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Systems Studies Uncover miR-146a as a Target in Leishmania major Infection Model.

ABSTRACT: Leishmaniasis, the second most neglected tropical disease, has been reported to affect approximately 12 million people worldwide. The causative protozoan parasite Leishmania has shown drug resistance to available chemotherapies, owing to which we need to look for better approaches to deal with the clinical situations. As per recent reports, several miRNAs have been found to be differentially expressed during Leishmania major infection in host macrophages. We aim to evaluate the impact of miRNA-mediated gene regulation on the key players of inflammation and macrophage dysfunction. The origin of Leishmania miRNAs and their processing is a questionable phenomenon as of yet. Through our study, we aim to provide a framework of their characterization. We amalgamate chemical systems biology and synthetic biology approaches to identify putative miRNA targets and unravel the complexity of host-pathogen gene regulatory networks.

SUBMITTER: Nimsarkar P

PROVIDER: S-EPMC7271362 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Systems Studies Uncover miR-146a as a Target in Leishmania major Infection Model.

Nimsarkar Prajakta P Ingale Prajakta P Singh Shailza S

ACS omega 20200518 21

Leishmaniasis, the second most neglected tropical disease, has been reported to affect approximately 12 million people worldwide. The causative protozoan parasite Leishmania has shown drug resistance to available chemotherapies, owing to which we need to look for better approaches to deal with the clinical situations. As per recent reports, several miRNAs have been found to be differentially expressed during Leishmania major infection in host macrophages. We aim to evaluate the imp ...[more]

PMID: 32548436

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Project description:BackgroundIn vitro assays are widely used in studies on pathogen infectivity, immune responses, drug and vaccine discovery. However, most in vitro assays display significant differences to the in vivo situation and limited predictive properties. We applied medium perfusion methods to mimic interstitial fluid flow to establish a novel infection model of Leishmania parasites.MethodsLeishmania major infection of mouse peritoneal macrophages was studied within the Quasi Vivo QV900 macro-perfusion system. Under a constant flow of culture media at a rate of 360μl/min, L. major infected macrophages were cultured either at the base of a perfusion chamber or raised on 9mm high inserts. Mathematical and computational modelling was conducted to estimate medium flow speed, shear stress and oxygen concentration. The effects of medium flow on infection rate, intracellular amastigote division, macrophage phagocytosis and macropinocytosis were measured.ResultsMean fluid speeds at the macrophage cell surface were estimated to be 1.45 x 10-9 m/s and 1.23 x 10-7 m/s for cells at the base of the chamber and cells on an insert, respectively. L. major macrophage infection was significantly reduced under both media perfusion conditions compared to cells maintained under static conditions; a 85±3% infection rate of macrophages at 72 hours in static cultures compared to 62±5% for cultures under slow medium flow and 55±3% under fast medium flow. Media perfusion also decreased amastigote replication and both macrophage phagocytosis (by 44±4% under slow flow and 57±5% under fast flow compared with the static condition) and macropinocytosis (by 40±4% under slow flow and 62±5% under fast flow compared with the static condition) as measured by uptake of latex beads and pHrodo Red dextran.ConclusionsPerfusion of culture medium in an in vitro L. major macrophage infection model (simulating in vivo lymphatic flow) reduced the infection rate of macrophages, the replication of the intracellular parasite, macrophage phagocytosis and macropinocytosis with greater reductions achieved under faster flow speeds.

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Systems Studies Uncover miR-146a as a Target in Leishmania major Infection Model.

Publications

Systems Studies Uncover miR-146a as a Target in <i>Leishmania major</i> Infection Model.

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