Genetic evidence for the aggravation of Plasmodium falciparum malaria by interleukin 4.
BACKGROUND
Severe malaria (SM) due to Plasmodium falciparum causes millions of child deaths in sub-Saharan Africa. It comprises a variety of clinical disorders, including cerebral malaria (CM) and severe anemia (SA). In previous work, we have shown that interferon gamma and interleukin 12 protect against CM. Here, we investigated whether interleukin 4 (IL-4) aggravates the risk of severe disease.


METHODS
We prospectively recruited children with CM (n = 240), SA (n = 101), and uncomplicated malaria (UM) (n = 42) in Bamako, Mali, and measured IL-4 production in plasma by enzyme-linked immunosorbent assay. We then assessed the influence of 11 polymorphisms on predisposition to SM by the family-based association test (FBAT).


RESULTS
IL-4 concentrations were higher in children with CM than in children with UM during malaria (P = .003). FBAT analyses showed that the most significant association was between the IL4 variable-number tandem repeat (VNTR) 1/2 genotype and SM (P < .001); an association was also observed for IL4 -33 C/T, rs2243267 G/C, rs2243268 C/A, and rs2243282 C/A (P < .05). Interestingly, we found that the plasma concentration of IL-4 was higher in subjects with the IL4 VNTR 1/2 or 1/1 genotype than with the IL4 VNTR 2/2 genotype (P = .003).


CONCLUSIONS
These results support the view that IL-4 may be a risk factor for SM. IL-4 may aggravate the disease by interfering with type 1 T helper cell differentiation or by promoting local inflammation at sites of parasite sequestration.
Cabantous
Sandrine
S
Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 906, Faculté de Médecine, Aix-Marseille Université, IFR88, 27 blvd. Jean Moulin, Marseille, France. sandrine.cabantous@univmed.fr
Poudiougou
Belco
B
Oumar
Aboubacar A
AA
Traore
Abdoualye
A
Barry
Abdoulaye
A
Vitte
Joana
J
Bongrand
Pierre
P
Marquet
Sandrine
S
Doumbo
Ogobara
O
Dessein
Alain J
AJ
D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D015847:Interleukin-4 / Q000097:blood / Q000235:genetics*; D016779:Malaria, Cerebral / Q000235:genetics* / Q000276:immunology; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
C508598:IL4 protein, human; D015847:Interleukin-4