Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism

• Type of Material: Article
• Authors: Chrispin Chaguza, Wellcome Sanger Institute; Marie Yang, University of Liverpool; Jennifer E. Cornick, University of Liverpool; Mignon du Plessis, National Institute for Communicable Diseases; Rebecca A. Gladstone, Wellcome Sanger Institute; Brenda A. Kwambana-Adams, University College London; Stephanie W. Lo, Wellcome Sanger Institute; Chinelo Ebruke, London School of Hygiene & Tropical Medicine; Gerry Tonkin-Hill, Wellcome Sanger Institute; Chikondi Peno, Malawi Liverpool Wellcome Trust Clinic Research Programm; Madikay Senghore, London School of Hygiene & Tropical Medicine; Stephen K. Obaro, University of Nebraska; Sani Ousmane, Centre de Recherche Médicale et Sanitaire; Gerd Pluschke, Swiss Tropical and Public Health Institute; Jean-Marc Collard, Centre de Recherche Médicale et Sanitaire; Betuel Sigauque, Centro de Investigação em Saúde da Manhiça; Neil French, University of Liverpool; Keith Klugman, Emory University; Robert S. Heyderman, Malawi Liverpool Wellcome Trust Clin Res Programm; Lesley McGee, Centers for Disease Control and Prevention; Martin Antonio, London School of Hygiene & Tropical Medicine; Robert Breiman, Emory University; Anne von Gottberg, National Institute for Communicable Diseases; Dean B. Everett, Malawi Liverpool Wellcome Trust Clinic Research Programm; Aras Kadioglu, University of Liverpool; Stephen D. Bentley, Wellcome Sanger Institute
• Language: English
• Date: 2020-10-08
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s42003-020-01290-9
• Title of Journal or Parent Work: COMMUNICATIONS BIOLOGY
• Volume: 3
• Issue: 1
• Start Page: 559
• End Page: 559
• Grant/Funding Information: This study was funded by the Bill and Melinda Gates Foundation (grant number: OPP1023440 and OPP1034556). C.C., G.T. and S.D.B. were supported by funding from the Joint Programme Initiative for Antimicrobial Resistance (JPIAMR). The contents of this paper are solely the responsibility of the authors and does not necessarily represent the official views of their affiliated institutions and the funding agencies.
• Keywords: INVASIVE-DISEASE; Science & Technology - Other Topics; Life Sciences & Biomedicine - Other Topics; VIRUS; AFFINITY LAMININ RECEPTOR; Multidisciplinary Sciences; OUTBREAK; STREPTOCOCCUS-PNEUMONIAE SEROTYPE-1; VACCINE; SURFACE PROTEIN; Biology; PSPC; Life Sciences & Biomedicine; CHILDREN; Science & Technology; MENINGITIS
• Research Categories: Health Sciences, Immunology; Health Sciences, Public Health; Biology, Virology

Abstract

Hyper-virulent Streptococcus pneumoniae serotype 1 strains are endemic in Sub-Saharan Africa and frequently cause lethal meningitis outbreaks. It remains unknown whether genetic variation in serotype 1 strains modulates tropism into cerebrospinal fluid to cause central nervous system (CNS) infections, particularly meningitis. Here, we address this question through a large-scale linear mixed model genome-wide association study of 909 African pneumococcal serotype 1 isolates collected from CNS and non-CNS human samples. By controlling for host age, geography, and strain population structure, we identify genome-wide statistically significant genotype-phenotype associations in surface-exposed choline-binding (P = 5.00 × 10−08) and helicase proteins (P = 1.32 × 10−06) important for invasion, immune evasion and pneumococcal tropism to CNS. The small effect sizes and negligible heritability indicated that causation of CNS infection requires multiple genetic and other factors reflecting a complex and polygenic aetiology. Our findings suggest that certain pathogen genetic variation modulate pneumococcal survival and tropism to CNS tissue, and therefore, virulence for meningitis.