Patent filarial infection modulates malaria-specific type 1 cytokine responses in an IL-10-dependent manner in a filaria/malaria-coinfected population

Abstract

The effect of filarial infections on malaria-specific immune responses was investigated in Malian villages coendemic for filariasis (Fil) and malaria. Cytokines were measured from plasma and Ag-stimulated whole blood from individuals with Wuchereria bancrofti and/or Mansonella perstans infections (Fil(+); n = 19) and those without evidence of filarial infection (Fil(-); n = 19). Plasma levels of IL-10 (geometric mean [GM], 22.8 vs 10.4) were higher in Fil(+) compared with Fil(-), whereas levels of IFN-inducible protein (IP)-10 were lower in Fil(+) (GM, 66.3 vs 110.0). Fil(+) had higher levels of spontaneously secreted IL-10 (GM, 59.3 vs 6.8 pg/ml) and lower levels of IL-2 (1.0 vs 1.2 pg/ml) than did Fil(-). Although there were no differences in levels of Staphylococcus aureus enterotoxin B-induced cytokines between the two groups, Fil(+) mounted lower IL-12p70 (GM, 1.11 vs 3.83 pg/ml; p = 0.007), IFN-gamma (GM, 5.44 vs 23.41 pg/ml; p = 0.009), and IP-10 (GM, 29.43 vs 281.7 pg/ml; p = 0.007) responses following malaria Ag (MalAg) stimulation compared with Fil(-). In contrast, Fil(+) individuals had a higher MalAg-specific IL-10 response (GM, 7318 pg/ml vs 3029 pg/ml; p = 0.006) compared with those without filarial infection. Neutralizing Ab to IL-10 (but not to TGFbeta) reversed the down-regulated MalAg-specific IFN-gamma and IP-10 (p < 0.001) responses in Fil(+). Together, these data demonstrate that filarial infections modulate the Plasmodium falciparum-specific IL-12p70/IFN-gamma secretion pathways known to play a key role in resistance to malaria and that they do so in an IL-10-dependent manner.

FIGURE 1

Plasma cytokine levels in filaria-uninfected (Fil⁻; open triangles) and filaria-infected (Fil⁺; closed triangles) individuals (Figure 1A). Levels of cytokines produced spontaneously in whole blood cultures from filaria-uninfected (Fil⁻; open triangles) and filaria-infected (Fil⁺; closed triangles) individuals (Figure 1B). Each triangle represents an individual patient; the horizontal bar represents the geometric mean for each group. Each triangle represents an individual patient; the horizontal bar represents the geometric mean for each group.

FIGURE 2

Levels of malaria Ag-stimulated cytokines produced in whole blood cultures from filaria-uninfected (Fil⁻; open triangles) and filaria-infected (Fil⁺; closed triangles) individuals. Each triangle represents the net cytokine production from an individual patient; the horizontal bar represents the geometric mean for each group.

FIGURE 3

Levels of cytokine produced in response to SEB, PPD, and BmA stimulation in whole blood cultures of filaria-uninfected (Fil⁻; hatched bars) and filaria-infected (Fil⁺; solid bars) individuals. Each bar represents the geometric mean of the net production of each cytokine. * p < 0.05,

FIGURE 4

Effect of neutralizing anti-IL-10 and anti-TGFβ Ab on the levels of malaria-specific cytokine production in whole blood cultures of filaria-infected patients. Cytokines were measured in supernatants of whole blood cultures stimulated with malaria Ag in the presence or absence (isotype control) of neutralizing anti-IL-10 (A, top), anti-TGFβ (A, bottom) Ab alone or in combination (B). Each line represents the net concentration of a given cytokine for an individual patient in the presence or absence of the neutralizing Ab shown.

FIGURE 5

Source of IL-10 production by CD4+ cells in MalAg-stimulated cultures. Shown are four representative scatter plots from two representative Fil- (left panels) and two representative Fil+ (right panels) subjects. The numbers in each quadrant represent the percentage of total CD4+ cells for each individual.