Genetic Determinants of Susceptibility to Mycobacterial Infections: IRF8, A New Kid on the Block

Abstract

Genetic and population studies suggest that onset, progression and ultimate outcome of infection with Mycobacteria, including the agent of tuberculosis Mycobacterium tuberculosis, are strongly influenced by genetic factors. Family-based and case-control linkage and association studies have suggested a complex genetic component for susceptibility to tuberculosis. On the other hand, patients with inborn errors in the IL12/IFNγ circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination. The study of such MSMD (Mendelian Susceptibility to Mycobacterial Diseases) patients has provided much insight into innate and acquired immune defenses against mycobacteria. Parallel genetic analyses in mouse models of mycobacterial infections have also indicated complex genetic control, and have provided candidate genes for parallel testing in humans. Recently, mutations in human IRF8 were discovered and shown to cause two distinct forms of a novel primary immunodeficiency and associated susceptibility to mycobacteria. Autosomal recessive IRF8 deficiency is caused by mutation K108E and associated with severe disease with complete depletion of monocytes and dendritic cells. Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells. These findings have established that IRF8 is required for ontogeny of the myeloid lineage and for host response to mycobacteria. The ongoing study of the IRF8 transcriptome has shown promise for the identification of IRF8 dependent pathways that play a critical role in host defense against mycobacteria in particular, and against intracellular pathogens in general.

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

“…Similarly, it is currently unknown to what extent the well-documented anti-inflammatory effects of the EPCR ligand aPC involve the competitive inhibition of EPCR-dependent PAR2 signaling on innate immune cells. The evolutionary conserved functions of Peli1, Irf8, and the Malt1-Bcl10-Card9 complex in humans, together with emerging evidence for the role of these pathways in human inflammatory disease, 32,[51][52][53] warrant further investigations into the potentially conserved function of the TF-EPCR-PAR2 signaling axis in human immune cells.…”

Frequency of Mycobacterium bovis and mycobacteria in primary immunodeficiencies

“…Mendelian Susceptibility to Mycobacterial Diseases MSMD has especially been associated with defects in the IL12B, IL12RB1, IRF8, ISG15, NEMO, IFNGR1, IFNGR2, STAT1, IRF8, and CYBB genes (15)(16)(17)(18)(19)(20)(21)(22). In addition, susceptibility to mycobacterial infections may be observed in combined immune deficiencies and X-linked hyper IgM syndrome (2).…”

Critical Role for a Subset of Intestinal Macrophages in Shaping Gut Microbiota in Adult Zebrafish

“…Accordingly, the irf8 mutants had an abnormal Lawsonia outgrowth in their gut microbiota. Given that our data strongly link irf8 loss with complement deficiency, and loss-of-function mutations in C1q genes are associated with immunodeficiencies and autoimmune conditions in mammals (Botto, 1998; Brown et al, 2002; Degn et al, 2011; Macedo and Isaac, 2016; Roumenina et al, 2011; Warren et al, 2002), we propose that C1q defects may underlie the susceptibility to gut microbial dysbiosis we found in zebrafish irf8 mutants and possibly also to infections known in IRF8-deficient animals and humans, but this requires further investigation (Hambleton et al, 2011; Langlais et al, 2016; Salem and Gros, 2013). In support of this, the role of complement genes in hostmicrobe interactions and modulation of cutaneous microbiota has previously been shown (Chehoud et al, 2013; Hajishengallis et al, 2013, 2017; Hasegawa et al, 2014).…”