Meza, K. A. | Search bioRxiv

bioRxiv2024

Immunity against Mycobacterium avium induced by DAR-901 and BCG

The prevalence of pulmonary nontuberculous mycobacteria (NTM) is increasing in Europe and North America. Most pulmonary NTM are caused by Mycobacterium avium complex (MAC). The treatment of pulmonary MAC is suboptimal with failure rates ranging from 30% to 40% and there is a need to develop new vaccines. In this study, we tested the ability of two whole cell vaccines, DAR-901 (heat killed M. obuense) and BCG (live attenuated M. bovis), to induce MAC cross-reactive immunity by first immunizing BALB/c mice and then performing IFN-{gamma} ELISPOT assay after overnight stimulation of splenocytes with live MAC. To study the ability of these vaccines to protect against MAC infection, BALB/c mice were vaccinated with DAR-901 (intradermal) or BCG (subcutaneous or intranasal) and challenged with aerosolized MAC 4 weeks later. Some mice vaccinated with BCG were treated with clarithromycin via gavage. Lung CFU in immunized mice and unvaccinated controls were quantified 4 weeks after infection. Our results showed that i) DAR-901 induced cross-reactive immunity to MAC and the level of MAC cross-reactive immunity was similar to the level of immunity induced by BCG, ii) DAR-901 and BCG protect against aerosol MAC, iii) mucosal BCG vaccination provided the best protection against MAC challenge, and iv) BCG vaccination did not interfere with anti-MAC activities of clarithromycin.

immunology↗

bioRxiv2020

Th17 cells provide direct protective effects that limit stomach parasite burden following orogastric mucosal Trypanosoma cruzi infection

Trypanosoma cruzi is the intracellular parasite of Chagas disease, a chronic condition characterized by cardiac and gastrointestinal morbidity. Protective immunity requires CD4+ T cells, and Th1 cells and IFN-{gamma} are important players in host defense. More recently, Th17 cells and IL-17 have been shown to exert protective functions in systemic T. cruzi infection. However, it remains unclear whether Th17 cells and IL-17A protect against mucosal infection, which is an important cause of human outbreaks. We found that IL-17RA knock-out (KO) mice are highly susceptible to orogastric infection, indicating an important function for this cytokine in mucosal immunity to T. cruzi. To investigate the specific role of Th17 cells for mucosal immunity, we reconstituted RAG1 KO mice with T. cruzi-specific T cell receptor transgenic Th17 cells prior to orogastric T. cruzi challenges. We found that Th17 cells provided protection against gastric mucosal T. cruzi infection, indicated by significantly lower stomach parasite burdens. In vitro macrophage infection assays revealed that protection by Th17 cells is reversed with IL-17A neutralization or loss of macrophage NADPH oxidase activity. Consistent with this, in vivo, mice lacking functional NADPH oxidase were not protected by Th17 cell transfer. These data are the first report that Th17 cells protect against mucosal T. cruzi infection, and identify a novel protective mechanism involving the induction of NADPH oxidase activity in macrophages by IL-17A. These studies provide important insights for Chagas vaccine development, and more broadly, increase our understanding of the diverse roles of Th17 cells in host defense.

immunology↗