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Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica

ABSTRACT: Parasitic worms (helminths) ensure their survival to establish chronic infection within mammalian hosts by strategically regulating their host s immune responses. Deciphering the mechanisms behind this immune modulation will inform the development of novel strategies for infection control. It is now understood that the co-ordinated control of gene expression by non-coding RNAs (ncRNA) underpins the activation and regulation of immune cells. However, it is also clear that pathogens (including helminths) secrete their own ncRNAs to manipulate host gene expression and influence immune outcomes to infection. To discriminate the contribution of host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with Fasciola hepatica. This revealed an enrichment of several parasitic-derived miRNAs (fhe-miR-277b-3p, fhe-miR-71a-5p, fhe-miR-125b-5p, fhe-miR-125a-5p) within macrophages at 6hr and 18hr after infection which is coincident with the parasite s migration through the peritoneal cavity. Target prediction analysis indicated that these Fasciola miRNAs regulated host genes associated with the activation of host pro-inflammatory macrophages (Hif1 , Nod1, Nlrp6 and P2rx7). Concomitantly, there was a distinct shift in host ncRNA expression in response to infection, which was most significant at 5 days post-infection. Although, analysis suggested that these host ncRNAs target a different cohort of genes (Adar1, Igf1 and Plec) to the parasite miRNAs, the functional outcome was predicted to be the same, with a reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Combined, these observations uncover the interplay between host and parasitic ncRNAs and reveals a complementary regulation of the immune response that allows the parasite to evade immune detection and promotes tissue repair for the host. This level of characterisation of the ncRNA landscape during helminth infection is highly novel and provides a new understanding of the molecular impact that these parasites have on host immune cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE263895 | GEO | 2024/09/30

REPOSITORIES: GEO

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Project description:Effective management and control of parasitic infections on farms depends on their early detection. Traditional serological diagnostic methods for Fasciola hepatica infection in livestock are specific and sensitive, but currently the earliest detection of the parasite only occurs at approximately three weeks post-infection. At this timepoint, parasites have already entered the liver and caused the tissue damage and immunopathology that results in reduced body weight and loss in productivity. Here, we investigated whether the differential abundance of micro(mi)miRNAs in sera of F. hepatica-infected sheep has potential as a tool for the early diagnosis of infection. Using miRNA sequencing analysis, we discovered specific profiles of sheep miRNAs at both the pre-hepatic and hepatic infection phases in comparison to non-infected sheep. In addition, six F. hepatica-derived miRNAs were specifically identified in sera from infected sheep. Thus, a panel of differentially expressed miRNAs comprising four sheep (miR-3231-3p; miR133-5p; 3957-5p; 1197-3p) and two parasite miRNAs (miR-124-3p; miR-Novel-11-5p) were selected as potential biomarkers. The expression of these candidates in sera samples from longitudinal sheep infection studies collected between 7 days and 23 weeks was quantified using RT-qPCR and compared to samples from age-matched non-infected sheep. We identified oar-miR-133-5p and oar-miR-3957-5p as promising biomarkers of fasciolosis, detecting infection as early as 7 days. The differential expression of the other selected miRNAs was not sufficient to diagnose infection; however, our analysis found that the most abundant forms of fhe-miR-124-3p in sera were sequence variants (IsomiRs) of the canonical miRNA, highlighting the critical importance of primer design for accurate diagnostic RT-qPCR. Accordingly, this investigative study suggests that certain miRNAs are biomarkers of F. hepatica infection and validates miRNA-based diagnostics for the detection of fasciolosis in sheep.

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Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica

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