Shared IgG Infection Signatures vs. Hemorrhage-Restricted IgA Clusters in Human Dengue: a Phenotype of Differential Class-Switch via TGFß1

Dengue fever is a mosquito-borne disease that affects nearly four millions of people every year. Vector control is the main strategy to contain the threat because no effective treatments are available for Dengue viruses. A new vaccine has recently been developed, but efficacies vary with both viral serotypes and exposure histories to vectors. Dengue fever is unique in that the most severe presentations of the disease often occur after the initial febrile stage. A second heterotypic infection is the most dangerous contributing factor for such complications as hemorrhage, plasma leakage, or even circulatory collapse. Cross-reactive antibodies have been suggested to play aberrant roles in these situations, including the paradoxical enhancement of disease severity. Recent advances in next-generation sequencing (NGS) have allowed clonal characterization of antibody repertoires. In this study we used NGS to analyze both IgG and IgA immune repertoires from Dengue patients. Statistical heuristics efficiently revealed four infection signatures from IgG repertoires, two of which were identical to prior discoveries. IgA repertoires were found more dissimilar to IgG repertoires among those patients with hemorrhages. Diversity profiles of IgA repertoires between patients with or without hemorrhages were more distinct than those between IgG repertoires. Variations of IgA repertoires as summarized by principal component analysis were sufficient to classify patients in accord with the phenotype. Further analyses revealed seven IgA clusters closely associated with various forms of bleedings in Dengue fever. In sum, our results not only demonstrated an efficient pipeline to discover infection signatures but also revealed hidden relationships between IgA repertoires and hemorrhages in Dengue fever.