| 11. |
- Ghorbani, Mahin, et al.
(author)
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Persistence of salivary antibody responses after COVID-19 vaccination is associated with oral microbiome variation in both healthy and people living with HIV
- 2023
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Journal article (peer-reviewed)abstract
- Coevolution of microbiome and immunity at mucosal sites is essential for our health. Whether the oral microbiome, the second largest community after the gut, contributes to the immunogenicity of COVID-19 vaccines is not known. We investigated the baseline oral microbiome in individuals in the COVAXID clinical trial receiving the BNT162b2 mRNA vaccine. Participants (n=115) included healthy controls (HC; n=57) and people living with HIV (PLHIV; n=58) who met the study selection criteria. Vaccine-induced Spike antibodies in saliva and serum from 0 to 6 months were assessed and comparative analyses were performed against the individual salivary 16S ASV microbiome diversity. High- versus low vaccine responders were assessed on general, immunological, and oral microbiome features. Our analyses identified oral microbiome features enriched in high- vs. low-responders among healthy and PLHIV participants. In low-responders, an enrichment of Gram-negative, anaerobic species with proteolytic activity were found including Campylobacter, Butyrivibrio, Selenomonas, Lachnoanaerobaculum, Leptotrichia, Megasphaera, Prevotella and Stomatobaculum. In high-responders, enriched species were mainly Gram-positive and saccharolytic facultative anaerobes: Abiotrophia, Corynebacterium, Gemella, Granulicatella, Rothia, and Haemophilus. Combining identified microbial features in a classifier using the area under the receiver operating characteristic curve (ROC AUC) yielded scores of 0.879 (healthy controls) to 0.82 (PLHIV), supporting the oral microbiome contribution in the long-term vaccination outcome. The present study is the first to suggest that the oral microbiome has an impact on the durability of mucosal immunity after Covid-19 vaccination. Microbiome-targeted interventions to enhance long-term duration of mucosal vaccine immunity may be exploited.
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| 12. |
- Healy, Katie, et al.
(author)
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Salivary IgG to SARS-CoV-2 indicates seroconversion and correlates to serum neutralization in mRNA-vaccinated immunocompromised individuals
- 2022
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In: Med. - : Cell Press. - 2666-6359 .- 2666-6340. ; 3:2, s. 137-153.e3
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Journal article (peer-reviewed)abstract
- Background: Immunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves oral cavity, a primary site of infection, is presently unknown.Methods: Immunocompromised patients (n = 404) and healthy controls (n = 82) participated in a prospective clinical trial (NCT04780659) encompassing two doses of the mRNA BNT162b2 vaccine. Primary immunodeficiency (PID), secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL) patients were included. Salivary and serum immunoglobulin G (IgG) reactivities to SARS-CoV-2 spike were measured by multiplex bead-based assays and Elecsys anti-SARS-CoV-2 S assay.Findings: IgG responses to SARS-CoV-2 spike antigens in saliva in HIV and HSCT/CAR-T groups were comparable to those of healthy controls after vaccination. The PID, SOT, and CLL patients had weaker responses, influenced mainly by disease parameters or immunosuppressants. Salivary responses correlated remarkably well with specific IgG titers and the neutralizing capacity in serum. Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded area under the curve (AUC) = 0.95 and positive predictive value (PPV) = 90.7% for the entire cohort after vaccination.Conclusions: Saliva conveys vaccine responses induced by mRNA BNT162b2. The predictive power of salivary spike IgG makes it highly suitable for screening vulnerable groups for revaccination.
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| 13. |
- Iovino, Federico, et al.
(author)
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pIgR and PEC AM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion
- 2017
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 214:6, s. 1619-1630
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Journal article (peer-reviewed)abstract
- Streptococcus pneumoniae is the main cause of bacterial meningitis, a life-threating disease with a high case fatality rate despite treatment with antibiotics. Pneumococci cause meningitis by invading the blood and penetrating the blood-brain barrier (BBB). Using stimulated emission depletion (STED) super-resolution microscopy of brain biopsies from patients who died of pneumococcal meningitis, we observe that pneumococci colocalize with the two BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1). We show that the major adhesin of the pneumococcal pilus-1, RrgA, binds both receptors, whereas the choline binding protein PspC binds, but to a lower extent, only pIgR. Using a bacteremia-derived meningitis model and mutant mice, as well as antibodies against the two receptors, we prevent pneumococcal entry into the brain and meningitis development. By adding antibodies to antibiotic (ceftriaxone)-treated mice, we further reduce the bacterial burden in the brain. Our data suggest that inhibition of pIgR and PECAM-1 has the potential to prevent pneumococcal meningitis.
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| 14. |
- Lagerqvist, Nina, et al.
(author)
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Evaluation of 11 SARS-CoV-2 antibody tests by using samples from patients with defined IgG antibody titers
- 2021
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- We evaluated the performance of 11 SARS-CoV-2 antibody tests using a reference set of heat-inactivated samples from 278 unexposed persons and 258 COVID-19 patients, some of whom contributed serial samples. The reference set included samples with a variation in SARS-CoV-2 IgG antibody titers, as determined by an in-house immunofluorescence assay (IFA). The five evaluated rapid diagnostic tests had a specificity of 99.0% and a sensitivity that ranged from 56.3 to 81.6% and decreased with low IFA IgG titers. The specificity was > 99% for five out of six platform-based tests, and when assessed using samples collected ≥ 22 days after symptom onset, two assays had a sensitivity of > 96%. These two assays also detected samples with low IFA titers more frequently than the other assays. In conclusion, the evaluated antibody tests showed a heterogeneity in their performances and only a few tests performed well with samples having low IFA IgG titers, an important aspect for diagnostics and epidemiological investigations.
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| 15. |
- Muschiol, Sandra, et al.
(author)
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A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
- 2006
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In: National Academy of Sciences, USA. - Washington : Proceedings of the National Academy of Sciences. ; , s. 14566-71
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Conference paper (other academic/artistic)abstract
- The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3beta to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.
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| 16. |
- Muschiol, Sandra
(author)
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Small molecule inhibitors of type III secretion and their effect on chlamydia development
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Chlamydiae are obligate intracellular pathogens that cause a variety of diseases with clinical and public health importance. Like many Gram-negative bacteria, Chlamydiae employ a type III secretion (T3S) system for invasion and establishment of a protected intracellular niche for successful replication and survival within host cells. Understanding the role of T3S and bacterial effector proteins in Chlamydia infection will provide new insights into chlamydial pathogenesis and is important to identify novel therapeutic targets for drug intervention. In this thesis we employed different small molecule inhibitors of T3S activity in Yersinia, named INPs, and analyzed their effect on Chlamydia development. In addition, we identified and characterized a new family of T3S effector proteins. In paper I, we assessed the effect of INP0400 on C. trachomatis development and invasion. INP0400 caused a dose and growth phase-dependent inhibition of RB multiplication at micromolar concentrations. When INP0400 was given at different stages during the infectious cycle, we observed a partial inhibition of Chlamydia entry, inhibition of translocation of IncG and IncA and a bacterial detachment from the inclusion membrane during the late stage of infection concomitant with an inhibition of RB to EB conversion causing a marked decrease in infectivity. Our data suggest that INPs impair progression through the infectious cycle suggesting that the T3S system is essential for Chlamydia pathogenesis. In paper II, we found that INP0010 displays a strong growth inhibitory effect on C. pneumoniae development, affects translocation of the C. pneumoniae effector proteins IncB and IncC and leads to down-regulation of T3S associated genes collectively suggesting that INP0010 impairs T3S activity in C. pneumoniae. In paper III, we further investigated the effect of INPs on Chlamydia invasion. We show that INPs impair Chlamydia development after entry into host cells because the efficiency of C. trachomatis L2 and C. caviae entry into epithelial cells was not altered in the presence of INPs. Moreover, entry appeared normally with recruitment of actin and the small GTPases Rac, Cdc42 and Arf6 to the bacterial entry site. Finally, in paper IV we set out to identify novel T3S effectors in Chlamydia. We found a family of chlamydial proteins, represented by a C-terminal domain of unknown function referred to as DUF582 that contains an amino-terminal T3S signal. C. trachomatis members of this family were expressed late during the infectious cycle and found to be secreted into the lumen of the inclusion and the cytoplasm of infected cells.
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| 17. |
- Pathak, Anuj, et al.
(author)
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Factor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Streptococcus pneumoniae evades C3-mediated opsonization and effector functions by expressing an immuno-protective polysaccharide capsule and Factor H (FH)-binding proteins. Here we use super-resolution microscopy, mutants and functional analysis to show how these two defense mechanisms are functionally and spatially coordinated on the bacterial cell surface. We show that the pneumococcal capsule is less abundant at the cell wall septum, providing C3/C3b entry to underlying nucleophilic targets. Evasion of C3b deposition at division septa and lateral amplification underneath the capsule requires localization of the FH-binding protein PspC at division sites. Most pneumococcal strains have one PspC protein, but successful lineages in colonization and disease may have two, PspC1 and PspC2, that we show affect virulence differently. We find that spatial localization of these FH-recruiting proteins relative to division septa and capsular layer is instrumental for pneumococci to resist complement-mediated opsonophagocytosis, formation of membrane-attack complexes, and for the function as adhesins.
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| 18. |
- Reithuber, Elisabeth, et al.
(author)
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THCz : Small molecules with antimicrobial activity that block cell wall lipid intermediates
- 2021
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 118:47
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Journal article (peer-reviewed)abstract
- Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate-containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II-binding antibiotics, makes THCz promising scaffolds for development of cell wall-targeting antimicrobials.
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