Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum?

Abstract

Background: The 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 findings: We 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.

Conclusions: Controlling 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.

Figure 1. Severity of 13 malaria-associated symptoms in Amazonians with uncomplicated infection with Plasmodium vivax (A; n = 84), P. falciparum (B; n = 27) or both species (C; n = 11), diagnosed by thick-smear microscopy and confirmed by real-time PCR.

Symptoms are abbreviated as follows: fever  =  Fev; chills  =  Chi; sweating  =  Swe; headache  =  Hea; myalgia  =  Mya; arthralgia  =  Art; abdominal pain  =  Abd; nausea  =  Nau; vomiting  =  Vom; dizziness  =  Diz; cough  =  Cou; dyspnea  =  Dys; diarrhea  =  Dia. Each bar segment represents the proportion of subjects reporting a given symptom as absent (no shading), mild (light gray), moderate (dark gray) or severe (black).