Aerosol vaccination with Bacille Calmette-Guerin induces a trained innate immune phenotype in calves

Abstract

Abstract M. bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine for use against tuberculosis (TB). BCG is known to reduce childhood mortality from infections other than TB. The unspecific protection induced by BCG has been associated with the induction of memory-like traits identified as ‘trained’ immunity. In humans and mice, in vitro and in vivo BCG training leads to enhanced production of proinflammatory cytokines in response to secondary unrelated pathogens. While BCG nonspecific protective effects have been studied extensively in humans and mice, it has not been defined in agricultural species. Here, we show that in vitro BCG training induces increased transcription of proinflammatory cytokines upon restimulation with the TLR agonists. Importantly, in vivo, aerosol BCG vaccination of calves induced a ‘trained’ phenotype in PBMCs, that lead to a significantly enhanced TLR-induced proinflammatory cytokine response compared to PBMCs from unvaccinated calves. Similar to the long-term training effects of BCG reported in humans, our results suggest that in young calves, the effects of BCG induced innate training last for at least 3 months in circulating immune cells. Interestingly, however, aerosol BCG vaccination did not ‘train’ innate cells at the mucosal level, as alveolar macrophages from aerosol BCG vaccinated calves did not mount an enhanced inflammatory response to secondary stimulation, compared to cells isolated from control calves. Together, our results suggest that, like mice and humans, the innate immune system of calves can be ‘trained’; and that BCG vaccination could be used as an immunomodulatory strategy to reduce disease burden in juvenile food animals before the adaptive immune system has fully matured.