Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation

• Published in: PLoS neglected tropical diseases 2021-07, Vol.15 (7), p.e0009638-e0009638
• Main Authors: Heirwegh, Ellen, MacLean, Emily, He, Jinlei, Kamhawi, Shaden, Sagan, Selena M., Olivier, Martin
• Format: Article
• Language: English
• Subjects: Acids; Biology and Life Sciences; Blood; Bone marrow cells; Chromatography; Cutaneous leishmaniasis; Development and progression; Disease transmission; Exosomes; Extracellular; Extracellular vesicles; Fever; Health aspects; Immune response; In vitro methods and tests; Infections; Inflammation; Inflammatory response; Inoculation; Interferon regulatory factor 3; Kinases; Leishmania; Leishmania major; Leishmaniasis, Cutaneous; Lesions; Leukocytes; MAP kinase; Mass spectrometry; Meals; Medicine and Health Sciences; Microscopy; Modulation; Parasites; Parasitic diseases; Pathology; Phenotypes; Protozoa; Public health; Receptors; RNA virus infections; Scientific imaging; Skin; Skin diseases; Skin lesions; TLR3 protein; Toll-like receptors; Tropical diseases; Vector-borne diseases; Vectors; Viruses
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0009638

Background The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV). Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis. Methodology/Principal findings In vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV's hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone. Conclusion/Significance Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.