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Non-diphtheriae Corynebacterium species are associated with decreased risk of pneumococcal colonization during infancy

Abstract

Streptococcus pneumoniae (pneumococcus) is a leading cause of severe infections among children and adults. Interactions between commensal microbes in the upper respiratory tract and S. pneumoniae are poorly described. In this study, we sought to identify interspecies interactions that modify the risk of S. pneumoniae colonization during infancy and to describe development of the upper respiratory microbiome during infancy in a sub-Saharan African setting. We collected nasopharyngeal swabs monthly (0–6 months of age) or bimonthly (6–12 months of age) from 179 mother–infant dyads in Botswana. We used 16S ribosomal RNA gene sequencing to characterize the nasopharyngeal microbiome and identified S. pneumoniae colonization using a species-specific PCR assay. We detect S. pneumoniae colonization in 144 (80%) infants at a median age of 71 days and identify a strong negative association between the relative abundance of the bacterial genera Corynebacterium within the infant nasopharyngeal microbiome and the risk of S. pneumoniae colonization. Using in vitro cultivation experiments, we demonstrate growth inhibition of S. pneumoniae by secreted factors from strains of several Corynebacterium species isolated from these infants. Finally, we demonstrate that antibiotic exposures and the winter season are associated with a decline in the relative abundance of Corynebacterium within the nasopharyngeal microbiome, while breastfeeding is associated with an increase in the Corynebacterium relative abundance. Our findings provide novel insights into the interspecies interactions that contribute to colonization resistance to S. pneumoniae and suggest that the nasopharyngeal microbiome may be a previously unrecognized mechanism by which environmental factors influence the risk of pneumococcal infections during childhood. Moreover, this work lays the foundation for future studies seeking to use targeted manipulation of the nasopharyngeal microbiome to prevent infections caused by S. pneumoniae.

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Fig. 1: Alpha diversity of the nasopharyngeal microbiome among mother–infant dyads in Botswana.
Fig. 2: Composition of the nasopharyngeal microbiome among mother–infant dyads in Botswana.
Fig. 3: State transitions of the nasopharyngeal microbiome during infancy.
Fig. 4: Associations between environmental exposures and the composition of the nasopharyngeal microbiome during infancy.
Fig. 5: Strain-specific inhibition of pneumococcal growth by Corynebacterium.

Availability of data and materials

The sequencing dataset supporting the conclusions of this study is available in the Sequence Read Archive (PRJNA698366). The statistical files and script used for data analyses are also publicly available (https://github.com/mskelly7/Coryne_Sp_manuscript).

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Acknowledgements

We would like to thank Copan Italia (Brescia, Italy) for the donation of the MSwab media and flocked swabs used in the collection of nasopharyngeal specimens. We also thank the Duke University School of Medicine for the use of the Microbiome Core Facility, which performed the DNA extractions for this research. We offer sincere gratitude to the children and families who participated in this research.

Funding

This research was supported by a Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene Postdoctoral Fellowship in Tropical Infectious Diseases, by Children’s Hospital of Philadelphia and the Pincus Family Foundation, and through core services from the Penn Center for AIDS Research, a National Institutes of Health (NIH)-funded program (P30-AI045008). MSK and CKC received financial support from the NIH through the Duke Center for AIDS Research (P30-AI064518). MSK was supported by a NIH Career Development Award (K23-AI135090) and a research grant from the Society for Pediatric Research. PCS received funding from the NIH through a Research Project Grant (7R01-GM108494). SMP was supported by a VECD Global Health Fellowship, funded by the Office of AIDS Research and the Fogarty International Center of the NIH (D43-TW009337). APS and TAM received financial support from the NIH through the Penn Center for AIDS Research (P30-AI045008).

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MSK, APS, TA, KAF, JFR SSS, CKC and PCS contributed to the study concept and design. MSK, CP, YY, JNA, SMP, JHH, RRY, MS, SB, TL, TM, MZP, JJ, CRP collected the data or assisted with data analysis or interpretation. MSK drafted the paper and all other authors revised it critically for important intellectual content. All authors approved of the final version of the paper.

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Correspondence to Matthew S. Kelly.

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The authors declare no competing interests.

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This study was approved by the Botswana Ministry of Health, the Princess Marina Hospital ethics committee, and institutional review boards at the University of Pennsylvania, Duke University, and McMaster University. Written informed consent was obtained from all participants or their legal guardians.

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Kelly, M.S., Plunkett, C., Yu, Y. et al. Non-diphtheriae Corynebacterium species are associated with decreased risk of pneumococcal colonization during infancy. ISME J (2021). https://doi.org/10.1038/s41396-021-01108-4

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