The effects of CGAS-STING-TBK1 pathway and NKT cell-activating ligand alpha-galactosylceramide on LEISHMANIA MAJOR infection and protection

2022-2-8
Dünüroğlu, Emre
Leishmaniasis is a multi-faceted group of diseases caused by various species of Leishmania protozoa. Depending on the infecting Leishmania species, the disease manifests as recurrent cutaneous, mucocutaneous or visceral leishmaniasis all of which can be devastating for infected individuals. Lack of a protective vaccine and the rise of drug resistances in Leishmania spp. prompted us to explore preventative vaccine candidates and novel drugs against Leishmania major. In the first part of this thesis, we evaluated the role of cGAS-STING-TBK1 DNA- sensing pathway in the context of Leishmania major infection. Our findings showed that the absence of cGAS, STING or TBK1 proteins significantly diminished parasite loads of differentiated THP-1 macrophages. In contrast to STING-KO THP-1 cells, this effect was not due to reduced phagocytic capacities of cGAS- and TBK1-KO THP-1 cells. Similarly, gene expression analysis pointed to increased expression of genes which code for proteins that may aid in parasite control in KO cell lines. Furthermore, treatment of WT THP-1 cells with amlexanox, a TBK1 inhibitor, reduced both phagocytosis of Leishmania major promastigotes and replication of amastigotes inside phagolysosomes. Our results suggest that cGAS-STING-TBK1 pathway might be exploited by Leishmania major to promote a pro-parasitic vi environment in macrophages which can partially be reversed with the TBK1 inhibitor, amlexanox. In the second part of this thesis, we examined the degree of immunoprotection induced by Leishmania major exosomes, soluble Leishmania antigens (SLA) or whole lyophilized parasites combined with an NKT-cell inducing ligand, α- Galactosylceramide (α-GalCer), in BALB/c mice. While all of the vaccine candidates protected against Leishmania major, SLA and lyophilized parasites combined with α-GalCer were the most promising groups amongst them.

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Citation Formats
E. Dünüroğlu, “The effects of CGAS-STING-TBK1 pathway and NKT cell-activating ligand alpha-galactosylceramide on LEISHMANIA MAJOR infection and protection,” M.S. - Master of Science, Middle East Technical University, 2022.