Host susceptibility to rotavirus infection and development of antibody-based immunotherapy

摘要: Rotavirus infects mature enterocytes of the small intestine young children and cause gastroenteritis, leading to approximately 500 000 deaths annually worldwide, 85 % which occur in developing world. The main objectives thesis were investigate host genetic factors differential susceptibility rotavirus infections develop an antibody-based oral therapy against infections. Reduced TLR3 expression was previously suggested be associated with In Paper I, we thus investigated rotavirusspecific IgG antibody responses from individuals (IgA competent or deficient) using two SNPs (rs3775291 rs5743305). We concluded that these polymorphisms elevated titers IgA deficient, but not individuals. addition, recent vitro studies have HBGAs (H type 1 Lewis antigens) serve as putative receptors for VP8*, play a role vivo. II, therefore studied effect FUT2 (rs601338) FUT3 genes (rs28362459, rs3894326, rs812936 rs778986) on serum neutralizing levels P[6] P[8]. specific Wa strain (P[8]) significantly higher secretors (individuals intact FUT2), suggesting secretor individuals, expressing b antigen, are more prone than non-secretors. recently developed rotavirus, may confer safe, immediate efficient viral neutralization protection. Probiotic bacteria represent attractive delivery system fragments other proteins gastrointestinal tract. III, combination including engineered L. rhamnosus GG binding domains protein G HBC shown effective reducing prevalence, severity, duration diarrhea mouse pup model RRV infection comparison alone wild-type HBC. IV, vectors co-production VHHs: ARP1 ARP3, by paracasei BL23. Both (secreted anchored) bind broad range human serotypes vitro. V, fusion IgG1 Fc (Fc-ARP1) confers markedly increased protection neonatal rotavirus-induced diarrhea, Fc-mediated rotavirus. These antibodybased treatments could further used alternative complement current vaccines. LIST OF SCIENTIFIC PAPERS I. Mutations toll-like receptor 3 rotavirus-specific antibodies IgA-deficient IgA-sufficient Gunaydin G, Nordgren J, Svensson L, Hammarstrom Clinical vaccine immunology : CVI 2014; 21:298-301. II. gene determines Swedish population. G*, J*, Sharma S, Submitted. III. Engineered Lactobacillus IgG-binding G: Capture hyperimmune bovine colostrum model. Zhang R, Marcotte H. Vaccine 32:470-7. IV. Co-expression anti-rotavirus (llama VHH fragments) Lactobacillus: Development functionality containing cassettes tandem. Alvarez B, Lin Y, PloS One 9(4): e96409. V. Fusion llama single domain (ARP1) induced diarrhea. H, Manuscript. ADDITIONAL PUBLICATIONS NOT INCLUDED Integrative lactobacilli. Martin MC, Pant N, Ladero Andersen KK, Martinez MA, Appl Environ Microbiol. 2011 Mar;77(6):2174-9. Lewis-negative phenotype is strong restriction factor P[8] S*, Bucardo F*, Nasir W, Ouermi D, Nitiema LW, Becker-Dreps Simpore Larson CONTENTS