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

Chaguza, ChrispinORCID logo; Yang, Marie; Cornick, Jennifer E; du Plessis, MignonORCID logo; Gladstone, Rebecca A; Kwambana-Adams, Brenda A; Lo, Stephanie W; Ebruke, Chinelo; Tonkin-Hill, GerryORCID logo; Peno, Chikondi; +16 more...Senghore, Madikay; Obaro, Stephen K; Ousmane, Sani; Pluschke, Gerd; Collard, Jean-Marc; Sigaùque, Betuel; French, Neil; Klugman, Keith P; Heyderman, Robert S; McGee, LesleyORCID logo; Antonio, MartinORCID logo; Breiman, Robert F; von Gottberg, Anne; Everett, Dean B; Kadioglu, Aras; and Bentley, Stephen DORCID logo (2020) Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism. Communications biology, 3 (1). 559-. ISSN 2399-3642 DOI: 10.1038/s42003-020-01290-9
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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.


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