microRNAs: Critical Players during Helminth Infections

Abstract

microRNAs (miRNAs) are a group of small non-coding RNAs that regulate gene expression post-transcriptionally through their interaction with the 3' untranslated regions (3' UTR) of target mRNAs, affecting their stability and/or translation. Therefore, miRNAs regulate biological processes such as signal transduction, cell death, autophagy, metabolism, development, cellular proliferation, and differentiation. Dysregulated expression of microRNAs is associated with infectious diseases, where miRNAs modulate important aspects of the parasite-host interaction. Helminths are parasitic worms that cause various neglected tropical diseases affecting millions worldwide. These parasites have sophisticated mechanisms that give them a surprising immunomodulatory capacity favoring parasite persistence and establishment of infection. In this review, we analyze miRNAs in infections caused by helminths, emphasizing their role in immune regulation and its implication in diagnosis, prognosis, and the development of therapeutic strategies.

Keywords: Brugia; Fasciola; Schistosoma; immunomodulation; miRNAs.

Figure 1

microRNAs during Schistosoma infection. (A) MiRNA expression in Schistosoma. In the parasite, the expression of miRNAs varies at different developmental stages; some are gender-biased. Parasite miRNAs are involved in the regulation of sexual differentiation, maturation, mating, and reproduction; (B) Role of miRNAs in liver injury and hepatic fibrosis. Several miRNAs are dysregulated and documented as pro-fibrogenic (favoring fibrosis; red) or anti-fibrogenic (inhibiting fibrosis; green). Schistosoma eggs produce both responses in liver tissue. Adult Schistosoma parasites accumulate in mesenteric vasculature and release miRNAs-EVs with immunomodulatory effects; (C) Effects of Schistosoma miRNAs released in EVs on target cells. Schistosoma releases miRNAs-EVs to regulate the host’s immune response. These miRNAs-EVs are composed of sma-miR-10, sma-miR-125, and sma-bantam in S. mansoni, while miR-125b and bantam are found in S. japonicum EVs. During S. mansoni infection, EVs fuse with T lymphocytes. The release of miR-10 into the T cell cytoplasm modulates the signaling pathway through MAP3K7 and regulates genes negatively depending on NF-kβ activation, diminishing T cell differentiation into Th2 subpopulations. Alternatively, during infection of mice by S. japonicum, EVs fuse with macrophages, and miRNA content inhibits the TLR-mediated inflammation (Sj-miR-125b) or stimulates the production and release of TNF-α to the extracellular environment, a molecule related to parasite development and survival. This process also promotes the increase in the macrophage population and may influence gene expression in Schistosoma. Adobe Illustrator was used to elaborate the figure.

Figure 2

microRNAs during Fasciola infection. (A). miRNAs are expressed differentially in the morphological stages of Fasciola. Thus, different miRNAs are expressed in adult parasites and juvenile stages of F. gigantica. (B). F. hepatica releases miRNAs in EVs involved in parasite–host interaction. For example, F. hepatica releases fhe-miR-125, which hijacks the host macrophage miRNA machinery mimicking host miR-125b to regulate innate immune responses. Adobe Illustrator was used to elaborate the figure.

Figure 3

microRNAs during B. malayi infection. (A). MiRNAs identified in B. malayi. Specific miRNAs with gender-biased expression have been identified in B. malayi. Thus, bma-miR-5364, bma-miR-71, and the bma-miR-36 family regulate biological processes, including host immune modulation. (B). Alteration of host’s miRNAs during B. malayi infection. Infection by this parasite induces miRNA upregulation related to immune dysfunction. Alternatively, this parasite can induce NeMφ differentiation that can exert an anti-proliferative effect on lymphocytes, mediated by cell-to-cell contact. For its part, miRNA EVs derived from the parasite (bma-miR-100 and bma-miR-34) are internalized by functional DCs. In the cytoplasm, they modulate mTOR signaling pathways, cellular proliferation, differentiation, and apoptosis-related genes. Adobe Illustrator was used to elaborate the figure.