REI_MSMD · Inborn errors of translation reinitiation in humans with Mendelian susceptibility to mycobacterial disease

Inborn errors of translation reinitiation in humans with Mendelian susceptibility to mycobacterial disease

The clinical outcome of any infection varies considerably between individuals, ranging from silent infection in most, to lethal disease in a few. Tuberculosis (TB), caused by Mycobacterium tuberculosis, has been a deadly infectious disease, with at least one billion deaths in the last 2,000 years. However, infection with M. tuberculosis is silent or benign in >90% of infected individuals. Forward genetics studies of rare patients with clinical disease due to the weakly virulent Bacillus Calmette–Guérin (BCG) live-attenuated vaccine against TB, or atypical environmental mycobacteria (EM) led to the discovery of human genetic and immunological determinants of TB. Severe disease due to BCG or EM in otherwise healthy individuals, particularly those without HIV infection or immunosuppression, is referred to as Mendelian susceptibility to mycobacterial disease (MSMD) because of the frequent occurrence of multiplex families and parental consanguinity. MSMD is relatively rare, occurring in ~1 in 50,000 individuals, and is typically ‘isolated’ (~75% of cases) or, rarely, ‘syndromic’ (~25%). Patients with isolated MSMD are otherwise healthy and normally resistant to most common microbes, except, occasionally, other intramacrophagic pathogens, including some bacteria (e.g. Salmonella), fungi (e.g. Coccidioidomyces), and parasites (e.g. Leishmania). Over the last 25 years, the discovery of inborn errors of interferon-gamma (IFN-) immunity has defined the root cause and immunological mechanism of MSMD and TB. With one possible exception (ZNFX1 deficiency), all genetic defects underlying both isolated and syndromic MSMD perturb IFN- immunity (germline mutations of genes encoding IFN-R1, IFN-R2, IFN-, STAT1, IRF1, JAK1, IL-12Rß1, IL-12Rß2, IL-23R, IL-12p40, TYK2, SPPL2A, IRF8, NEMO, CYBB, ISG15, USP18, RORT, and T-bet). Many genetic defects directly impair the production of IFN-, or the response to this cytokine (IFN-R1, IFN-R2, JAK1, STAT1, IRF1), whereas others affect the production of, or response to the IFN--inducing cytokines IL-12, IL-23, and ISG15 (IL-12Rß1, IL-12Rß2, IL-23R, IL-12p40, TYK2, ISG15). Deficiencies of the IL-12-specific IL-12Rß230 and IL-23-specific IL-23R also underlie MSMD, suggesting that neither of these two IFN--inducing cytokines is dispensable for antimycobacterial immunity. Human genetic studies of MSMD have, thus, revealed that IL-12- and IL-23-dependent IFN-γ immunity is essential for host defense against weakly virulent mycobacteria. Upon infection with mycobacteria, macrophages produce IL-12 and IL-23, which stimulate natural killer (NK) and T lymphocytes to produce IFN-. Several lymphocyte subsets have been identified as critical producers of IFN- and mediators of antimycobacterial immunity: patients with autosomal recessive (AR) SPPL2A or RORT deficiency, or with autosomal dominant (AD) IRF8 deficiency suffer from MSMD due to a lack of T-helper (TH) 1* cells, whereas AR T-bet deficiency impairs the development and IFN- production of NK cells, innate-like adaptive lymphocyte subsets (mucosal-associated invariant T cells [MAIT], V2+ T, and invariant natural killer [iNKT] cells), and TH1 cells. In IL-12Rß1-, IL-12Rß2-, and IL-23R-deficient patients, these subsets (NK, MAIT, V2+ T, iNKT, TH1 and TH1*) also fail to produce IFN- in response to IL-12 and/or IL-23. IFN- can stimulate most cell types, but is crucial for the killing of mycobacteria within phagocytes, and it also boosts the production of IL-12 and IL-23 by these cells, forming a positive feedback loop. Molecular genetics studies of MSMD have revealed the mechanisms of antimycobacterial immunity in humans in natura, demonstrating that IFN- acts as a key antimycobacterial cytokine rather than an antiviral interferon. Severe viral diseases are rare in patients with MSMD, occurring mostly in patients with syndromic MSMD who also have impaired IFN-/ immunity (mutations of JAK1, STAT1, TYK2). Moreover, the study of MSMD has led to the discovery of both rare and common determinants of clinical TB, which is caused by M. tuberculosis, a bacterium 1,000 times more virulent than those implicated in MSMD2. Most genetic etiologies of MSMD have incomplete penetrance for MSMD and can manifest as genetic etiologies of TB. Moreover, homozygosity for the common P1104A allele of TYK2 selectively impairs the IL-23-dependent induction of IFN- and accounts for about 1% of cases of TB in patients of European descent. The study of MSMD has, therefore, had both biological and medical implications. However, a clear genetic etiology has yet to be found for about half the MSMD patients identified to date, implying that our understanding of antimycobacterial immunity is incomplete. In this context, we searched for new genetic causes and immunological mechanisms of MSMD.

Data: CORDIS, © European Union