Uncontrolled inflammation is a major contributor to pathogenicity development during many chronic parasitic infections, including African trypanosome infections. Hence, therapies should aim at re-establishing the balance between pro - and anti-inflammatory responses to reduce tissue damage. Our experiments uncovered that macrophage migration inhibitory factor (MIF) plays a pivotal role in trypanosomiasis-associated pathogenicity development. Hereby, MIF-deficient and neutralizing anti-MIF antibody-treated wild type (WT) T. brucei-infected mice exhibited decreased inflammatory responses, reduced liver damage and anemia (i.e. the most prominent pathogenicity features) compared to WT control mice. The reduced tissue damage coincided with reduced infiltration of pathogenic monocytic cells and neutrophils, whereby neutrophil-derived MIF contributed more significantly than monocyte-derived MIF to tissue damage. MIF also promoted anemia development by suppressing red blood cell production and enhancing their clearance. The clinical significance of these findings follows from human genetic data indicating that low-expression (protective) MIF alleles are enriched in Africans. The current findings therefore offer promise for human translation and open the possibility of assessing MIF levels or MIF genotype as an indication of an individual's risk for severe trypanosomiasis. Furthermore, given the unmet medical need of African trypanosomiasis affecting millions of people, these findings highlight MIF as a potential new therapeutic target for treatment of trypanosomiasis-associated pathogenicity.
Vyšlo v časopise: MIF Contributes to Associated Immunopathogenicity Development. PLoS Pathog 10(9): e32767. doi:10.1371/journal.ppat.1004414 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004414
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