Date Published: February 22, 2019
Publisher: Public Library of Science
Author(s): Mariana Guerra-Maupome, Dua X. Vang, Jodi L. McGill, Joyoti Basu.
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine for use against tuberculosis (TB); however, it is known to reduce childhood mortality from infections other than TB. The unspecific protection induced by BCG vaccination has been associated with the induction of memory-like traits of the innate immune system identified as ‘trained’ immunity. In humans and mouse models, in vitro and in vivo BCG training leads to enhanced production of monocyte-derived proinflammatory cytokines in response to secondary unrelated bacterial and fungal pathogens. While BCG has been studied extensively for its ability to induce innate training in humans and mouse models, BCG’s nonspecific protective effects have not been defined in agricultural species. Here, we show that in vitro BCG training induces a functional change in bovine monocytes, characterized by increased transcription of proinflammatory cytokines upon restimulation with the toll-like receptor agonists. Importantly, in vivo, aerosol BCG vaccination in young calves also induced a ‘trained’ phenotype in circulating peripheral blood mononuclear cells (PBMCs), that lead to a significantly enhanced TLR-induced proinflammatory cytokine response and changes in cellular metabolism compared to PBMCs from unvaccinated control 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 can last for at least 3 months in circulating immune populations. Interestingly, however, aerosol BCG vaccination did not ‘train’ the innate immune response 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.
Evidence from epidemiological studies suggests that previous exposure to Mycobacterium bovis Bacillus Calmette-Guérin (BCG), a live attenuated vaccine used to prevent tuberculosis, reduces the risk of childhood mortality due to prevention of sepsis, diarrhea and respiratory infections [[1–4] and reviewed [5, 6]]. It has been suggested that the nonspecific disease resistance induced by BCG is mediated by an enhanced memory-like response of the innate immune system known as ‘trained’ immunity [7, 8].
BCG parenteral vaccination has long been known to have beneficial effects against childhood diseases other than TB, and it has recently become clear that these effects arise through a mechanism known as innate training or ‘trained’ immunity [7, 8, 16]. However, the nonspecific effects of BCG have yet to be studied in agricultural species. Here, we demonstrate that, consistent with previous studies in human and mouse models (11, 16, 29, 32, 33), BCG vaccination has the capacity to ‘train’ bovine PBMCs, leading to a significantly enhanced TLR-induced proinflammatory cytokine response compared to PBMCs from control calves (Fig 2). Thus, our observations have important clinical relevance, as they suggest that the use of BCG vaccination is likely to confer improved disease resistance, through at least 6 months of age, when the ‘window of susceptibility’ to infection with common diseases in juvenile animals is greatest.