Abstract
BCG has shown the ability to induce protection against unrelated pathogens, which likely depends on an immune mechanism known as innate immune memory or trained immunity. In this study, we evaluated the induction of innate memory by a recombinant BCG strain expressing the genetically detoxified S1 subunit of the pertussis toxin (rBCG-S1PT). In vitro pre-exposure of naïve murine macrophages to rBCG-S1PT increased their innate/inflammatory response (IL-6, TNF-α, and IL-10) to a subsequent challenge with unrelated pathogens, as compared to pre-exposure to wild-type BCG. Following LPS challenge, mice immunized with rBCG-S1PT produced higher levels of IFN-γ, while the release of other inflammatory cytokines was comparable to that measured after BCG immunization. SCID mice previously immunized with rBCG-S1PT and challenged with pathogenic Candida albicans displayed a similar survival curve as BCG-immunized mice but a lower CFU burden in the kidneys, suggesting an innate memory-dependent control of C. albicans infection. This study highlights the potential of recombinant BCG to increase innate immune memory and, ultimately, non-specific protection, more effectively than wild-type BCG. To our knowledge, this is the first report describing the potential of a recombinant BCG strain to strengthen innate immune memory responses.
Highlights
The BCG vaccine has been shown to be highly protective against the development of tuberculosis (TB) in children
We investigated whether rBCG-S1PT would confer innate memory on murine macrophages
Priming peritoneal macrophages with BCG or rBCG-S1PT induced the production of TNF-α, IL-10, and IL-1β, whereas the spontaneous high levels of IL-6 were not further increased by either BCG strain (Figure 2B)
Summary
The BCG vaccine has been shown to be highly protective against the development of tuberculosis (TB) in children. This centenary vaccine is in the vaccination programs of most developing countries. Several vaccine candidates are currently under clinical trials, including “improved” BCG-based recombinant vaccines (rBCG) that rely on the expression of antigens or immunomodulatory molecules to improve BCG immunogenicity and, protection induced against Mycobacterium tuberculosis [1]. Recombinant BCG expressing the genetically detoxified S1 subunit of the pertussis toxin (rBCG-S1PT) was demonstrated to induce protection in mice against Bordetella pertussis challenge. In an experimental model of asthma, previous immunization with rBCG-S1PT enhanced Th1 lung immunity and down-modulated the allergic response induced by ovalbumin [7]. RBCG-S1PT has shown to induce an increased inflammatory response in human peripheral blood mononuclear cells [8]
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