Host susceptibility to rotavirus infection and development of antibody-based immunotherapy
Year: 2014
Type: dissertation
Study design: Observational Study
Abstract: Rotavirus infects mature enterocytes of the small intestine of young children and \ncause gastroenteritis, leading to approximately 500 000 deaths annually \nworldwide, 85 % of which occur in the developing world. The main objectives \nof the thesis were to investigate host genetic factors leading to differential \nsusceptibility to rotavirus infections and to develop an antibody-based oral \ntherapy against the infections. \n \n \n \nReduced TLR3 expression was previously suggested to be associated with \nsusceptibility to rotavirus infections. In Paper I, we thus investigated rotavirusspecific IgG antibody responses from individuals (IgA competent or deficient) \nusing two TLR3 SNPs (rs3775291 and rs5743305). We concluded that these two \npolymorphisms were associated with elevated IgG titers in IgA deficient, but not \nin IgA competent individuals. In addition, recent in vitro studies have suggested \nthat HBGAs (H type 1 and Lewis antigens) serve as putative receptors for \nrotavirus VP8*, and play a role in susceptibility to infections in vivo. In Paper \nII, we therefore studied the effect of SNPs in the FUT2 (rs601338) and FUT3 \ngenes (rs28362459, rs3894326, rs812936 and rs778986) on the serum IgG \nantibody titers and neutralizing antibody levels to rotavirus P[6] and P[8]. The \nrotavirus specific serum IgG levels and neutralizing antibody titers to the Wa \nstrain (P[8]) of rotavirus were significantly higher in secretors (individuals with \nan intact FUT2), suggesting that secretor individuals, expressing the Lewis b \nantigen, are more prone to rotavirus (P[8]) infections than non-secretors. \n \n \n \nWe have recently developed an antibody-based therapy against rotavirus, which \nmay confer safe, immediate and efficient viral neutralization and protection. \nProbiotic bacteria represent an attractive delivery system for antibody fragments \nand other proteins in the gastrointestinal tract. In Paper III, the combination \ntherapy including engineered L. rhamnosus GG expressing IgG binding domains \nof protein G and HBC was shown to be more effective in reducing the \nprevalence, severity, and duration of diarrhea in a mouse pup model of RRV \ninfection in comparison to HBC alone or a combination of wild-type L. \nrhamnosus GG and HBC. In Paper IV, we developed vectors for co-production \nof two VHHs: ARP1 and ARP3, by engineered L. paracasei BL23. Both \nfragments (secreted or anchored) were shown to bind to a broad range of human \nrotavirus serotypes in vitro. In Paper V, we have shown that the fusion of the \nmouse IgG1 Fc to ARP1 (Fc-ARP1) confers a markedly increased protection \nagainst rotavirus in a neonatal mouse model of rotavirus-induced diarrhea, \nsuggesting a role for Fc-mediated neutralization of rotavirus. These antibodybased treatments could be further developed and used as an alternative or \ncomplement to current vaccines.
Source: Figshare
Author: Gökçe Günaydın
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1503068453