Identification of gene expression profiles in Leishmania major infection by integrated bioinformatics analyses

WOS: 000540814000017PubMed: 32360239Gene expression profiling in mouse models of leishmaniasis has given useful information to understand the molecular pathways active in lesions and to discover new diagnostic/therapeutic targets. Although the host response plays a critical role in protection from leishmaniasis and promoting disease severity, there are still unexplained aspects in the mechanism of non-healing cutaneous lesions, which need biomarkers for both targeted- therapy and diagnosis. To address this, transcriptional profiling of the skin lesions obtained from BALB/c mice infected with Leishmania major and healthy skin from naive mice were evaluated by bioinformatics analysis, and then the results were validated by Revers Transcriptase-PCR. Five genes among the up-regulated differentially expressed genes named FCGR4, CCL4, CXCL9, Arg1 and IL-1 beta were found to have relatively high diagnostic value for CL due to L. major. Pathway analysis revealed that Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) signaling pathways are active in cutaneous lesions, providing new insights for the understanding and treatment of leishmaniasis.Ege University Scientific Research Projects Foundation [TGA-2019-20180]We thank Ege University Scientific Research Projects Foundation (TGA-2019-20180) for Grant Support and Dr. Yusuf Ozbel for providing L. major cell line

Targeting of antitumor immune responses with live-attenuatedLeishmaniastrains in breast cancer model

Erdogan, Mumin/0000-0003-0048-444XWOS: 000556442100002PubMed: 32472473Background Cancer is a major cause of death worldwide and most of the therapeutic approaches are relatively ineffective in eliminating cancer especially due to drug resistance. As an alternative, therapy with live microorganisms can induce a robust proinflammatory and anti-cancer immune response in the microenvironment of the tumor. in the present study, we aimed to establish a model for taking the advantages of immune responses against intracellular protozoan parasites for cancer treatment. Methods Leishmania infantumandL. tropicawere used in our study as agents of visceral and cutaneous forms of the infection, respectively. After establishing 4T1 breast cancer in mice groups, live-attenuatedL. infantum(At-Li) and live-attenuatedL. tropica(At-Lt) treatments were performed and results were evaluated according to tumor volume, immune markers and histological examination. Results Live-attenuatedLeishmaniastrains regressed 4T1-breast cancer in mice and are nonpathogenic, and these strains induce an immune response against 4T1 breast cancer. It is shown that At-Lt is found to be more effective than At-Li in breast cancer treatment using different methods included in the study as analyses of immune parameters, and histopathological examination in tumor tissue besides spleen cells. the tumor grew more slowly by the immune-stimulant effect of live-attenuatedLeishmaniaparasites. Conclusion This promising therapy should be investigated for optimization in further studies with different cancer types andL. tropicamay be designed to express antigens to enhance tumor antigen-specific responses, which may further improve efficacy and immune memory development.Ege University Scientific Research Projects Foundation [BAP-15KSUAM003]We thank Ege University Scientific Research Projects Foundation (BAP-15KSUAM003) for Grant Support and Dr. ozgur Sahin for providing 4T1 breast cancer cell line

The Effect of BTK Inhibitor Ibrutinib on Leishmania infantum Infection In Vitro

Purpose Leishmaniasis is a neglected infectious disease affecting millions of people worldwide. Visceral leishmaniasis (VL), caused by Leishmania infantum and Leishmania donovani, is one of the main clinical forms of the disease and fatal if not treated promptly and properly. Despite being available for the last 70 years, current drugs used in the treatment of leishmaniasis have serious problems as they have high toxicity, require long-term administration and cause serious side-effects, leading to the emergence of resistant and relapse cases. Therefore, there is an urgent need for the discovery of novel antileishmanial molecules and the development of new treatment regimens. The drug used for chemotherapy of B-cell malignancies, Ibrutinib, an inhibitor of Bruton's Tyrosine Kinase (BTK), can offer a new therapeutic perspective due to the functions of BTK on intracellular signaling mechanism of macrophages, which are the primary resident cell for Leishmania. Hence, the study aimed to evaluate ibrutinib as a potential anti-Leishmanial drug. Method In this study, we evaluated the antileishmanial effect of Ibrutinib by in vitroL. infantum infection model using macrophages, with cell viability assay, parasite rescue assay, real-time qPCR. Results We showed that Ibrutinib was significantly more effective than the Glucantime against L. infantum. In addition, our data revealed that Ibrutinib inhibited parasite growth and load without impairing macrophage viability. Conclusions Consequently, due to its efficacy and safety, Ibrutinib may be a promising candidate for the treatment of VL caused by L. infantum as a host-targeted drug.Ege University, Scientific Research Projects Coordination [TGA-2019-20180]This work was supported by Ege University, Scientific Research Projects Coordination (Grant TGA-2019-20180)