Faculty Opinions recommendation of Bacterial subversion of cAMP signalling inhibits cathelicidin expression, which is required for innate resistance to Mycobacterium tuberculosis.

Antimicrobial peptides such as cathelicidins are an important component of innate immune defence against inhaled microorganisms and have demonstrated antimicrobial activity against Mycobacterium tuberculosis with in vitro models.Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo.We sought to determine whether the cathelicidin-related antimicrobial peptide (Cramp) gene, the murine functional homologue of the human cathelicidin gene (CAMP or LL-37), is required for regulating protective immunity during M. tuberculosis infection in vivo.We used Cramp -/-mice in a validated model of pulmonary tuberculosis and conducted cell-based assays with macrophages from these mice.We evaluated the in vivo susceptibility of Cramp -/-mice to infection and further dissected various proinflammatory immune responses against M. tuberculosis.We observed increased susceptibility of Cramp -/-mice to M. tuberculosis compared to wild type mice.Macrophages from Cramp -/-mice were unable to control M. tuberculosis growth in an in vitro infection model, were deficient in intracellular calcium influx and were defective in stimulating T-cells.Additionally, CD4 and CD8 T-cells from Cramp -/-mice produced less IFNβ upon stimulation.Furthermore, bacterial-derived cyclic-AMP modulated cathelicidin expression in macrophages.Our results demonstrate that cathelicidin is required for innate resistance to M. tuberculosis in a relevant animal model and is a key mediator in regulating the levels of pro-inflammatory cytokines by calcium and cyclic nucleotides.