Bacillus Calmette-Guerin-Trained Macrophages Elicit a Protective Inflammatory Response against the Pathogenic Bacteria Brucella abortus

Author(s)

de Araujo, Ana Carolina V. S. C. ; de Queiroz, Nina M. G. P. ; Marinho, Fabio V. ; Oliveira, Sergio C.

• Document type: Journal article
• Source: JOURNAL OF IMMUNOLOGY; v. 211, n. 5, p. 13-pg., 2023-09-01.

Abstract

The bacillus Calmette-Guerin (BCG) can elicit enhanced innate immune responses against a wide range of infections, known as trained immunity. Brucella abortus is the causative agent of brucellosis, a debilitating disease that affects humans and animals. In this study, we demonstrate that C57BL/6 mouse bone marrow-derived macrophages under BCG training enhance inflammatory responses against B. abortus. BCG-trained macrophages showed increased MHC class II and CD40 expression on the cell surface and higher IL-6, IL-12, and IL-1 beta production. The increase in IL-1 beta secretion was accompanied by enhanced activation of canonical and noncanonical inflammasome platforms. We observed elevated caspase-11 expression and caspase-1 processing in BCG-trained macrophages in response to B. abortus compared with untrained cells. In addition, these BCG-trained cells showed higher NLRP3 expression after B. abortus infection. From a metabolic point of view, signaling through the Akt/mammalian target of rapamycin/S6 kinase pathway was also enhanced. In addition, BCG training resulted in higher inducible NO synthase expression and nitrite production, culminating in an improved macrophage-killing capacity against intracellular B. abortus. In vivo, we monitored a significant reduction in the bacterial burden in organs from BCG-trained C57BL/6 mice when compared with the untrained group. In addition, previous BCG immunization of RAG-1-deficient mice partially protects against Brucella infection, suggesting the important role of the innate immune compartment in this scenario. Furthermore, naive recipient mice that received BM transfer from BCG-trained donors showed greater resistance to B. abortus when compared with their untrained counterparts. These results demonstrate that BCG-induced trained immunity in mice results in better control of intracellular B. abortus in vivo and in vitro. (AU)

• FAPESP's process: 22/15358-7 - The role of STING and the unfolded protein response on macrophage polarization and control of Brucella abortus infection
• Grantee: Sergio Costa Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 23/02577-5 - Study of the mechanisms responsible for trained immunity induced by Bacillus Calmette-Guérin (BCG) in infectious diseases and Cancer
• Grantee: Sergio Costa Oliveira
• Support Opportunities: Research Projects - Thematic Grants