Abstract
Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4+CD25+ regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4+CD25+Foxp3+CD127lo Treg cells were significantly elevated in patients with uncomplicated (UM; n = 17) and severe malaria (SM; n = 16) relative to exposed asymptomatic controls (AC; n = 10). In patients with SM, Treg cell frequency correlated positively with parasitemia (r = 0.79, p = 0.0003) and total parasite biomass (r = 0.87, p<0.001), both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII+ Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum–infected red blood cells dose dependently induced TNFRII+Foxp3hi Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII− Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII+Foxp3hi Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII+Foxp3hi Treg cells when developing effective malaria vaccines.
Highlights
Infection with Plasmodium falciparum causes over 1 million deaths each year and an effective malaria vaccine remains elusive
We investigated the relationship between Treg cells, parasite burden, and disease severity in adult malaria patients with either uncomplicated or severe malaria
We demonstrated that Treg cell frequency was elevated in malaria patients and associated with high parasite burden in severe malaria but not in uncomplicated malaria
Summary
Infection with Plasmodium falciparum causes over 1 million deaths each year and an effective malaria vaccine remains elusive. The cellular immune responses controlling parasite replication and disease severity in falciparum malaria are not fully understood. Treg cells suppress cellular immune responses through direct contact with immune effector cells and via the production of regulatory cytokines, including IL-10 [6,7]. Whilst it is understood that effector T cell responses are important components of host antiparasitic immunity [8,9], the role of Treg cells as suppressors of T cell responses in malaria remains unclear. In mouse experimental malaria models, Treg cells have been associated with increased [10,11] or delayed [12] disease progression. In each of these studies, Treg depletion was associated with improved control of parasite growth
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