Abstract
Visceral leishmaniasis caused by Leishmania (Leishmania) infantum in Latin America progress with hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and weight loss and maybe lethal mainly in untreated cases. miRNAs are important regulators of immune and inflammatory gene expression, but their mechanisms of action and their relationship to pathogenesis in leishmaniasis are not well understood. In the present study, we sought to quantify changes in miRNAs associated with immune and inflammatory pathways using the L. (L.) infantum promastigote infected- human monocytic THP-1 cell model and plasma from patients with visceral leishmaniasis. We identified differentially expressed miRNAs in infected THP-1 cells compared with non-infected cells using qPCR arrays. These miRNAs were submitted to in silico analysis, revealing targets within functional pathways associated with TGF-β, chemokines, glucose metabolism, inflammation, apoptosis, and cell signaling. In parallel, we identified differentially expressed miRNAs in active visceral leishmaniasis patient plasma compared with endemic healthy controls. In silico analysis of these data indicated different predicted targets within the TGF-β, TLR4, IGF-I, chemokine, and HIF1α pathways. Only a small number of miRNAs were commonly identified in these two datasets, notably with miR-548d-3p being up-regulated in both conditions. To evaluate the potential biological role of miR-548d-3p, we transiently transfected a miR-548d-3p inhibitor into L. (L.) infantum infected-THP-1 cells, finding that inhibition of miR-548d-3p enhanced parasite growth, likely mediated through reduced levels of MCP-1/CCL2 and nitric oxide production. Further work will be required to determine how miR-548d-3p plays a role in vivo and whether it serves as a potential biomarker of progressive leishmaniasis.
Highlights
The leishmaniases are vector-borne diseases caused by protozoan parasites of the order Kinetoplastida, family Trypanosomatidae, and genus Leishmania
We recently identified a role for miR548d-3p in cutaneous leishmaniasis caused by L. (Viannia) braziliensis. miR-548d-3p was differentially expressed in plasma from patients with active compared to self-healed cutaneous leishmaniasis and up-regulated in L. braziliensisinfected THP-1 cells
We studied miRNA abundance in plasma of patients with active visceral leishmaniasis (VL) caused by L. infantum compared to healthy nonendemic controls and in THP-1 cells infected in vitro with L. infantum compared to uninfected THP-1 cells
Summary
The leishmaniases are vector-borne diseases caused by protozoan parasites of the order Kinetoplastida, family Trypanosomatidae, and genus Leishmania. The leishmaniases are endemic in 98 countries, affecting 0.9 to 1.6 million people globally each year, and are considered the second most important of the neglected diseases caused by protozoa (Bi et al, 2018; Burza et al, 2018; Sasidharan and Saudagar, 2021; WHO, 2021). Transmission occurs when sand flies inject metacyclic promastigotes into the skin. These parasite forms enter phagocytic myeloid cells, transform into amastigotes, and proliferate, establishing the infection. The diversity of Leishmania parasites and vector species and host genetic and immunological conditions lead to different clinical presentations. An estimated 50 000 to 90 000 new cases of VL occur worldwide annually (WHO, 2021)
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