Gut Microbiota Modulates Lung Immunity against Mycobacterial Infection

Adequate induction of protective immunity is essential to control virulent mycobacterial infection. Homeostasis of gut microbiota via pattern-recognition receptors (PRRs) has been linked to modulation of local and systemic immunity, whereas the role in mycobacterial pulmonary infection is unknown. Our preliminary results showed that gut microbiota is critical for regulation of lung immunity against M. kansasii-induced pulmonary infection in mice. Dysbiosis exploited by broad-spectrum antibiotics (ABX, ampicillin, metronidazole, neomycin, vancomycin) or neomycin leads to mice succumbing to deadly disseminated M. kansasii infection. 16S rRNA-based next-generation sequencing revealed the significant change of gut microbiota in ABX- and neomycin-treat mice compared to the untreated and other antibiotics-treated mice. The induced innate and adaptive immunity against M. kansasii are diminished in ABX- and neomycin-treated mice. Furthermore, we identify that expression of C-type lectin (Mincle), instead of other PRRs, on monocytic myeloid cells is reduced and failed to be induced in antibiotics-treated mice after M. kansasii infection. Importantly, gut flora recolonization completely restored the gut microbiota and Mincle expression of ABX mice with intact immunity. Thus, in this proposal, we aimed to further unravel the underlying mechanism by which gut microbiota is required for establishment of robust lung immunity against mycobacteria. The proposal will be categorized into three stages: (1) Elucidating the molecular mechanism of gut microbiota-regulated anti-mycobacterium lung immunity involving optimal expression of Mincle and relevant pathways; (2) Uncovering the specific gut microbes and derived factors required for inducing anti-mycobacterium lung immunity by using 16S rRNA-based next-generation sequencing and; (3) Confirming the “Probiotics” role of microbes identified by using gnotobiotics mice model. This study will reveal the essential role of gut microbiota and the derived signals in establishing robust pulmonary anti-mycobacteria immune responses and in determining host immune responsiveness. The gut microbes identified will be utilized as probiotics, potentially applicable to clinical immunomodulation- based mycobacteria treatment and vaccine efficacy.

Project ID:PC10401-0630
External Project ID:MOST103-2320-B182-027-MY3