Comparative response of dendritic cells to pathogenic and non-pathogenic leptospira spp.

Abstract

Leptospirosis is a zoonotic disease caused by pathogenic Leptospira species, which consist of three groups and contain 4 subclades: pathogenic strains (P1), intermediate strains (P2), and non-pathogenic strains (S1 and S2). Infection of pathogenic leptospires occurs through contact with contaminated environments. Then, leptospires present in the bloodstream disseminate to target organs. Nowadays, the knowledge of the immune response to pathogenic and non-pathogenic leptospires during early infection is still limited. Due to the limitation of a susceptible host, immunological reagents for hamsters and strains of mice are limited and not available. Dendritic cells are the first cells to encounter leptospires found in the skin, while monocyte-derived dendritic cells (MoDCs) are found in the bloodstream in inflammatory areas. Therefore, the role of dendritic cells is important for leptospires infection. The major goal of this study is to compare the responses of dendritic cells to pathogenic and non-pathogenic leptospires in susceptible hosts. Five-week-old C3H/HeNJ mice were infected with either 1x103 or 1x106 inoculum dose of Leptospira interrogans serovar Pomona. All infected mice survived and did not develop an acute lethal infection. However, C3H/HeNJ mice infected with 1x106 cells showed kidney colonization of leptospires and pathological changes in the lung and kidney, including kidney fibrosis and small glomerular size. Therefore, C3H/HeNJ mice may be used as an animal model for sublethal leptospirosis.

Human monocyte-derived dendritic cells were used as an in vitro model to study the response of dendritic cells to leptospires. Immature MoDCs phagocytosed a limited number of both pathogenic and non-pathogenic strains. The pathogenic strains significantly induced apoptotic cells, impaired maturation, and increased IL-10 production. MoDC impairment inhibited naive CD4 proliferation, produced IL-10, and induced regulatory T cells. In contrast, the non-pathogenic strains induced MoDC maturation, and increased IL-12p70 and IL-10 production, leading to CD4 proliferation, IFN- γ production, and Th1 cell induction. Moreover, the transcriptome analysis found that the pathogenic strains were associated with genes regulating apoptosis and regulatory T cells, while non-pathogenic strains were associated with genes regulating the maturation of MoDCs and Th1 cells. Therefore, the pathogenic strains might reduce the MoDC maturation and induce T reg, resulting in inefficient elimination of pathogenic leptospiral infection. In contrast, the non-pathogenic strains might increase MoDC maturation and Th1 response, leading to bacterial clearance