Abstract
Fasciola hepatica, a global worm parasite of humans and their livestock, regulates host innate immune responses within hours of infection. Host macrophages, essential to the first-line defence mechanisms, are quickly restricted in their ability to initiate a classic protective pro-inflammatory immune response. We found that macrophages from infected animals are enriched with parasite-derived micro(mi)RNAs. The most abundant of these miRNAs, fhe-miR-125b, is released by the parasite via exosomes and is homologous to a mammalian miRNA, hsa-miR-125b, that is known to regulate the activation of pro-inflammatory M1 macrophages. We show that the parasite fhe-miR-125b loads onto the mammalian Argonaut protein (Ago-2) within macrophages during infection and, therefore, propose that it mimics host miR-125b to negatively regulate the production of inflammatory cytokines. The hijacking of the miRNA machinery controlling innate cell function could be a fundamental mechanism by which worm parasites disarm the early immune responses of their host to ensure successful infection.
Highlights
Fasciola hepatica, a global worm parasite of humans and their livestock, regulates host innate immune responses within hours of infection
To investigate whether miRNAs produced by F. hepatica contributed to the inhibition of macrophage activation in early infection, we orally infected BALB/c mice with F. hepatica metacercariae and searched for parasite miRNAs in peritoneal macrophages at selected time-points (6 h, 12 h, 24 h, 3 days and 5 days after infection) using RNASeq
We identified 10 F. hepatica miRNAs that were present within peritoneal macrophages of infected mice (Table 1)
Summary
A global worm parasite of humans and their livestock, regulates host innate immune responses within hours of infection. The parasite is one of the most successful helminths as it is found on every inhabited continent and infects the widest variety of mammalian hosts infected by any worm, including some that it has encountered only in relatively recent times (e.g. camelids and marsupials)[5,6] This implies a superior adaptation to the mammalian host and suggests that F. hepatica parasites have evolved a universal process of invasion, tissue migration and immune modulation. During the invasion and pre-hepatic migratory stage, animals display no clinical signs of infection, and, histologically, no significant inflammatory changes are observed in the intestinal wall or peritoneal cavity[7,8] This suggested that the parasites employ a mechanism(s) to disarm the host’s innate ‘early-response’ immune system to prevent their detection at a vulnerable time in their invasion. The absence of a classical host protective inflammatory response to invading F. hepatica implies that the parasite possesses an effective mechanism of control on macrophage activity
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