MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection.

Abstract

CD4+ T helper 1 (Th1) cells producing interferon gamma (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). MicroRNA 155 (miR155) promotes CD4+ Th1 responses and IFN-γ production by targeting suppressor of cytokine signaling-1 (SOCS1) and Src homology-2 domain-containing inositol 5-phosphatase 1 (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 Leishmania donovani infection in miR155 knockout (miR155KO) and wild-type (WT) C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads than WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice, suggesting the induction of a compensatory miR155-independent antileishmanial pathway. Leishmania antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-γ than controls. Interestingly, at later time points, levels of Th2-associated interleukin-4 (IL-4) and IL-10 were also lower in miR155KO splenocyte supernatants than in 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 antiparasitic 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 than 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.

• Authors: Sanjay Varikuti, Gayathri Natarajan, Greta Volpedo, Bhawana Singh, Omar Hamza, Gretchen V Messick, Mireia Guerau-de-Arellano, Tracey L Papenfuss, Steve Oghumu, Abhay R Satoskar
• Journal: Infection and immunity (Infect Immun) Vol. 87 Issue 8 (08 2019) ISSN: 1098-5522 [Electronic] United States
• PMID: 31182615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society for Microbiology.

Chemical References

• MicroRNAs
• Mirn155 microRNA, mouse
• Tumor Necrosis Factor-alpha
• Interferon-gamma

Topics

• Animals
• Granuloma (etiology)
• Interferon-gamma (physiology)
• Leishmania donovani
• Leishmaniasis, Visceral (immunology)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (physiology)
• Monocytes (physiology)
• T-Lymphocytes (immunology)
• Tumor Necrosis Factor-alpha (physiology)