesis of mycobacterial diseases (including tuberculosis) clarifying devastating medical problems. Moreover, the clinical implications will help the patients and their families not only in terms of molecular diagnosis, genetic counseling, and prognosis, but also in terms of treatment, as patients with impaired production of IFN-g can be treated with recombinant IFN-g.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professorin Jacinta Bustamante, Ph.D.