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

Chrispin Chaguza (1, 2) , Marie Yang (3) , Jennifer E. Cornick (3, 4) , Mignon Du Plessis (5, 6) , Rebecca A. Gladstone (1) , Brenda A. Kwambana-Adams (7, 8) , Stephanie W. Lo (1) , Chinelo Ebruke (8) , Gerry Tonkin-Hill (1) , Chikondi Peno (4, 9) , Madikay Senghore (8, 10) , Stephen K. Obaro (11, 12) , Sani Ousmane (13) , Gerd Pluschke (14) , Jean-Marc Collard (13) , Betuel Sigaùque (15) , Neil French (3) , Keith P. Klugman (16) , Robert S. Heyderman (4, 7) , Lesley Mcgee (17) , Martin Antonio (8, 18) , Robert F. Breiman (16) , Anne von Gottberg (5, 6) , Dean B. Everett (4, 9) , Aras Kadioglu (3) , Stephen D. Bentley (1, 2)

1 The Wellcome Trust Sanger Institute [Cambridge]
2 CAM - University of Cambridge [UK]
3 University of Liverpool
4 MLW - Malawi Liverpool Wellcome Trust Clinical Research Programme
5 NICD - National Institute for Communicable Diseases [Johannesburg]
6 WITS - University of the Witwatersrand [Johannesburg]
7 UCL - University College of London [London]
8 MRC - Medical Research Council Unit The Gambia
9 Edin. - University of Edinburgh
10 Harvard T.H. Chan School of Public Health
11 University of Nebraska Medical Center
12 IFAIN - International Foundation Against Infectious Diseases in Nigeria
13 CERMES - Centre de Recherche Médicale et Sanitaire (Niamey, Niger)
14 Swiss Tropical and Public Health Institute [Basel]
15 CISM - Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique]
16 Emory University [Atlanta, GA]
17 CDC - Centers for Disease Control and Prevention [Atlanta]
18 University of Warwick [Coventry]

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.

Domaines: Maladies infectieuses; Bactériologie; Santé publique et épidémiologie

Chrispin Chaguza, Marie Yang, Jennifer E. Cornick, Mignon Du Plessis, Rebecca A. Gladstone, et al.. Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism. Communications Biology, 2020, 3 (1), pp.559. ⟨10.1038/s42003-020-01290-9⟩. ⟨pasteur-03238211⟩