Autoreactive and parasite-specific IgG repertoires in asymptomatic and mild Plasmodium falciparum infection in Côte d’Ivoire

BACKGROUND: Naturally acquired immunity to Plasmodium falciparum involves parasite-specific antibodies as well as autoreactive responses that may contribute to immune regulation and tolerance. Characterizing these antibody repertoires across clinical phenotypes and transmission settings may help distinguish asymptomatic carriage from clinical malaria and identify biomarkers of exposure and protection. METHODS: We conducted a cross-sectional study in three malaria-endemic settings in Côte d'Ivoire (Korhogo, Man, and Abobo). Individuals with mild malaria (MM; n = 94) were enrolled across all three sites, whereas asymptomatic carriers (AS; n = 33) and endemic controls (EC; n = 39) were enrolled in Abobo only. Total IgG responses to P. falciparum (3D7 whole-parasite extract), self-antigens (human brain extract), and mosquito exposure (gSG6-P1) were measured by ELISA or Luminex. The breadth and specificity of autoreactive IgGs were assessed by PANAMA blotting followed by mass spectrometry. Multivariate analyses were used to identify antigenic signatures associated with clinical phenotype and, among MM individuals, differences in transmission intensity. RESULTS: Compared with MM, AS individuals exhibited lower total IgG reactivity to P. falciparum antigens but higher levels of autoreactive IgG3 with a broader antigenic repertoire. Proteomic analysis identified γ- and β-actin, as well as several metabolic enzymes (including succinate-CoA ligase, acetyl-CoA acyltransferase 2, acyl-CoA dehydrogenase, and glutaryl-CoA dehydrogenase) as targets distinguishing AS and EC from MM. Among MM cases, a cluster of brain antigens in the 50-75 kDa range differentiated sites with distinct transmission intensities. IgG responses to gSG6-P1 correlated with autoreactive IgG levels, suggesting an association between mosquito exposure and autoreactive immune responses. CONCLUSIONS: Asymptomatic P. falciparum infection in a high-transmission setting was associated with enhanced autoreactive IgG3 responses, a profile that may reflect clinical tolerance and cumulative exposure. Autoreactive antibody signatures, together with markers of mosquito exposure, may serve as candidate biomarkers of malaria exposure and naturally acquired immunity and could inform surveillance and control strategies in endemic areas.