Abstract
It is known that Trypanosoma congolense infection in mice is associated with increased production of proinflammatory cytokines by macrophages and monocytes. However, the intracellular signaling pathways leading to the production of these cytokines still remain unknown. In this paper, we have investigated the innate receptors and intracellular signaling pathways that are associated with T. congolense-induced proinflammatory cytokine production in macrophages. We show that the production of IL-6, IL-12, and TNF-α by macrophages in vitro and in vivo following interaction with T. congolense is dependent on phosphorylation of mitogen-activated protein kinase (MAPK) including ERK, p38, JNK, and signal transducer and activation of transcription (STAT) proteins. Specific inhibition of MAPKs and STATs signaling pathways significantly inhibited T. congolense-induced production of proinflammatory cytokines in macrophages. We further show that T. congolense-induced proinflammatory cytokine production in macrophages is mediated via Toll-like receptor 2 (TLR2) and involves the adaptor molecule, MyD88. Deficiency of MyD88 and TLR2 leads to impaired cytokine production by macrophages in vitro and acute death of T. congolense-infected relatively resistant mice. Collectively, our results provide insight into T. congolense-induced activation of the immune system that leads to the production of proinflammatory cytokines and resistance to the infection.
Highlights
African Trypanosomiasis, an infectious disease of humans and animals, is caused by various species of protozoan parasites belonging to the genus Trypanosoma
Because macrophages play a central role in resistance to experimental African trypanosomiasis [21, 22], we investigated their role in proinflammatory cytokine production and the molecular pathways involved in this process
We previously showed that the production of proinflammatory cytokine by splenic and liver macrophages following T. congolense infection contributes to disease and treatment with Berenil suppressed the production of these cytokines and prevents death in the highly susceptible mice [19]
Summary
African Trypanosomiasis, an infectious disease of humans and animals, is caused by various species of protozoan parasites belonging to the genus Trypanosoma. Because the parasites are purely extracellular but intravascular, they are unable to leave the circulation and are constantly exposed the to the host’s immune system. As a result, they have developed sophisticated evasion mechanisms including antigenic variation of the variant surface glycoprotein (VSG) [2, 3], polyclonal B-lymphocyte activation [4], and induction of immunosuppression [5,6,7]. BALB/c mice are highly susceptible to experimental T. congolense infection because they are unable to control the first wave of parasitemia and die within 8–10 days. The innate receptors, adaptor proteins and signaling pathways associated with T. congolense-induced cytokine production in macrophages are not known
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