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Sheng, Nongfei
Publications (7 of 7) Show all publications
Sheng, N., Mårell, L., Tumkur Sitaram, R., Svensäter, G., Westerlund, A. & Strömberg, N. (2024). Human PRH1, PRH2 susceptibility and resistance and Streptococcus mutans virulence phenotypes specify different microbial profiles in caries. EBioMedicine, 101, Article ID 105001.
Open this publication in new window or tab >>Human PRH1, PRH2 susceptibility and resistance and Streptococcus mutans virulence phenotypes specify different microbial profiles in caries
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2024 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 101, article id 105001Article in journal (Refereed) Published
Abstract [en]

Background: Lifestyle- and sucrose-dependent polymicrobial ecological shifts are a primary cause of caries in populations with high caries prevalence. In populations with low prevalence, PRH1, PRH2 susceptibility and resistance phenotypes may interact with the Streptococcus mutans adhesin cariogenicity phenotype to affect caries progression, but studies are lacking on how these factors affect the microbial profile of caries.

Methods: We analysed how the residency and infection profiles of S. mutans adhesin (SpaP A/B/C and Cnm/Cbm) phenotypes and commensal streptococci and lactobacilli influenced caries progression in a prospective case–referent sample of 452 Swedish adolescents with high (P4a), moderate (P6), and low (P1) caries PRH1, PRH2 phenotypes. Isolates of S. mutans from participants were analysed for adhesin expression and glycosylation and in vitro and in situ mechanisms related to caries activity.

Findings: Among adolescents with the resistant (P1) phenotype, infection with S. mutans high-virulence phenotypes was required for caries progression. In contrast, with highly (P4a) or moderately (P6) susceptible phenotypes, caries developed from a broader polymicrobial flora that included moderately cariogenic oral commensal streptococci and lactobacilli and S. mutans phenotypes. High virulence involved unstable residency and fluctuating SpaP ABC, B-1, or Cnm expression/glycosylation phenotypes, whereas low/moderate virulence involved SpaP A phenotypes with stable residency. Adhesin phenotypes did not display changes in individual host residency but were paired within individuals and geographic regions.

Interpretation: These results suggest that receptor PRH1, PRH2 susceptibility and resistance and S. mutans adhesin virulence phenotypes specify different microbial profiles in caries. Funding: Swedish Research Council and funding bodies listed in the acknowledgement section.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Adhesion, Caries, Commensal pathogen, Host susceptibility, PRH1/PRH2, Streptococcus mutans
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-221645 (URN)10.1016/j.ebiom.2024.105001 (DOI)38364699 (PubMedID)2-s2.0-85185567071 (Scopus ID)
Funder
Swedish Research CouncilRegion VästerbottenSwedish Dental AssociationUmeå University
Available from: 2024-03-06 Created: 2024-03-06 Last updated: 2024-03-06Bibliographically approved
Sheng, N. (2023). Revisiting dental caries as an immunodeficiency disorder. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Revisiting dental caries as an immunodeficiency disorder
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Karies som en immunbristsjukdom?
Abstract [en]

Worldwide, dental caries is the major human chronic disease, with billions of people affected in terms of life quality impairment and high society costs that consumes 5-10% of the global healthcare budget. In Western countries dental caries has declined dramatically, with a trajectory of 15% high-risk individuals with recurrent caries and a non-responder behavior to standard prevention. This dissertation work focuses on revisiting the primary causes of caries development by exploring human and Streptococcus mutans genetic variation in a prospective case-control sample of 452 Swedish adolescents followed from 12 and 17 years of age.

Genetic variation of PRH1 and PRH2, encoding acidic proline-rich protein receptors for indigenous oral streptococci and actinomycetes, specified high (P4a), moderate (P6) and low (P1) caries phenotypes of different risk and causal profiles (Paper I). Susceptible individuals thus classified into the immunodeficiency caries type (P4a) or the lifestyle caries type (P1) that accounted for naturally resistant individuals. Orthodontic treatment during adolescence exerted a further negative load that resulted in an even bigger difference in caries progression between P4a and P1 individuals. Importantly, immunodeficiency P4a individuals were identified as risk individuals at the clinic and therefore given extra fluoride.

Adhesin gene variation in S. mutans specified SpaP A/B/C and Cnm/Cbm adhesion types that matched individual caries progression (Paper II). The saliva/DMBT1 binding avidity of high cariogenicity SpaP and Cnm but not of low cariogenicity SpaP A types correlated positively with the caries activity of the individual strain donor. SpaP-guided MLST typing also revealed SpaP A/B/C biotypes with high SpaP B and low SpaP A cariogenicity lineages that besides adhesion differed in acid production and acid tolerance properties. The SpaP A/B/C receptor-binding V-regions had markedly different structures. 

In paper III, we found unstable residency of a mixed and fluctuating SpaP A/B/C adhesion mode, a high cariogenicity SpaP B-1 subtype and Cnm adhesin expression and glycosylation to contribute to mono-microbial caries progression in naturally resistant low caries P1 phenotypes. By, contrast, moderate- and high-caries P6 and P4a phenotypes contributed to poly- and meta-microbial caries progression. In addition, the S. mutans adhesion types showed specificity (tropism) for individual hosts and plausible family distribution patterns.

DMBT1 protein size isoforms I-III predicted caries progression but differently in the PRH1/PRH2 genetic background and influenced the infection profile of S. mutans adhesion and virulence types (Paper IV). Caries progression increased as DMBT1 isoform size decreased in the order of isoform I > II > III, suggesting that loss of the large isoform III glycotype may impair immunity. The finding that DMBT1 isoform variation did not add predictive power to the P4a+ but to P4a- phenotypes allowed a novel sick and health classification system.

In conclusion, PRH1, PRH2 may represent a pattern recognition and immunity pathway for tooth homeostasis and formation of the indigenous flora on teeth. It can predict prospective caries risk and might be implemented in caries prevention based on genetic risk and cause at the clinical level. DMBT1 appears as an evolutionary different but intertwined immunity pathway for surveillance of infectious agents in general at teeth and mucosal surfaces. The S. mutans organism is heterogenous with biotypes and lineages that match individual caries development. Narrowing both S. mutans and PRH1, PRH2 phenotypes suggest a mono- (P1), poly- (P6) and even meta- (P4a) microbial characters of dental caries.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 88
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 150
Keywords
caries, immunodeficiency, proline-rich proteins, DMBT1, S. mutans, adhesin, SpaP, Cnm, Cbm, collagen binding, caries risk stratification, precision dentistry
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-208357 (URN)978-91-8070-106-8 (ISBN)978-91-8070-107-5 (ISBN)
Public defence
2023-06-13, Hörsal B, 9 tr, Byggnad 1D, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-05-25 Created: 2023-05-22 Last updated: 2023-05-23Bibliographically approved
Alharbi, A. F., Sheng, N., Nicol, K., Strömberg, N. & Hollox, E. J. (2022). Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions. iScience, 25(5), Article ID 104189.
Open this publication in new window or tab >>Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions
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2022 (English)In: iScience, E-ISSN 2589-0042 , Vol. 25, no 5, article id 104189Article in journal (Refereed) Published
Abstract [en]

Discovering loci under balancing selection in humans can identify loci with alleles that affect response to the environment and disease. Genome variation data have identified the 5′ region of the DMBT1 gene as undergoing balancing selection in humans. DMBT1 encodes the pattern-recognition glycoprotein DMBT1, also known as SALSA, gp340, or salivary agglutinin. DMBT1 binds to a variety of pathogens through a tandemly arranged scavenger receptor cysteine-rich (SRCR) domain, with the number of domains polymorphic in humans. We show that the signal of balancing selection is driven by one haplotype usually carrying a shorter SRCR repeat and another usually carrying a longer SRCR repeat. DMBT1 encoded by a shorter SRCR repeat allele does not bind a cariogenic and invasive Streptococcus mutans strain, in contrast to the long SRCR allele that shows binding. Our results suggest that balancing selection at DMBT1 is due to host-microbe interactions of encoded SRCR tandem repeat alleles.

Place, publisher, year, edition, pages
Cell Press, 2022
Keywords
biological sciences, evolutionary mechanisms, genetics
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-194336 (URN)10.1016/j.isci.2022.104189 (DOI)000826167700008 ()2-s2.0-85128260749 (Scopus ID)
Available from: 2022-05-04 Created: 2022-05-04 Last updated: 2023-09-05Bibliographically approved
Strömberg, N., Esberg, A., Sheng, N., Mårell, L., Löfgren-Burström, A., Danielsson, K. & Källestål, C. (2017). Genetic- and Lifestyle-dependent Dental Caries Defined by the Acidic Proline-rich Protein Genes PRH1 and PRH2. EBioMedicine, 26, 38-46
Open this publication in new window or tab >>Genetic- and Lifestyle-dependent Dental Caries Defined by the Acidic Proline-rich Protein Genes PRH1 and PRH2
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2017 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 26, p. 38-46Article in journal (Refereed) Published
Abstract [en]

Dental caries is a chronic infectious disease that affects billions of people with large individual differences in activity. We investigated whether PRH1 and PRH2 polymorphisms in saliva acidic proline-rich protein (PRP) receptors for indigenous bacteria match and predict individual differences in the development of caries. PRH1 and PRH2 variation and adhesion of indigenous and cariogenic (Streptococcus mutans) model bacteria were measured in 452 12-year-old Swedish children along with traditional risk factors and related to caries at baseline and after 5-years. The children grouped into low-to-moderate and high susceptibility phenotypes for caries based on allelic PRH1, PRH2 variation. The low-to-moderate susceptibility children (P1 and P4a-) experienced caries from eating sugar or bad oral hygiene or infection by S. mutans. The high susceptibility P4a (Db, PIF, PRP12) children had more caries despite receiving extra prevention and irrespective of eating sugar or bad oral hygiene or S. mutans-infection. They instead developed 3.9-fold more caries than P1 children from plaque accumulation in general when treated with orthodontic multibrackets; and had basic PRP polymorphisms and low DMBT1-mediated S. mutans adhesion as additional susceptibility traits. The present findings thus suggest genetic autoimmune-like (P4a) and traditional life style (P1) caries, providing a rationale for individualized oral care.

Keywords
Acidic proline-rich proteins, Chronic infections, Dental caries, Host susceptibility, PRH1, PRH2
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-143131 (URN)10.1016/j.ebiom.2017.11.019 (DOI)29191562 (PubMedID)2-s2.0-85035200649 (Scopus ID)
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2023-05-22Bibliographically approved
Esberg, A., Sheng, N., Mårell, L., Claesson, R., Persson, K., Borén, T. & Strömberg, N. (2017). Streptococcus Mutans Adhesin Biotypes that Match and Predict Individual Caries Development. EBioMedicine, 24, 205-215
Open this publication in new window or tab >>Streptococcus Mutans Adhesin Biotypes that Match and Predict Individual Caries Development
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2017 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 24, p. 205-215Article in journal (Refereed) Published
Abstract [en]

Dental caries, which affects billions of people, is a chronic infectious disease that involves Streptococcus mutans, which is nevertheless a poor predictor of individual caries development. We therefore investigated if adhesin types of S.mutans with sucrose-independent adhesion to host DMBT1 (i.e. SpaP A, B or C) and collagen (i.e. Cnm, Cbm) match and predict individual differences in caries development. The adhesin types were measured in whole saliva by qPCR in 452 12-year-old Swedish children and related to caries at baseline and prospectively at a 5-year follow-up. Strains isolated from the children were explored for genetic and phenotypic properties. The presence of SpaP B and Cnm subtypes coincided with increased 5-year caries increment, and their binding to DMBT1 and saliva correlated with individual caries scores. The SpaP B subtypes are enriched in amino acid substitutions that coincided with caries and binding and specify biotypes of S. mutans with increased acid tolerance. The findings reveal adhesin subtypes of S. mutans that match and predict individual differences in caries development and provide a rationale for individualized oral care.

Keywords
Adhesion, Chronic infections, Dental caries, SpaP, Streptococcus mutans, Virulence
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-140203 (URN)10.1016/j.ebiom.2017.09.027 (DOI)000414392900033 ()28958656 (PubMedID)2-s2.0-85029795020 (Scopus ID)
Funder
Swedish Research Council, 10906
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2023-05-22Bibliographically approved
Sheng, N., Westerlund, A., Mårell, L., Österrman, L., Hollox, E., Larsson, P. & Strömberg, N.DMBT1 protein isoform and genetic polymorphisms that allow prediction and classification of individual caries progression.
Open this publication in new window or tab >>DMBT1 protein isoform and genetic polymorphisms that allow prediction and classification of individual caries progression
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(English)Manuscript (preprint) (Other academic)
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-208347 (URN)
Available from: 2023-05-22 Created: 2023-05-22 Last updated: 2023-05-22
Sheng, N., Mårell, L., Sitaram, R. T., Svensäter, G., Westerlund, A. & Strömberg, N.Narrowed Streptococcus mutans adhesion and human receptor phenotypes that match mono-, poly- and metamicrobial characters of dental caries.
Open this publication in new window or tab >>Narrowed Streptococcus mutans adhesion and human receptor phenotypes that match mono-, poly- and metamicrobial characters of dental caries
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(English)Manuscript (preprint) (Other academic)
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-208346 (URN)
Available from: 2023-05-22 Created: 2023-05-22 Last updated: 2023-05-22
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