Ag85a-S2 Activates cGAS-STING Signaling Pathway in Intestinal Mucosal Cells

Abstract

Brucellosis is a zoonotic disease caused by Gram-negative bacteria. Most of the brucellosis vaccines in the application are whole-bacteria vaccines. Live-attenuated vaccines are widely used for brucellosis prevention in sheep, goats, pigs, and cattle. Thus, there is also a need for an adjuvanted vaccine for human brucellosis, because the attenuated Brucella vaccines now utilized in animals cause human illness. Here, we developed a live-attenuated Brucella suis strain 2 vaccine (S2) adjuvanted with Ag85a (Ag85a-S2). We found that Ag85a-S2 activated cGAS-STING pathways both in intestinal mucosal cells in vivo and in the BMDM and U937 cell line in vitro. We demonstrated that the cGAS knockout significantly downregulated the abundance of interferon and other cytokines induced by Ag85a-S2. Moreover, Ag85a-S2 triggered a stronger cellular immune response compared to S2 alone. In sum, Ag85a-S2-mediated enhancement of immune responses was at least partially dependent on the cGAS-STING pathway. Our results provide a new candidate for preventing Brucella pathogens from livestock, which might reduce the dosage and potential toxicity compared to S2.

THEME: “Vaccines and Vaccine Adjuvants/Immunomodulators for Infectious Diseases”

“…In the 2nd edition of the special issue, Dang et al developed a novel adjuvanted live-attenuated vaccine for human brucellosis, which is a zoonotic bacterial disease [ 21 ]. The existing live-attenuated Brucella vaccines cause reproductive health issues in cattle and were potentially pathogenic in humans due to the high dosage requirement.…”

“…In this study, the authors have demonstrated that the use of Ag85a (a Mycobacterium tuberculosis cell wall derived diacylglycerol acyltransferase involved in lipid body formation) as an immune modulatory adjuvant significantly enhances CD4 + T and CD8 + T lymphocyte responses compared to vaccine alone. Knockout studies suggested that Ag85a achieves this protective immune response by activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway and, hence, could be a solution to circumvent the high dose associated toxicity of live-attenuated Brucella vaccines in animals and humans [ 21 ].…”