In Malian children the serologic cytokine milieu at baseline and at the time of an acute falciparum malaria infection appears to be altered by the presence of an underlying schistosomiasis infection. At baseline, the Th2 (IL-4, IL-6, and IL-10) and IFN-γ cytokine levels were elevated in Sch(+) children. An expected robust inflammatory response to erythrocytic falciparum infection was also observed in this study, but when we controlled for age and parasitemia, both IL-6 and IL-10 levels in children who were 4 to 8 years old and IL-10 levels in children who were 9 to 14 years old appeared to be blunted in the presence of S. hematobium compared to the levels in schistosomiasis-negative controls. IL-4 levels measured at the time of an acute malaria infection inversely correlated with the time to first malaria infection; i.e., the longer the time to the malaria episode, the lower the levels of IL-4 at the time of infection in the volunteers. Although the significance of this phenomenon is unclear, we postulate that the Th2-enriched environment elicited by chronic schistosomiasis protects against acquisition of a secondary infection (i.e., malaria). Moreover, it is reasonable to speculate that in individuals who do sustain a malaria infection, the resultant cytokine response is altered by this polarizing Th2 environment.
Concomitant infections have been shown to alter the host immunologic response. Mice with ova-producing S. mansoni
infections have impaired lesional healing and an altered Th1/Th2 balance after Leishmania major
), an enhanced ability to expel Trichuris muris
via Th2 cytokine-dependent mechanisms (5
), and an altered immune response to Plasmodium
). An underlying nematode infection impairs protective immunity to murine erythrocytic malaria via mechanisms involving transforming growth factor β and IL-10, whereas eradication of the nematode infection restores protective immunity (28
). Furthermore, the immunologic response to murine malaria vaccination is blunted by the presence of an underlying nematode infection (29
). Elevated levels of plasma IFN-γ and TNF-RII were found in Senegalese children who were 7 to 15 years old and were coinfected with S. hematobium
and P. falciparum
compared to children with malaria alone (7
). Rather than increases in the levels of proinflammatory cytokines in coinfected children, we observed a blunting of Th2 cytokine production, representing an altered immune response to the malaria insult. Low IL-10/TNF-α ratios have been described in association with anemia and cerebral malaria complications and suggest that there is a loss of the counterregulatory anti-inflammatory function of IL-10 (18
). We did observe a reduction in the IL-10/TNF-α cytokine ratio (but not in the IL-10/IFN-γ cytokine ratio) for Sch(+) children compared with Sch(−) children who were 9 to 14 years old, suggesting that there was a loss of anti-inflammatory regulation. However, this does not appear to be the operative mechanism underlying the clinical protection against malaria afforded the younger 4- to 8-year-old Sch(+) children. Moreover, our results have to be evaluated in the context that serum cytokine levels may not represent cytokine levels in the cellular microenvironment. Cellular immunologic studies are necessary to further delineate the mechanisms behind helminth-induced protection against malarial disease.
An IL-4-rich environment may polarize the cytokine response toward Th2 predominance (4
). Th2 cytokine production appears to be critical for the development of immunity to falciparum malaria. IL-4 levels have been shown to correlate with age, development of antibody to malaria antigen, and malaria protection and are believed to play a role in parasite clearance (1
-derived IL-4 has been shown to be critical in the development of memory CD8+
T-cell responses to malaria liver stage antigens (2
). We found that background IL-4 levels were elevated in children with schistosomiasis. Interestingly, the same children had been monitored for 175 days without acquiring malaria, suggesting that IL-4 has a role in mediating protection against malaria. Our paradoxical observation of an inverse correlation between IL-4 levels and time to first malaria infection seems to be at odds with this finding. Further conclusions concerning the role of IL-4 in mediating protection against malaria cannot be made without documenting IL-4 levels prior to malaria infection in individual children and prospectively monitoring the children to determine malaria acquisition. Further clinical and cellular studies are needed to address this question.
The finding that the IFN-γ level was elevated at baseline in the Sch(+) group was surprising in that enhanced Th2 cytokine production but not Th1 cytokine production is expected in response to worm ovipositing. Ordinarily, extrinsic Th2 cytokine stimulation would polarize CD8+
T cells to secrete Th2 cytokines (26
). This paradoxical finding has also been obtained for mice immunized against S. mansoni
, where CD8+
T-cell production of IFN-γ and IL-10 was found to be driven by IL-4 derived from CD4+
T cells (24
). In schistosomiasis, it is thought that CD8+
cells (demonstrated to be critical in the granulomatous response to egg deposition) (34
) may secrete IFN-γ in response to ova-induced IL-4 production in order to down-regulate Th2 production and therefore host immunopathology. We observed a direct correlation between IFN-γ and IL-4 in Sch(+) children who were 4 to 8 years old, contradicting findings reported in other malaria studies performed in the absence of schistosomiasis (19
). To our knowledge, these are the first human data demonstrating this phenomenon.
Although there is no a priori reason to believe that serum cytokine levels are different at the beginning and at the end of the transmission season, our conclusions were limited by our inability to measure cytokine levels in all enrolled children prior to the onset of malaria transmission; instead, we relied on cytokine levels measured in individuals who did not succumb to malaria infection as representative background levels. The effect of other concomitant infections is unknown. The baseline prevalence of intestinal infections before albendazole therapy was similar at the time of enrollment. The prevalence of adult human immunodeficiency virus is quite low in the region (1 to 2%), and filarial infection (i.e., Loa loa, Onchocerca volvulus, or Wuchereria bancrofti) was undetectable in pilot studies conducted with 120 area children. Every attempt was made to enroll healthy individuals, but we cannot exclude the possibility that occult infections altered cytokine measurements.
In summary, these studies revealed that the polarized Th2-enriched environment induced by underlying schistosomiasis modulates the human immune response, possibly affecting the incidence and severity of concomitant falciparum malaria. Our results demonstrated that there were elevated background Th2-biased cytokine levels, as well as elevated IFN-γ levels, in children with schistosomiasis compared to uninfected children and suggested that IL-4 and IL-10 may play significant roles in modulating the host response to malaria infection. Additional studies at a cellular level to investigate the cytokine responses to specific schistosomal and malarial antigens are critical to further discern the immunomodulatory role of schistosomes in the presence of secondary antigen stimuli. This research may have a direct impact on the implementation of malaria vaccination in the developing world.