MIF Contributes to Trypanosoma brucei Associated Immunopathogenicity Development

Abstract

African trypanosomiasis is a chronic debilitating disease affecting the health and economic well-being of many people in developing countries. The pathogenicity associated with this disease involves a persistent inflammatory response, whereby M1-type myeloid cells, including Ly6Chigh inflammatory monocytes, are centrally implicated. A comparative gene analysis between trypanosusceptible and trypanotolerant animals identified MIF (macrophage migrating inhibitory factor) as an important pathogenic candidate molecule. Using MIF-deficient mice and anti-MIF antibody treated mice, we show that MIF mediates the pathogenic inflammatory immune response and increases the recruitment of inflammatory monocytes and neutrophils to contribute to liver injury in Trypanosoma brucei infected mice. Moreover, neutrophil-derived MIF contributed more significantly than monocyte-derived MIF to increased pathogenic liver TNF production and liver injury during trypanosome infection. MIF deficient animals also featured limited anemia, coinciding with increased iron bio-availability, improved erythropoiesis and reduced RBC clearance during the chronic phase of infection. Our data suggest that MIF promotes the most prominent pathological features of experimental trypanosome infections (i.e. anemia and liver injury), and prompt considering MIF as a novel target for treatment of trypanosomiasis-associated immunopathogenicity.

Trypanosoma brucei brucei causes a rapid and persistent influx of neutrophils in the spleen of infected mice

“…Single-cell spleen suspensions were prepared at 0, 4,5,6,7,8,9,10,14,17,21,24 and 28 days post-infection (dpi) as previously described. 13 Unless otherwise stated, cell suspensions were re-suspended in 0.05% FBS BD FACSFlow Sheath Fluid.…”

Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

“…Interestingly, at the later stages of infection their MHC-II expression was significantly higher in TgAlbCre-IL10 -/mice compared to WT and LysM-IL-10 -/mice ( Fig 4C), indicative of a higher monocyte activation level. Likewise, the number of polymorphonuclear cells (PMN), which were also documented to contribute to trypanosome-infection associated pathogenicity [22], were found to progressively increase in all groups as the infection progresses, yet reaching significantly higher levels in TgAlbCre-IL10 -/mice at the later infection stages than in WT and LysM-IL-10 -/mice ( Fig 4B). Finally, the number of Ly6C low patrolling monocytes, which were documented to attenuate tissue injury [24], significantly dropped in TgAlbCre-IL10 -/mice at later infection stages ( Fig 4B).…”

“…Although early peak parasitemia was similar in all mouse strains, TgAlbCre-IL10 -/mice exhibited significantly higher parasitemia levels during the later stage of infection as well as an increased weight gain (due to increased spleen and liver weight), more severe anemia and a significantly reduced median survival time (Fig 2A-2D, median survival time WT: 102 ± 26; LysM-IL-10 -/-: 100 ± 14, TgAlbCre-IL10 -/ : 50 ± 10 days). To confirm that the observed differences were not due to intrinsic gross abnormalities in the TgAlbCre-IL10 -/mice, these mice were infected with another strain of trypanosomes, namely T. brucei, which induces a more acute infection with low systemic levels of IL-10 [22,23]. As shown in S2 Fig, compared to WT mice, TgAlbCre-IL10 -/mice exhibited a similar parasitemia, anemia and weight loss profile and had a similar survival profile in this model.…”

“…During chronic infections with trypanosomatids, including African trypanosomes, hepatosplenomegaly develops as an additional complication associated with the disease [20,22,23,28]. This pathological feature results in the overall increase in T. congolense infection-associated mouse body weight ( Fig 2C) [20,29].…”

The non-mammalian MIF superfamily

“…In contrast to the other Plasmodium spp., Pyo-MIF appears to have a role in liver stage development and thus plays an important role in completion of its lifecycle (Miller et al, 2012). Finally, though MIF was also found to be involved in African trypanosomosis-associated pathogenicity (Stijlemans et al, 2014, 2016), so far no reports are documented on the involvement of trypanosomal MIF. Yet, it is highly likely that these protozoa also harbor a homologue given their “close relationship” with Leishmania and Plasmodium.…”