Abstract
African trypanosomosis (AT) is a chronically debilitating parasitic disease of medical and economic importance for the development of sub-Saharan Africa. The trypanosomes that cause this disease are extracellular protozoan parasites that have developed efficient immune escape mechanisms to manipulate the entire host immune response to allow parasite survival and transmission. During the early stage of infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS), involving classically activated macrophages (i.e., M1), is required for initial parasite control. Yet, the persistence of this M1-type MPS activation in trypanosusceptible animals causes immunopathology with anemia as the most prominent pathological feature. By contrast, in trypanotolerant animals, there is an induction of IL-10 that promotes the induction of alternatively activated macrophages (M2) and collectively dampens tissue damage. A comparative gene expression analysis between M1 and M2 cells identified galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF) as novel M1-promoting factors, possibly acting synergistically and in concert with TNF-α during anemia development. While Gal-3 enhances erythrophagocytosis, MIF promotes both myeloid cell recruitment and iron retention within the MPS, thereby depriving iron for erythropoiesis. Hence, the enhanced erythrophagocytosis and suppressed erythropoiesis lead to anemia. Moreover, a thorough investigation using MIF-deficient mice revealed that the underlying mechanisms in AT-associated anemia development in trypanosusceptible and tolerant animals are quite distinct. In trypanosusceptible animals, anemia resembles anemia of inflammation, while in trypanotolerant animals’ hemodilution, mainly caused by hepatosplenomegaly, is an additional factor contributing to anemia. In this review, we give an overview of how trypanosome- and host-derived factors can contribute to trypanosomosis-associated anemia development with a focus on the MPS system. Finally, we will discuss potential intervention strategies to alleviate AT-associated anemia that might also have therapeutic potential.
Highlights
African trypanosomes are extracellular protozoan parasites causing debilitating diseases of medical, veterinary, and socio economical importance that adversely affect the economic develop ment of sub-Saharan Africa [1,2,3]
Acute anemia seems to develop as part of the innate immune response upon infec tion, where parasite-derived factors, such as parasite-derived extracellular vesicles (EVs), as well as host-derived IFN-γ trigger M1 cell differentiation that in turn produce pro-inflammatory molecules to control the infection
The release of parasite-derived EVs in concert with host-derived TNF-α affect red blood cells (RBCs) survival and thereby fuels RBC elimination trough erythrophagocytosis (Figure 2). This is followed by a partial recovery, mediated most likely via extramedullary erythropoie sis, as a homeostatic reaction and a transient IL-10 production to dampen the pathogenic effects of the M1
Summary
African trypanosomes are extracellular protozoan parasites causing debilitating diseases of medical, veterinary, and socio economical importance that adversely affect the economic develop ment of sub-Saharan Africa [1,2,3]. Various methods have been implemented to control African trypanosomiasis [19]; including (i) vector control [20], (ii) reduc ing the proximity of livestock to reservoir hosts, (iii) development op trypanotolerant livestock (disease-resistant breeds) [5, 21], and (iv) using trypanocidal drugs [22] Their success is lim ited due to the fact that these techniques are often used locally and not necessarily in a coordinated fashion [23], game animals func tion as parasite reservoir without exhibiting pathological signs [24], and the rapid emergence of drug-resistant trypanosomes, thereby undermining their efficacy and leading to the widespread outbreaks of trypanosomiasis [19, 25, 26]. We aim at (i) giving an overview of how trypanosome-derived and host-derived factors can affect the MPS and contribute to trypanosomosis-associated anemia development and (ii) discussing on potential intervention strate gies to alleviate African trypanosomosis (AT)-associated anemia that might have therapeutic potential
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