Abstract
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.
Highlights
Evidence from epidemiological studies suggests that previous exposure to Mycobacterium bovis Bacillus Calmette-Guerin (BCG), a live attenuated vaccine used to prevent tuberculosis, reduces the risk of childhood mortality due to prevention of sepsis, diarrhea and respiratory infections [[1,2,3,4] and reviewed [5, 6]]
Bovine monocytes primed in vitro with BCG mounted an enhanced response to LPS or Pam3CSK4 compared to non- trained cells, characterized by higher expression of TNFα and interleukin 6 (IL-6). These results suggest that, similar to observations in humans and mice models [16, 34, 39], in vitro BCG priming of bovine monocytes induces increased responsiveness to secondary unrelated stimuli, as measured by expression of the proinflammatory cytokines TNFα and IL-6
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 peripheral blood mononuclear cells (PBMCs), leading to a significantly enhanced TLR-induced proinflammatory cytokine response compared to PBMCs from control calves (Fig 2)
Summary
Evidence from epidemiological studies suggests that previous exposure to Mycobacterium bovis Bacillus Calmette-Guerin (BCG), a live attenuated vaccine used to prevent tuberculosis, reduces the risk of childhood mortality due to prevention of sepsis, diarrhea and respiratory infections [[1,2,3,4] and reviewed [5, 6]]. Trained immunity is induced primarily in myeloid cells (monocytes and macrophages) and natural killer (NK) cells [8,9,10,11], after previous exposure to some live vaccines like BCG, measles and yellow fever, as well as to some microbial components of pathogens [11,12,13,14,15,16,17], which results in superior cytokine expression and enhanced capacity to prevent infection. Evidence that trained immunity mediates the nonspecific protective effects seen after BCG vaccination came from proof-of-principle experimental studies In these studies, BCG vaccination of severe combined immunodeficiency (SCID) or recombination-activating gene 1 (rag1)-deficient mice induced protection against subsequent lethal Candida albicans (C. albicans) infection via a mechanism that requires macrophages and proinflammatory cytokine production, both prototypical innate immune components [9, 16, 19]. Mice vaccinated with BCG show increased resistance to malaria infection, which is associated with increased transcription of antimicrobial proteins compared with nonvaccinated mice [20]
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