Home Economics American Trypanosomiasis Chagas Disease, Second Edition: One Hundred Years of Research
Control of T. cruzi infection requires the activation of multiple immune effector mechanisms in relation to the presence of both extracellular trypomastigotes and intracellular amastigotes. Host protection is mainly governed by IFNs and IL-17. IFN-y is required for controlling parasite multiplication, while IL-17 rather prevents damage due to excessive inflammation. The role of this latter cytokine has been more recently disclosed and surprisingly, shown to be produced early during the infection by B cells through an unprecedented mechanism. It is also worth noting that neutrophils and iNKT cells seem to have an important role in the very initial steps of the infection, without forgetting the essential contribution of NK cells and macrophages later on, as well as CD81 T cells. The parasite disposes of various mechanisms allowing it to establish slowly as well as to escape the diversified immune response. Its ability to temporarily limit Ag presentation through MHC class I molecules (delaying the recognition of infected host cells by cytotoxic lymphocytes) and to favor the release of amastigotes (through host cell apoptosis) that invade preferentially unactivated macrophages, is particular. Late chronic infection in humans is associated with the progressive disappearance of early activated T cells and waning of T cell responses, at least in the absence of reinfections.
Trans-sialidases, mucins, and cruzipain are the main parasite molecules regulating the host response in conjunction with several parasite PRR-ligands, not all identified to date. Variations in the expression of these polymorphic molecules between parasite genotypes/DTUs are more and more recognized as determining the virulence of T. cruzi. The host genetic background also accounts for susceptibility or resistance to infection in relation to its ability to produce better and more rapidly protective or immunoregulatory cytokines.
Among microbicidal molecules produced by host cells, nitric oxide has for long been identified as pivotal in infected mice, since the parasite is well equipped to resist reactive oxygen species. However, it has to be kept in mind that NO also exerts dramatically adverse effects for the host by inducing immunosuppression and lymphocyte apoptosis. This dampens the immune response and induces alternatively activated macrophages unable to control the infection. IRG proteins might be more important than thought for controlling parasite multiplication in humans.
Comprehension of the inability to eliminate the parasite is progressing and should, hopefully, come up with immunotherapeutic strategies helping to cure lifelong chronically infected people, keeping in mind that it remains to be known if the host would actually benefit from a better efficient immune response in the long term, since it might have pathological consequences in some chronically infected individuals.
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