Vitamin D increases the human endosomal TLR response against Mycobacterium tuberculosis nucleic acids

Abstract

Abstract Mycobacterium tuberculosis (Mtb) infects macrophages where it avoids elimination by interfering with host defense mechanisms. Type I IFNs are produced by activation of endosomal TLRs after recognition of nucleic acids. TLR importance is underlined by the fact that the TLR-adaptor molecule MyD88 pathway in macrophages is important in confining Mtb within phagolysosomes, mycobacterial clearance, and an adequate innate and adaptive immune response against Mtb. Vitamin D (VD) has a positive effect in macrophage activation, phagocytosis, restriction of Mtb growth, and killing of the mycobacteria. We aimed to characterize the endosomal TLR-signaling of human macrophages, as they are appear crucial in determining the fate of the disease, and explore if variations in Type I IFN responses correlate with differences in Mtb nucleic acids derived from different Mtb genotypes. Stimulation with DNA from Mtb of different lineages elicited differential NF-κB and IRF inflammatory responses in THP-1 derived macrophages. We also studied the effect of VD on these responses, as it is known to activate macrophages and enhance their antimycobacterial activity. Pretreatment with VD increased the response to DNA from HN878 and virulent strain H37Rv. It also enhanced the response to RNA from M. smegmatis and attenuated M. bovis strain BCG. No previous study has evaluated Type I or Type II IFNs response differences between different Mtb strains. This is of great importance as type I IFNs appear to strongly inhibit macrophages responsiveness to IFN-γ, and are associated with active TB. Understanding VD-mediated activation occurring at the pulmonary alveoli will impact the design of novel therapeutic and successful immunization strategies.