The cGAS/STING Pathway Is Important for Dendritic Cell Activation but Is Not Essential to Induce Protective Immunity against <b><i>Mycobacterium tuberculosis</i></b> Infection

Abstract

Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most studies on the role of STING activation in Mtb infection have focused on macrophages. Moreover, a detailed investigation of the role of STING during Mtb infection in vivo is required. Here, we deciphered the involvement of STING in the activation of dendritic cells (DCs) and the host response to Mtb infection in vivo. In DCs, this adaptor molecule was important for Ifn-β expression and IL-12 production as well as for the surface expression of the activation markers CD40 and CD86. We also documented that Mtb DNA induces STING activation in murine fibroblasts. In vivo Mtb aerogenic infection induced the upregulation of the STING and cGAS (cyclic GMP-AMP synthase) genes, and Ifn-β pulmonary expression was dependent on both sensors. However, mice deficient for STING or cGAS presented a similar outcome to wild-type controls, with no major alterations in body weight gain, bacterial burden, or survival. Lung inflammation, proinflammatory cytokine production, and inflammatory cell recruitment were similar in STING- and cGAS-deficient mice compared to wild-type controls. In summary, although the STING pathway seems to be crucial for DC activation during Mtb infection, it is dispensable for host protection in vivo.

Sodium Butyrate Abrogates the Growth and Pathogenesis of Mycobacterium bovis via Regulation of Cathelicidin (LL37) Expression and NF-κB Signaling

“…Previous study reported that M. bovis induced the induction of proinflammatory cytokines via activation of NF-κB signaling pathway in macrophages (Wang et al, 2016). However, recent study reported that NaB inhibited LPS-induced NF-κB signaling (Marinho et al, 2018).…”

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

“…The duality of the STING adaptor molecule, sensing nucleic acids from both the host and the pathogen, is central to explaining the exacerbated response to silica pre-exposure plus M. tuberculosis infection. STING is activated after M. tuberculosis infection in vivo (Collins et al, 2015;Marinho et al, 2018); however, silica pre-exposure induces STING expression and leads to the exacerbation of STING aggregation in the perinuclear region of host cells after M. tuberculosis infection. Administration of M.tb DNA in vivo leads to STING activation and recapitulates STING aggregation after silica pre-conditioning.…”

“…M. tuberculosis residing in the macrophage release DNA, which is detected by the cytosolic surveillance system through cyclic guanosine monophosphate (cGMP)-AMP synthase (cGAS), triggering activation of the stimulator of IFN genes (STING) adaptor molecule and inducing IFNI responses (Collins et al, 2015;Manzanillo et al, 2012;Wassermann et al, 2015;Watson et al, 2015). While the STING pathway contributes to the host response to infection, including bacterial infections (Marinho et al, 2017), it does not seem essential to control in vivo M. tuberculosis infection (Collins et al, 2015;Marinho et al, 2018). (legend continued on next page)…”

Inhibition of Sting rescues lupus disease by the regulation of Lyn-mediated dendritic cell differentiation

“…The cGAS/STING pathway is essential for DC activation 35 both Sting-sufficient and Sting-deficient mice ( Fig. 5A and 5C).…”