Protein structure shapes immunodominance in the CD4 T cell response to yellow fever vaccination.

The live attenuated yellow fever (YF) vaccine is a highly effective human vaccine and induces long-term protective neutralizing antibodies directed against the viral envelope protein E. The generation of such antibodies requires the help of CD4 T cells which recognize peptides derived from proteins in virus particles internalized and processed by E-specific B cells. The CD4 T helper cell response is restricted to few immunodominant epitopes, but the mechanisms of their selection are largely unknown. Here, we report that CD4 T cell responses elicited by the YF-17D vaccine are focused to hotspots of two helices of the viral capsid protein and to exposed strands and loops of E. We found that the locations of immunodominant epitopes within three-dimensional protein structures exhibit a high degree of overlap between YF virus and the structurally homologous flavivirus tick-borne encephalitis virus, although amino acid sequence identity of the epitope regions is only 15-45%. The restriction of epitopes to exposed E protein surfaces and their strikingly similar positioning within proteins of distantly related flaviviruses are consistent with a strong influence of protein structure that shapes CD4 T cell responses and provide leads for a rational design of immunogens for vaccination.

Rapid-Antigen Test Negative Malaria in a Traveler Returning From Thailand, Molecularly Diagnosed as Plasmodium knowlesi.

Plasmodium knowlesi has been identified in the last decade as a fifth species causing malaria in areas of South East Asia. Due to its short erythrocytic cycle, rapid development of high parasitemia and severe manifestations are frequently observed. Therefore, prompt diagnosis of infection is essential to prevent complications, but the low sensitivity of rapid diagnostic tests for P knowlesi pose a diagnostic challenge in acute settings. In this study, we report the case of a German traveler to Thailand, who was treated for P knowlesi malaria after returning to Germany. Rapid antigen test for malaria was negative on presentation. Diagnosis of a nonfalciparum malaria was made based on microscopy, and species definition was determined using polymerase chain reaction technique.

Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens.

In malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child's susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (T(regs)) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4(+)CD25(lo) T cells and CD4(+)CD25(hi) FOXP3(+) cells (T(regs)) were enriched from CBMC. T(reg) frequency and HLA-DR expression on T(regs) were significantly greater for Kenyan as compared with North American CBMC (p < 0.01). CBMC/CD4(+) T cells cultured with P. falciparum blood-stage Ags induced production of IFN-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25(hi) cells augmented the Ag-driven IFN-γ production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of T(regs) to CD4(+)CD25(lo) cells suppressed spontaneous and malaria Ag-driven production of IFN-γ in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, T(regs) only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-ß did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces T(regs) that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these T(regs) postnatally could modify a child's susceptibility to malaria infection and disease.