Abstract
BackgroundThe mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. Methodology/Principal FindingsWe measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF)-α receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85), P. falciparum (n = 30), or both species (n = 12), and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL)-10, which correlated positively with parasite density, and elevated IL-10/TNF-α, IL-10/interferon (IFN)-γ, IL-10/IL-6 and sTNFRII/TNF-α ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-α receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species.ConclusionsControlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction of regulatory cytokines may be a critical mechanism protecting vivax malaria patients from severe clinical complications.
Highlights
Malaria is the most devastating protozoan disease afflicting humans
It has been suggested that P. vivax elicits greater host inflammation per parasitized red blood cell than P. falciparum [21,22], we recently found a bias towards regulatory cytokines in uncomplicated vivax malaria in Brazil [23]
Study Participants We recruited three groups of subjects exposed to hypoendemic malaria transmission in northwestern Brazil: (a) symptomatic malaria patients infected with P. vivax, P. falciparum or both species, (b) asymptomatic carriers of low-density P. vivax infection, and (c) healthy, non-infected controls
Summary
Plasmodium falciparum causes around 0.5–3 million deaths, mostly in sub-Saharan Africa [1], while P. vivax, the most widespread human malaria parasite [2], causes 130–390 million clinical episodes [3]. Clearing malaria parasites without inducing major host pathology requires a finely tuned balance between inflammatory and regulatory cytokine responses, whose timing and magnitude is crucial in determining malaria patient outcome [9]. Once parasitemia is under control, regulatory cytokines such as IL-10 and transforming growth factor (TGF)-b are required to reduce the risk of severe disease [13,14,15]. The mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum
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