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The contribution of kinetoplast DNA to Leishmania major experimental infection and evaluation of Leishmania extracellular vesicle based vaccine against cutaneous Leishmaniasis in BALB/C mice

Ayanoğlu, İhsan Cihan
Cutaneous Leishmaniasis (CL) is a neglected vector borne parasitic infection that manifests as self-healing skin lesions or cause debilitating large chronic or recurring lesions. CL is endemic in Turkey and its incidence rate is on the rise due to immigration of refugees from affected regions. Leishmania parasites harbor a unique mitochondrial DNA structure called kinetoplast DNA (kDNA), consisting of giant networks of catenated mini and maxi-circles. The role of kDNA in infection is poorly understood. In the first part of this thesis, we evaluated the possible contribution of kDNA to Leishmania major experimental infection. Herein we show that stimulation of immune cells with kDNA increases the parasite load in vitro and exacerbates disease progression in L.major induced BALB/c model of CL. Our results suggest that kDNA may have a role in facilitating parasite evasion from the immune system through induction of type-I interferon signaling pathways. The absence of an available licensed vaccine coupled with the cost, toxicity and drug resistance associated with drugs used for treatment, necessitates the development of an effective preventive vaccine. In the second part of this thesis, we explored the immunoprotective and immunotherapeutic potential of Leishmania antigen-rich extracellular vesicles (exosomes) in combination with CpG ODN, cGAMP or glycolipid based (αGalCER) vaccine adjuvants. Our results demonstrated that chemically inactivated L.major exosomes exhibited immunotherapeutic effects when combined with D-ODN, resulting in reduction in parasite loads in infected BALB/c mice. Vaccination studies revealed that exosomes adjuvanted with αGalCER provided immunoprotection in L.major induced BALB/c model of CL.