Neutrophil Paralysis in Plasmodium vivax Malaria

Abstract

Background The activation of innate immune responses by Plasmodium vivax results in activation of effector cells and an excessive production of pro-inflammatory cytokines that may culminate in deleterious effects. Here, we examined the activation and function of neutrophils during acute episodes of malaria. Materials and Methods Blood samples were collected from P. vivax -infected patients at admission (day 0) and 30–45 days after treatment with chloroquine and primaquine. Expression of activation markers and cytokine levels produced by highly purified monocytes and neutrophils were measured by the Cytometric Bead Assay. Phagocytic activity, superoxide production, chemotaxis and the presence of G protein-coupled receptor (GRK2) were also evaluated in neutrophils from malaria patients. Principal Findings Both monocytes and neutrophils from P. vivax -infected patients were highly activated. While monocytes were found to be the main source of cytokines in response to TLR ligands, neutrophils showed enhanced phagocytic activity and superoxide production. Interestingly, neutrophils from the malaria patients expressed high levels of GRK2, low levels of CXCR2, and displayed impaired chemotaxis towards IL-8 (CXCL8). Conclusion Activated neutrophils from malaria patients are a poor source of pro-inflammatory cytokines and display reduced chemotactic activity, suggesting a possible mechanism for an enhanced susceptibility to secondary bacterial infection during malaria.

Role of G protein-coupled receptor kinases in cell migration

“…High GRK2 expression in neutrophils from malaria patients suggests a possible mechanism for an enhanced susceptibility to secondary bacterial infection during malaria [47].…”

The immunological balance between host and parasite in malaria

“…HO-1 is induced especially abundantly in neutrophils and is highest in patients with severe malaria, and HO-1 mRNA correlated with IL-10 mRNA levels in whole blood . In contrast, neutrophils from P. vivax patients are activated and their phagocytic activity and superoxide production is significantly enhanced, although they have a decreased chemotactic activity (Leoratti et al 2012). Whether also P. vivax exacerbates Salmonella infections remains to be investigated; however, intracellular killing mechanisms do not seem to be impaired with P. vivax.…”

Parasite virulence, co-infections and cytokine balance in malaria

“…In fact, plasma concentrations of IL-10/TNF-alpha and IL-10/IFN-gamma ratios correlate positively with P. vivax parasitemias 41,43,47,48 and return to their normal range after antimalarial treatment. 43,46,49 Interestingly, however, high IL-10 levels do not eventually translate into overwhelming parasitemias, since P. vivax blood stages can only infect reticulocytes, which comprise less than 1% of the circulating pool of red blood cells.…”

“…60,61 Human malaria can increase the susceptibility to concurrent bacteremia by inducing neutrophil dysfunction, with reduced chemotaxis and oxidative burst. 49,62 Induction of heme oxygenase-1 (HO-1)…”

“…42 As in experimental murine infections, peripheral blood mononuclear cells from P. vivax malaria patients produce extremely high levels of IL-1beta when exposed ex vivo to bacterial components such as LPS. 8,49,59 In fact, infectious comorbidities were common in two recent case series of severe vivax malaria 71,72 and may have further contributed to potentially inflammationrelated complications of these infections, such as endothelial dysfunction leading to respiratory distress and circulatory shock, as well as severe anemia.…”