Abstract
Leishmaniases are severe vector-borne diseases affecting humans and animals, caused by Leishmania protozoans. Immune polarization plays a major role in determining the outcome of Leishmania infections: hosts displaying M1-polarized macrophages are protected, while those biased on the M2 side acquire a chronic infection, that could develop into an overt and potentially deadly disease. The identification of the factors involved in M1 polarization is essential for the design of therapeutic and prophylactic interventions, including vaccines. Infection by the filarial nematode Dirofilaria immitis could be one of the factors that interfere with leishmaniasis in dogs. Indeed, filarial nematodes induce a partial skew of the immune response towards M1, likely caused by their bacterial endosymbionts, Wolbachia. Here we have examined the potential of AsaiaWSP, a bacterium engineered for the expression of the Wolbachia surface protein (WSP), as an inductor of M1 macrophage activation and Leishmania killing. Macrophages stimulated with AsaiaWSP displayed a strong leishmanicidal activity, comparable to that determined by the choice-drug amphotericin B. Additionally, AsaiaWSP determined the expression of markers of classical macrophage activation, including M1 cytokines, ROS and NO, and an increase in phagocytosis activity. Asaia not expressing WSP also induced macrophage activation, although at a lower extent compared to AsaiaWSP. In summary, our study, while providing a strong evidence for the immune-stimulating properties of Wolbachia, highlights the translational potential of AsaiaWSP in the areas of the immune-prophylaxis and therapy of leishmaniases, as well as of other diseases that could be subverted by M1 macrophage activation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Significance Innate immunity and macrophage polarization play a major role in determining the outcome of several diseases, from cancer to viral infections. A model disease to investigate macrophage polarization is leishmaniasis: hosts displaying M1-polarized macrophages are protected, while those biased on the M2 side develop a severe disease. Here we have explored the potential of the bacterium Wolbachia as a source of immune-polarizing molecules. Our results show that the Wolbachia surface protein, delivered through a bacterial vehicle, determines potent M1 macrophage activation, with effective killing of Leishmania parasites. Besides their translational prospect for immune-therapy and prophylaxis of leishmaniases, our results are also relevant to the wide spectrum of pathological conditions that could be subverted by M1 macrophage activation.
