Uncovering the role of CBLB for innate immune responses regulating systemic dissemination during a Non-Tuberculous Mycobacterial infection

Abstract

Abstract Non-Tuberculous Mycobacteria (NTM) are ubiquitous and cause chronic lung infections to fatal disseminated diseases in immunocompromised individuals. The incidence and prevalence of NTM infections are increasing globally, mainly due to the surging numbers of immunocompromised patients. The diagnosis is often misleading, and the emergence of multi-drug resistant NTM has deprived the treatment options. Innate immune responses, dictated by immune regulators, shape the clinical outcomes of NTM infections. Here, we describe the role of an E3 ubiquitin ligase, CBLB, for innate immunity against an NTM infection. We found that the absence of CBLB, under T-cell deficiency, enhanced the bacterial burden and dissemination following both intravenous and intratracheal infections. Strikingly, CBLB fostered an early induction of granulomatous inflammation, which thwarts the dissemination. CBLB-deficiency caused a significant reduction of NK cell numbers, but not their intrinsic functions. Further, we found that CBLB was required to augment the numbers of inflammatory monocytes and conventional dendritic cells, the latter, additionally, for their activation. Thus, our findings suggest that CBLB plays an essential role in eliciting protective innate immune responses to control the growth and dissemination of NTM during T-cell deficiency.