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MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes.

ABSTRACT: Tropical theileriosis is a lymphoproliferative disease caused by the intracellular schizonts of Theileria annulata, an apicomplexan parasite. It causes severe infection in cattle and the untreated cattle would possibly die within 3-4 weeks of infection. The chemotherapy for this disease is largely dependent on the use of hydroxynaphthoquinone, namely buparvaquone. There have been reports recently of the development of resistance against this drug in T. annulata. Hence, identification of new drug molecule(s) or repurposing of existing drug molecule(s) against T. annulata is quite important. Here, we present the screening of 400 compounds included in the open-access Pathogen box from Medicine for Malaria Venture (MMV) to discover the novel compounds with potential inhibitory activity against T. annulata infected bovine leucocytes. We identified two compounds, MMV000062 and MMV560185, with IC₅₀ values of 2.97 μM and 3.07 μM, respectively. MMV000062 and MMV560185 were found non-toxic to BoMac cells with CC₅₀ values 34 μM and > 100 μM, respectively. The therapeutic indices of these compounds, MMV000062 and MMV560185, were calculated as more than 33 and 11, respectively. Further, it was observed that the parasite-infected cells under long-term culture were unable to recover with these compounds. We further deciphered that MMV560185 kills the infected cell by activation of TNFR-1 mediated extrinsic pathway of the apoptosis. The phenotypic characteristics of apoptosis were confirmed by Transmission Electron Microscopy. Our results suggest that it may be possible to develop MMV560185 further for chemotherapeutics of tropical theilerosis.

SUBMITTER: Araveti PB

PROVIDER: S-EPMC8761611 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tropical theileriosis is the disease caused by tick-transmitted apicomplexan parasite Theileria annulata, which has ability to transform bovine leukocytes, including B cells, macrophage cells, and dendritic cells. The T. annulata transformed cells are characterized as uncontrolled proliferation and shared some cancer-like phenotypes. The mechanism of the transformation by T. annulata is still not understood well. In previous reports, the subtelomere-encoded variable secreted proteins (SVSP) of T. parva were considered to contribute to phenotypic changes of the host cell, but the role of SVSP of T. annulata in host-pathogen relationship remains unknown. In the present study, a member of SVSP family, TA05575 of T. annulata was selected as the target molecule to analyze its expression profiles in different life cycle stages of T. annulata by qPCR and investigate its subcellular distribution of different passages of T. annulata transformed cells using confocal experiments. From the results, the transcription level of TA05575 at schizont stage was significantly higher than the other two life stages of T. annulata, and the protein of TA05575 was mainly distributed in nucleus of T. annulata infected cells. In addition, the potential proteins of host cells interacting with TA05575 were screened by Yeast-two hybrid system. The results of Co-IP experiment confirmed that TA05575 interacted with RBMX2-like protein that participated in transcription regulation of cells. In addition, a novel BiFC assay and flow cytometry were carried out, and the results further revealed that TA05575-RBMX2-like pair was directly interacted in cell context. Moreover, this interacting pair was found to distribute in intracellular compartments of HEK293T cells by using confocal microscopy. The results of the present study suggest that TA05575 may contribute for cells transformation due its distribution. According to the function of RBMX2, the interaction of TA05575 and RMMX2-like will provide a new information to further understand the mechanisms of cells transformation by T. annulata.

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MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes.

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