Oral administration of Lactococcus lactis delivered heat shock protein 65 attenuates atherosclerosis in low-density lipoprotein receptor-deficient mice

Abstract

Lactococcus is a genus of Gram positive food-grade bacteria that has been widely used as a vaccine platform for the safe delivery of heterologous antigens. Many reports support the involvement of inflammation and immunity in atherosclerosis as well as the role of autoimmunity to heat shock proteins (HSPs) in the progression of atherogenesis. In this study, experiments were specifically designed to investigate the effect of oral administration of mycobacterial heat shock protein 65 (HSP65) delivered by Lactococcus lactis (L. lactis) on atherogenesis. Two types of HSP65-encoding plasmids for intracellular expression or secretion were constructed, and then transformed into L. lactis NZ9000. Oral administration of two recombinant L. lactis strains both induced suppression of HSP65-specific proliferation, accompanied by elevation of Interleukin-10 (IL-10) production and reduction of interferon-gamma (IFN-γ) level. Inducible HSP65-specific tolerance exerted a protective effect on atherosclerotic lesion formation and endothelial damage in low-density lipoprotein receptor-deficient (LDL-RD) mice model, while no obvious pathological abnormalities were observed. In conclusion, delivery of HSP65 at the intestinal mucosa by recombinant L. lactis provides a novel approach for the prevention of atherosclerosis. The results further illustrate the potential of using genetically modified L. lactis as a safe and effective vaccine delivery to elicit antigen-specific tolerance for treatment of autoimmune diseases.