Abstract
Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4+ T cells’ proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.
Highlights
Mycobacterium bovis, the causative agent of tuberculosis in cattle, is an important intracellular pathogen that can cross species barriers and trigger disease in humans and other mammals [1]
The cyclic GMP-AMP synthase (cGAS) pathway can be activated by cytosolic pathogenic DNA or self-DNA, which induces type I interferon (IFN) production. cGAS has been identified as an important interferon-stimulated gene (ISG) [9]
Wasserman et al found that punctate cGAS staining was up-regulated in macrophages during M. tuberculosis infection [11], and DNA transfection was co-localized with cGAS in many domains
Summary
Mycobacterium bovis, the causative agent of tuberculosis in cattle, is an important intracellular pathogen that can cross species barriers and trigger disease in humans and other mammals [1]. Infected DCs generally enhance the expression of some adhesion molecules and T-cell co-stimulatory molecules, such as CD40, CD80, CD83, and CD86 These surface markers are highly expressed on mature DCs, which play an important role in antigen presentation and adaptive immune responses. We hypothesized that the maturation and activation of bone marrow-derived dendritic cells (BMDCs) were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway during M. bovis infection. Using a targeted knockdown technique, we found that the cGAS pathway was activated by M. bovis, which promoted the maturation and antigen presentation of BMDCs. our research showed that cGAS and DCs played a critical role in connecting the innate and adaptive immune responses, which would be considered as the particular target for the development of drugs and vaccines against tuberculosis infection
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