Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria.

BACKGROUND: Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood. METHODS: We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community. RESULTS: Acute malaria was marked by elevated levels of proinflammatory and regulatory cytokines and expansion of the inflammatory "intermediate" monocyte subset that returned to levels of healthy asymptomatic children 6 weeks later. Monocytes displayed activated phenotypes during acute malaria, with changes in surface expression of markers important to innate and adaptive immunity. Functionally, acute malaria monocytes and monocytes from asymptomatic infected children had impaired phagocytosis of P. falciparum-infected erythrocytes relative to asymptomatic children with no blood-stage infection. Monocytes from both acute malaria and recovery time points displayed strong and equivalent cytokine responsiveness to innate immune agonists that were independent of infection status. Monocyte transcriptional profiles revealed regulated and balanced proinflammatory and antiinflammatory and altered phagocytosis gene expression patterns distinct from malaria-naive monocytes. CONCLUSION: These observations provide insights into monocyte functions and the innate immune response during uncomplicated malaria and suggest that asymptomatic parasitemia in children is not clinically benign. FUNDING: Support for this work was provided by NIH/National Institute of Allergy and Infectious Diseases (R01AI095192-05), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene, and the Rainbow Babies & Children's Foundation.

Suppression of circulating IgD+CD27+ memory B cells in infants living in a malaria-endemic region of Kenya.

BACKGROUND: Plasmodium falciparum infection leads to alterations in B cell subset distribution. During infancy, development of peripheral B cell subsets is also occurring. However, it is unknown if infants living a malaria endemic region have alterations in B cell subsets that is independent of an age effect. METHODS: To evaluate the impact of exposure to P. falciparum on B cell development in infants, flow cytometry was used to analyse the distribution and phenotypic characteristic of B cell subsets in infant cohorts prospectively followed at 12, 18 and 24 months from two geographically proximate regions in western Kenya with divergent malaria exposure i.e. Kisumu (malaria-endemic, n = 24) and Nandi (unstable malaria transmission, n = 21). RESULTS: There was significantly higher frequency and absolute cell numbers of CD19+ B cells in Kisumu relative to Nandi at 12(p = 0.0440), 18(p = 0.0210) and 24 months (p = 0.0493). No differences were observed between the infants from the two sites in frequencies of naïve B cells (IgD+CD27-) or classical memory B cells (IgD-CD27+). However, immature transitional B cells (CD19+CD10+CD34-) were higher in Kisumu relative to Nandi at all three ages. In contrast, the levels of non-class switched memory B cells (CD19+IgD+CD27+) were significantly lower overall in Kisumu relative to Nandi at significantly at 12 (p = 0.0144), 18 (p = 0.0013) and 24 months (p = 0.0129). CONCLUSIONS: These data suggest that infants living in malaria endemic regions have altered B cell subset distribution. Further studies are needed to understand the functional significance of these changes and long-term impact on ability of these infants to develop antibody responses to P. falciparum and heterologous infections.