B. abortus down modulates inflammation in monocytes/macrophages through mTOR activation

Abstract

Brucellosis, caused by Brucella spp, is a disease with a large inflammatory component. B. abortus has been shown to activate cells of innate immunity, inducing the secretion of pro-inflammatory factors. However, B. abortus has different mechanisms whereby it modulates the immune response, in order to evade it and survive intracellularly. mTOR (mammalian target of rapamycin) is a protein kinase that regulates essential signaling pathways, regulating several cellular functions, such as innate immunity, among others. The aim of this work was to elucidate whether B. abortus can modulate the functionality of monocytes and macrophages through the activation of mTOR. B. abortus was capable to activate mTOR (evaluated by flow cytometry) during the infection of human monocytes and murine macrophages (RAW 264.7). As heat-killed B. abortus recapitulates the effect, we concluded that bacterial viability is not necessary to induce mTOR activation. A significant increase in the expression of TNF-α (p<0.0005), IL-6 (p<0.05), IL-1 (p<0.005) and IL-10 (p<0.05), as well as metalloproteinase (MMP)-9 (p<0.0005) was observed when infected-cells were pre-treated with rapamycin, a pharmacological inhibitor of mTOR. Together, our results demonstrate that B. abortus activates mTOR, which negatively regulates the inflammatory response, potentially contributing to the escape of the immune response, allowing B. abortus to survive within monocytes/macrophages for prolonged periods, generating an infection.