Polybacterial mucosal vaccine protects against viral respiratory infections and induces trained immunity

Abstract

Recurrent respiratory tract infections (RRTI) are very frequent in childhood due to the immature state of the immune system and the traditional therapeutic strategies just rely on antibiotic treatments. However, the etiology of RRTIs is diverse, with viruses being the most common cause of the disease. Thus, alternative approaches that tackle this heal¬th issue are needed. In this direction, several studies have shown that bacterial preparations provide protection against RRTI through the modulation of both cellular and humoral responses. MV130 is a sublingual preparation of different whole inactivated bacteria that are frequently present in the human respiratory tract. Its efficacy against RRTIs has been already demonstra¬ted both in adults and in children, but its mechanism of action remains unexplored. Herein, we observed that MV130 treatment in mice provided protection against both Vaccinia and Influen¬za A respiratory infections and this was reflected into less weight loss and better survival than control mice. Indeed, MV130-treated mice showed a reduced viral load in the lungs at day three post infection. Moreover, MV130 treatment causes a general infiltration of both myeloid and lymphoid cell populations in the lungs. Several studies indicate that certain microbial stimuli can induce functional, metabolic and epigenetic changes in innate immune cells resulting in long-las¬ting improved response to a secondary infection. This phenomenon is termed trained immunity. Therefore, we hypothesized that MV130 could confer protection by inducing trained immunity. We observed that MV130 provides protection to mice against systemic Candida albicans infec¬tion, a benchmark in vivo model of trained immunity. Moreover, the protective effect of MV130 was reproduced in mice that lack T and B lymphocytes. Following metformin treatment, which inhibits the mTOR pathway and thus impairs trained immunity, mice pretreated with MV130 lost the protection against Influenza A respiratory infection. MV130 is also able to educate myeloid progenitors, which can give rise in vitro to trained mature cells. Finally, we found that MV130 is able to induce trained immunity in human monocytes, promoting metabolic and epigenetic mo¬dulation and enhanced cytokine production. Thus, these results highlight the important role of MV130 mediated-cross protection through generation of innate immune memory.