MyD88 signalling in myeloid cells is sufficient to prevent chronic mycobacterial infection

Abstract

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis that is responsible for almost 1.5 million deaths per year. Sensing of mycobacteria by the host's immune system relies on different families of receptors present on innate immune cells. Amongst them, several members of the TLR family are involved in the activation of immune cells by mycobacteria, yet the in vivo contribution of individual TLRs to the protective immune response remains controversial. On the contrary, MyD88, the adaptor molecule for most TLRs, plays a non-redundant role in the protection against tuberculosis and mice with a complete germline deletion of MyD88 succumb very early to infection. MyD88 is expressed in both immune and non-immune cells, but it is not clear whether control of mycobacteria requires ubiquitous or cell-type specific MyD88 expression. Therefore, using novel conditional switch-on mouse models, we aimed to investigate the importance of MyD88 signalling in DCs and macrophages for the induction of protective effector mechanisms against mycobacterial infection. We conclude that specific reactivation of MyD88 signalling in CD11c-or lysozyme M-expressing myeloid cells during Mycobacterium bovis Bacille Calmette-Guerin infection is sufficient to restore systemic and local inflammatory cytokine production and to control pathogen burden. Keywords: Conditional switch-on mice r Dendritic cells r Macrophages r Mycobacteria r MyD88Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSince the discovery of Mycobacterium tuberculosis (Mtb) as the causal agent of tuberculosis, massive efforts have been made to understand the mechanisms underlying mycobacterial persistence. Despite current knowledge, it is still unclear why the immune response is insufficient to eradicate the bacteria and Correspondence: Prof. Tim Sparwasser e-mail: Sparwasser.Office@mh-hannover.de why almost 90% of Mtb-infected patients develop a chronic silent infection [1].Transmission of mycobacteria occurs mostly through the respiratory tract. Here, alveolar macrophages and DCs that patrol the lungs capture mycobacteria by phagocytosis using different receptors (e.g. DC-SIGN, mannose receptor, complement receptor, scavenger receptor class A, pulmonary surfactant-associated protein A, surfactant protein A, Fc receptor, CD14, CD40 and CD44) [2][3][4]. Exposure of macrophages and DCs to mycobacteria or their products activates members of the TLR family, leading to a cascade of events necessary for the orchestration of an OFF , but not in WT mice (Fig. 1A). Interestingly, these differences persisted even after longer periods of time (Fig. 1B). In addition, we also found higher bacterial burdens in the liver of MyD88 OFF mice at all time points evaluated and all infectious doses tested (Fig. 1B, Supporting Information Fig. 4A Fig. 2A). However, Rag1 deficiency led to an even higher number of bacteria in the lungs and liver than MyD88 deficiency ( Fig. 2A). Additionally, bacte...

Epstein–Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis

“…These genes have been demonstrated to be important regulators in inflammation and infection by modulating differentiation of hematopoietic progenitor cells or activation of immune cells as well as chemokine and cytokine production. Myd88 is a key component of cytokine production in the Toll-like receptor and IL1b signaling pathway [12]. Granulocyte/macrophage colonystimulating factor (GM-CSF) which is encoded by the CSF2 gene regulates macrophages activation in the process of MTB infection [13].…”

Epithelium‐specific MyD88 signaling, but not DCs or macrophages, control acute intestinal infection with Clostridium difficile

“…In order to study the specific role of MyD88 in the epithelium as well as DCs and macrophages, we used the MyD ON mouse model for Cre-mediated activation of functional MyD88. We and others have shown that this model allows the precise study of direct consequences of cell type-specific TLR-mediated signaling on the immune response [27,30,[36][37][38][39]. This gain-offunction model enabled us, as demonstrated previously, to restrict functional MyD88 signaling to the intestinal epithelium or CD11c + MNPs, encompassing both DCs and macrophages in intestinal tissues, while all other cells and tissues of the body remain deficient for MyD88 [30].…”

The -938C>A Polymorphism inMYD88Is Associated with Susceptibility to Tuberculosis: A Pilot Study

“…Indeed, MyD88 is critical for dendritic cell's potential to induce the differentiation of naive T cells into effector T cells producing IFN- γ , while reactivation of MyD88 signaling in CD11c or lysozyme M-expressing myeloid cells during Mycobacterium bovis infection is sufficient to restore systemic and local inflammatory cytokine production and to control pathogen burden. TNF- α and IFN- γ are particularly important in promoting the formation and function of the granulomas, whereas IL-10 is one of the main negative regulators of the response in both sarcoidosis and TB [7, 15, 29]. …”