MIF-Mediated Hemodilution Promotes Pathogenic Anemia in Experimental African Trypanosomosis

Abstract

Animal African trypanosomosis is a major threat to the economic development and human health in sub-Saharan Africa. Trypanosoma congolense infections represent the major constraint in livestock production, with anemia as the major pathogenic lethal feature. The mechanisms underlying anemia development are ill defined, which hampers the development of an effective therapy. Here, the contribution of the erythropoietic and erythrophagocytic potential as well as of hemodilution to the development of T. congolense-induced anemia were addressed in a mouse model of low virulence relevant for bovine trypanosomosis. We show that in infected mice, splenic extramedullary erythropoiesis could compensate for the chronic low-grade type I inflammation-induced phagocytosis of senescent red blood cells (RBCs) in spleen and liver myeloid cells, as well as for the impaired maturation of RBCs occurring in the bone marrow and spleen. Rather, anemia resulted from hemodilution. Our data also suggest that the heme catabolism subsequent to sustained erythrophagocytosis resulted in iron accumulation in tissue and hyperbilirubinemia. Moreover, hypoalbuminemia, potentially resulting from hemodilution and liver injury in infected mice, impaired the elimination of toxic circulating molecules like bilirubin. Hemodilutional thrombocytopenia also coincided with impaired coagulation. Combined, these effects could elicit multiple organ failure and uncontrolled bleeding thus reduce the survival of infected mice. MIF (macrophage migrating inhibitory factor), a potential pathogenic molecule in African trypanosomosis, was found herein to promote erythrophagocytosis, to block extramedullary erythropoiesis and RBC maturation, and to trigger hemodilution. Hence, these data prompt considering MIF as a potential target for treatment of natural bovine trypanosomosis.

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

“…Hepatocyte-IL-10 attenuates African trypanosomiasis-associated pathogenicity Hepatocyte-IL-10 attenuates African trypanosomiasis-associated pathogenicity increased serum AST (aspartate aminotransferase, reflecting systemic tissue injury) and ALT (alanine aminotransferase, reflecting liver injury) levels as well as creatinine (reflecting kidney injury) levels ( Fig 5A-5C). In TgAlbCre-IL10 -/mice, this observation coincides with increased serum levels of pro-inflammatory cytokines (IFN-γ, TNF, IL-12p70, IL-6 and MIF) which were documented to contribute to T. congolense-induced tissue destruction ( Fig 5D) Hepatocyte-IL-10 attenuates African trypanosomiasis-associated pathogenicity [20,[25][26][27]. In line with previous observations, LysM-IL-10 -/mice also showed higher systemic levels of TNF compared to WT mice [15].…”

“…Conversely, absence of the upstream regulator of the inflammatory cascade, i.e. macrophage migration inhibitory factor (MIF), has been shown to correlate with an attenuated inflammatory immune response and a concordantly reduced immunopathology during the course of infection, which is associated with an extended survival time [20]. This phenotype coincides with increased systemic levels of IL-10 during the later stages of infection [20].…”

“…macrophage migration inhibitory factor (MIF), has been shown to correlate with an attenuated inflammatory immune response and a concordantly reduced immunopathology during the course of infection, which is associated with an extended survival time [20]. This phenotype coincides with increased systemic levels of IL-10 during the later stages of infection [20]. Hence, a well-timed and balanced order of pro-inflammatory cytokine promoting factors followed by an anti-inflammatory response is required to attenuate infection-associated pathogenicity.…”

Intravital microscopy: Imaging host–parasite interactions in lymphoid organs

“…Direct and indirect bone marrow involvement in pathology has been suggested for parasites including Plasmodium spp., (Alano, 2017;Baro et al, 2017;De Niz et al, 2018;Duffier et al, 2016;Farfour et al 2012;Joice et al, 2014;Lee et al, 2017;Lee et al, 2018;Mayor & Alano, 2015;Messina et al, 2018;Neveu et al, 2018;Rogers et al, 2000;Smalley et al 1981;Waseem et al, 2016;Wickramasinghe et al, 1987), Toxoplasma gondii (Brouland et al, 1996), Leishmania spp., (Ali & Hussain, 2014;Hellal & Kundu, 2013;Kumar et al, 2007), Schistosoma spp., (Azevedo et al, 2015;Jones & Leday, 2014;Kamal et al 1989) and Trypanosoma spp. (Baena Terán et al, 2012;Bockstal, Guirnalda, et al, 2011;Bockstal, Geurts, & Magez, 2011;Carbajosa et al, 2017;De Diego et al 1998;Felizardo et al, 2018;Habila et al, 2014;Mabbott & Sternberg, 1995;Müller et al, 2018;Obishakin et al 2014;Souza et al, 2014;Stijlemans et al, 2016).…”

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.…”