miR155 contributes to host immunity against L. donovani but is not essential for resolution of infection.

Varikuti, Sanjay; Natarajan, Gayathri; Volpedo, Greta; Singh, Bhawana; Hamza, Omar; Messick, Gretchen V; Guerau-de-Arellano, Mireia; Papenfuss, Tracey L; Oghumu, Steve; Satoskar, Abhay R

CD4+ T helper 1 (Th1) cells producing interferon-γ (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). Micro RNA 155 (miR155) promotes CD4+ Th1 response and IFN-γ production by targeting Suppressor of cytokine signaling-1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP-1) and therefore could play a role in the resolution of VL. To determine the role of miR155 in VL, we monitored the course of L. donovani infection in miR155KO and WT C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads compared to WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice suggesting induction of a compensatory miR155-independent anti-leishmanial pathway. Leishmania antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-γ compared to controls. Interestingly, at later time points, levels of Th2-associated IL-4 and IL-10 were also lower in mir155KO splenocyte supernatants compared to WT mice. On the other hand, miR155KO mice displayed significantly higher levels of IFN-γ, iNOS, and TNF-α gene transcripts in their livers than WT mice, indicating that distinct organ-specific anti-parasitic mechanisms were involved in control of L. donovani infection in miR155KO mice. Throughout the course of infection organs of miR155KO mice showed significantly more PDL1 expressing Ly6Chi inflammatory monocytes compared to WT mice. Conversely, blockade of Ly6Chi inflammatory monocyte recruitment in miR155KO mice significantly reduced parasitic loads indicating that these cells contributed to disease susceptibility. In conclusion, we found that miR155 contributes to the control of L. donovani but is not essential for infection resolution.