Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation
| Autor: | Emily MacLean, Jinlei He, Shaden Kamhawi, Selena M. Sagan, Martin Olivier, Ellen Heirwegh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Phlebovirus Physiology RC955-962 Disease Vectors White Blood Cells Mice 0302 clinical medicine Medical Conditions Animal Cells Immune Physiology Arctic medicine. Tropical medicine Medicine and Health Sciences Leishmania major Myeloid Cells Sandfly Fever Sicilian Virus Vector (molecular biology) Immune Response Receptors Interferon Protozoans Leishmania Mice Knockout Innate Immune System biology Coinfection Chemotaxis Eukaryota Extracellular vesicle Cell Motility Infectious Diseases Cytokines Female Cellular Types Chemokines Public aspects of medicine RA1-1270 Research Article MAP Kinase Signaling System Immune Cells Immunology Leishmaniasis Cutaneous Bunyaviridae Infections Cell Line 03 medical and health sciences Signs and Symptoms Cutaneous leishmaniasis medicine Parasitic Diseases Animals Inflammation Blood Cells Macrophages Public Health Environmental and Occupational Health Organisms Biology and Life Sciences Leishmaniasis Cell Biology Molecular Development medicine.disease biology.organism_classification Parasitic Protozoans Immunity Innate Sandfly Insect Vectors Sand Flies Toll-Like Receptor 3 Mice Inbred C57BL Species Interactions 030104 developmental biology Co-Infections Immune System Interferon Regulatory Factor-3 Clinical Medicine 030215 immunology Developmental Biology |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 15, Iss 7, p e0009638 (2021) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | 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. Author summary The leishmaniases are a group of chronic infectious diseases caused by parasites of the genus Leishmania. The disease poses a great public health risk; millions of people are affected annually. In addition, leishmaniasis is characterized by widely varying clinical manifestations, for which the cause is still unknown. Parasites of the genus Leishmania are the ethological agents of the disease and are vectored by phlebotomine sandflies. While examining sections of the sandfly midgut, we noted viral entities, later identified as phleboviruses. Interestingly, there is a large overlap in the geographic distribution of L. major and Sandfly Fever Sicilian Virus (SFSV); this led us to hypothesize that viral presence could influence disease severity. With the use of various wild-type and knock-out mouse models, we deduced that co-infection with SFSV indeed affected disease severity, leading to exacerbated skin lesions and higher parasite numbers. However, this was not paralleled by the modulation of immunomodulatory molecules. Our findings demonstrate that viral presence may facilitate parasite entry into host cells. Overall, our research constitutes novel findings that contribute toward a better understanding of the mechanisms underlying leishmaniasis infections. |
| Databáze: | OpenAIRE |
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