Splenic marginal zone B cells restrict Mycobacterium tuberculosis infection by shaping the cytokine pattern and cell-mediated immunity.

Understanding the role of B cells in tuberculosis (TB) is crucial for developing new TB vaccines. However, the changes in B cell immune landscapes during TB and their functional implications remain incompletely explored. Using high-dimensional flow cytometry to map the immune landscape in response to Mycobacterium tuberculosis (Mtb) infection, our results show an accumulation of marginal zone B (MZB) cells and other unconventional B cell subsets in the lungs and spleen, shaping an unconventional B cell landscape. These MZB cells exhibit activated and memory-like phenotypes, distinguishing their functional profiles from those of conventional B cells. Notably, functional studies show that MZB cells produce multiple cytokines and contribute to systemic protection against TB by shaping cytokine patterns and cell-mediated immunity. These changes in the immune landscape are reversible upon successful TB chemotherapy. Our study suggests that, beyond antibody production, targeting the regulatory function of B cells may be a valuable strategy for TB vaccine development.

Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular.

Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of pyrazinamide. The most potent hit, indole propionic acid [IPA; 3-(1H-indol-3-yl)propanoic acid], a metabolite produced by the gut microbiota, was profiled in vivo The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In a mouse model of acute M. tuberculosis infection, IPA reduced the bacterial load in the spleen 7-fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates.