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  • Immunopathology pipeline to study potential host directed therapy targets in cutaneous leishmaniasis.

    • Immunopathology pipeline to study potential host directed therapy targets in cutaneous leishmaniasis.

    Abstract number
    296
    DOI
    10.22443/rms.mmc2021.296
    Corresponding Email
    [email protected]
    Session
    Stream 5: High-plex Cytometry
    Authors
    Dr Nidhi Dey (4), Dr Sujai Senarathna (3), Dr Luiza Reis (2), Dr Srija Moulik (1), Dr Marcela Montes De Oca (4), Dr Pegine Walrad (4), Dr Hiro Goto (2), Dr Mitali Chatterjee (1), Dr Dimitris Lagos (4), Dr Shalindra Ranasinghe (3), Prof Paul Kaye (4)
    Affiliations
    1. Institute of Postgraduate Medical Education and Research
    2. Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina, Universidade de São Paulo
    3. University of Sri Jayewardenepura
    4. York Biomedical Research Institute, University of York
    Keywords

    Immunopathology

    Host directed therapy

    FFPE

    Tissue transcriptomics

    RNA- FISH

    Digital Spatial Profiling

    Leishmaniasis

    Abstract text

    Cutaneous leishmaniasis (CL) is a neglected tropical disease that is characterised by chronic inflammation in skin lesions leading to lifelong scars, disability, or even social stigma1-3. Drug treatment are limited; pentavalent antimonials (e.g. sodium stibogluconate; SSG) are still the first line drugs for CL, despite protracted and painful treatment regimens4-5. Studies on animal models have suggested that severity of the disease can be modulated by use of host directed therapies when used alone or in conjunction with drug therapy6. Additionally, experimental data indicates that the efficacy of anti-parasitic drugs require drug-immune synergy7-9, but mechanistic insight from patients is lacking. In this study, we have established a multi-centre pathology pipeline to study disease mechanisms. Starting with RNA-Seq transcriptomic analysis of whole blood and pathogen genome sequencing, we couple targeted transcriptomics (Nanostring Pan Cancer Immune Profiling panel) with Nanostring Digital Spatial Profiling (DSP) of FFPE skin biopsies. We then confirm our finding using computational quantification of single cell IHC and RNA-FISH. We applied this pipeline to study immunopathology of CL caused by L. donovani infection in Sri Lanka. We studied FFPE skin biopsies from patients, both at presentation and early after the initiation of drug treatment. Immune-targeted transcriptomics revealed reduced expression of immune checkpoint molecules upon treatment. We confirmed reduced expression of both PD-L1 and IDO1 on a second validation cohort using DSP and quantitative immunohistochemistry. Using dual IHC-FISH, we show that intra cellular parasitism increases the expression of both IDO1 and PD-L1 on CD68+ monocytes/macrophages. Crucially, early reduction of PD-L1 but not IDO-1 was predictive of a faster cure rate (odds ratio = 4.88) and occurred in parallel with reduction of parasite load. Our data suggests that initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition of T cell immunity, facilitating immune-drug synergy and clinical cure. Our findings demonstrate that PD-L1 expression can be used as an early predictor of faster clinical response to SSG treatment and support the use of PD-L1 inhibition as adjunct host directed therapy in CL in Sri Lanka.

    References

    1.           World Health Organization. Leishmaniasis.   (2019, March 14).

    2.            Drugs for Neglected Diseases initiative. About leishmaniasis.  (2019,).

    3.            Pires, M., Wright, B., Kaye, P.M., da Conceicao, V. & Churchill, R.C. The impact of leishmaniasis on mental health and psychosocial well-being: A systematic review. PLoS One 14, e0223313 (2019).

    4.            de Menezes, J.P., Guedes, C.E., Petersen, A.L., Fraga, D.B. & Veras, P.S. Advances in Development of New Treatment for Leishmaniasis. Biomed Res Int 2015, 815023 (2015).

    5.            Singh, K., Garg, G. & Ali, V. Current Therapeutics, Their Problems and Thiol Metabolism as Potential Drug Targets in Leishmaniasis. Curr Drug Metab 17, 897-919 (2016).

    6.         Novais F.O., Amorim C. F., Scott P. Host-Directed Therapies for Cutaneous Leishmaniasis. Front Imm 12, 957 (2021)

    7.          Dalton, J.E. & Kaye, P.M. Immunomodulators: use in combined therapy against leishmaniasis. Expert Rev Anti Infect Ther 8, 739-742 (2010).

    8.          Sbaraglini, M.L., et al. Neglected Tropical Protozoan Diseases: Drug Repositioning as a Rational Option. Curr Top Med Chem 16, 2201-2222 (2016).

    9.          Rao, S.P.S., et al. Drug Discovery for Kinetoplastid Diseases: Future Directions. ACS Infect Dis 5, 152-157 (2019).


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