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- Günaydın, Gökçe
(författare)
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Host susceptibility to rotavirus infection and development of antibody-based immunotherapy
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rotavirus infects mature enterocytes of the small intestine of young children and cause gastroenteritis, leading to approximately 500 000 deaths annually worldwide, 85 % of which occur in the developing world. The main objectives of the thesis were to investigate host genetic factors leading to differential susceptibility to rotavirus infections and to develop an antibody-based oral therapy against the infections. Reduced TLR3 expression was previously suggested to be associated with susceptibility to rotavirus infections. In Paper I, we thus investigated rotavirusspecific IgG antibody responses from individuals (IgA competent or deficient) using two TLR3 SNPs (rs3775291 and rs5743305). We concluded that these two polymorphisms were associated with elevated IgG titers in IgA deficient, but not in IgA competent individuals. In addition, recent in vitro studies have suggested that HBGAs (H type 1 and Lewis antigens) serve as putative receptors for rotavirus VP8*, and play a role in susceptibility to infections in vivo. In Paper II, we therefore studied the effect of SNPs in the FUT2 (rs601338) and FUT3 genes (rs28362459, rs3894326, rs812936 and rs778986) on the serum IgG antibody titers and neutralizing antibody levels to rotavirus P[6] and P[8]. The rotavirus specific serum IgG levels and neutralizing antibody titers to the Wa strain (P[8]) of rotavirus were significantly higher in secretors (individuals with an intact FUT2), suggesting that secretor individuals, expressing the Lewis b antigen, are more prone to rotavirus (P[8]) infections than non-secretors. We have recently developed an antibody-based therapy against rotavirus, which may confer safe, immediate and efficient viral neutralization and protection. Probiotic bacteria represent an attractive delivery system for antibody fragments and other proteins in the gastrointestinal tract. In Paper III, the combination therapy including engineered L. rhamnosus GG expressing IgG binding domains of protein G and HBC was shown to be more effective in reducing the prevalence, severity, and duration of diarrhea in a mouse pup model of RRV infection in comparison to HBC alone or a combination of wild-type L. rhamnosus GG and HBC. In Paper IV, we developed vectors for co-production of two VHHs: ARP1 and ARP3, by engineered L. paracasei BL23. Both fragments (secreted or anchored) were shown to bind to a broad range of human rotavirus serotypes in vitro. In Paper V, we have shown that the fusion of the mouse IgG1 Fc to ARP1 (Fc-ARP1) confers a markedly increased protection against rotavirus in a neonatal mouse model of rotavirus-induced diarrhea, suggesting a role for Fc-mediated neutralization of rotavirus. These antibodybased treatments could be further developed and used as an alternative or complement to current vaccines.
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| 2. |
- Günaydin, Gökce, et al.
(författare)
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Impact of Q-Griffithsin anti-HIV microbicide gel in non-human primates : In situ analyses of epithelial and immune cell markers in rectal mucosa
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin(+) cells, CD4(+) cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin(+) cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4(+) cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4(+) cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4(+) lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4(+) rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa.
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| 3. |
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| 4. |
- Nordgren, Johan, et al.
(författare)
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Both lewis and secretor status mediate susceptibility to rotavirus infections in a rotavirus genotype-dependent manner.
- 2014
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Ingår i: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591 .- 1058-4838. ; 59:11, s. 1567-73
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Tidskriftsartikel (refereegranskat)abstract
- The live oral rotavirus (RV) vaccines have shown a reduced efficacy in Africa. Recent in vitro studies have shown binding of the RV surface protein (VP4) to histo-blood group antigens (HBGAs) in an RV genotype-dependent manner, suggesting them to be putative receptors for RV. The diversity of HBGA phenotypes in different ethnic populations, combined with prevalence/absence of specific RV genotypes, led us to hypothesize whether the genetic variations in HBGAs in a population limit susceptibility to certain RV genotypes, plausibly leading to reduced vaccine efficacy.
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| 5. |
- Vanpouille, Christophe, et al.
(författare)
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The progestin medroxyprogesterone acetate affects HIV-1 production in human lymphoid tissue explants in a dose-dependent and glucocorticoid-like fashion
- 2021
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- The association between the use of the injectable contraceptive depot medroxyprogesterone acetate and HIV-1 susceptibility has been addressed mainly in respect to the changes occurring in the female genital mucosa and blood. However, one of the main sites of HIV-1 pathogenesis is lymphoid organs. To investigate the immunoregulatory effect of medroxyprogesterone acetate (MPA) at this site, human tonsillar tissue explants were infected ex vivo with either a CCR5 (BaL) or CXCR4 (LAI) HIV-1 variant and the release of p24gag and cytokines was measured in culture supernatant. The response to MPA was compared with that elicited by treatment with progesterone (P4) and dexamethasone (DEX), which selectively binds the glucocorticoid receptor, in donor-matched explant cultures. MPA treatment reduced the replication of both tested HIV-1 strains as well as the production of the mediators of inflammation IL-1β, IL-17A and CCL5, but not CCL20, in a similar way to DEX, whereas P4 had no effect on HIV-1 replication. The magnitude of both MPA and DEX-mediated responses was proportional to the length of exposure and/or administered dose. Blockage of the progesterone and glucocorticoid receptors with mifepristone abolished all observed changes in HIV-1 and cytokine production, and was associated with increased IL-22 levels in HIV-infected explants. Our data indicate that elevated doses of MPA may affect the immune responses in lymphoid tissue in a glucocorticoid-like fashion with an immediate impact on local HIV-1 replication.
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