lnflammation amplified by a viral endosymbiont revealed extensive lymphatic connections facilitating metastatic dissemination of intracellular and free Leishmania parasites


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PhD thesis: a PhD thesis.
lnflammation amplified by a viral endosymbiont revealed extensive lymphatic connections facilitating metastatic dissemination of intracellular and free Leishmania parasites
Jha Baijayanti
Fasel Nicolas
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Université de Lausanne, Faculté de biologie et médecine
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Leishmaniasis is a neglected tropical disease, caused by the human protozoan parasite Leishmania Spp. Given its prevalence in East Africa, South America, Southeast Asia, and the Mediterranean countries, it is a major diffusing global health problem currently. With an estimated 700000 to 1 million new cases annually, it affects more than 12 million people worldwide right now and causing over 20000 deaths per year. Leishmaniasis is spread to humans by the bite of a female phlebotomine sandfly vector and can have various outcomes, which itself depends on the species of the infecting parasite, immune-competence of the host, and various environmental factors. Cutaneous leishmaniasis (CL) is the most common form that can have further have various outcomes, and sometimes progress to a more severe form where parasite metastasize to form secondary lesions, leading to disseminated or mucocutaneous leishmaniasis (DCL or MCL). L guyanensis (Lgy) causes CL but 5-10% of all infections result in metastatic complications due to the presence of the cytoplasmic Leishmania RNA Virus (LRV1). The double-stranded RNA (dsRNA) within LRV is recognized by host Toll-like receptor 3 (TLR3) and has been linked with disease exacerbation, severe disease chronicity, treatment failure, clinical relapse along with mounting a potent tissue-damaging proinflammatory response. Our lab established the LRV1-exacerbated metastatic model of lfng-1- mice with LgyLRV1+ infections (as compared to LgyLRV1-), which correlated with extremely reduced IFN-y levels observed in human patients. We, therefore, aimed to unravel the dissemination process and define the major cell type(s) which transport these infective parasites to distant secondary lesion sites, thereby exhibiting severe metastasis. Our results corroborated that Lgy infection leads to severe inflammation of the primary inoculation site and is further exacerbated by the presence of LRV1. Moreover, Lgy parasites can hijack lymphatic vessels as efficient routes for the egress of infected cells to escape the local infection site for colonizing draining and non-draining lymph nodes. These infective parasites are disseminated initially through the lymph and efferent lymphatics, causing severe inflammation and infection of the draining LNs sequentially, to ultimately enter the circulatory system for systemic spread. Moreover, contrary to reported studies that Leishmania transport can occur only intracellularly by various phagocytes, we observed that Lgy parasites disseminated not only intracellularly but mostly as a free parasite; or by getting stuck to the surface of various migrating myeloid cells and even as amastigote clumps through lymph and blood. lnterestingly, they were also able to subvert even the phagocytic clearance by different resident and recruited immune cells and rather colonized the LNs for further growth and multiplication. This led to the intense infection of the blood which further disseminated these infective Lgy parasites to distant organs, favorable low-temperature niches, and skin extensively, causing the formation of newer lesions and permitting further transmission. We thus concluded that Lgy parasites could hijack the lymphatic network to reach the blood for a successful systemic spread and can disseminate in association with cells or even extracellularly on their own as free parasites.
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17/05/2021 12:31
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18/05/2021 6:36
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