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

Chrispin Chaguza; Marie Yang; Jennifer E. Cornick; Mignon du Plessis; Rebecca A. Gladstone; Brenda A. Kwambana-Adams; Stephanie W. Lo; Chinelo Ebruke; Gerry Tonkin-Hill; Chikondi Peno; Madikay Senghore; Stephen K. Obaro; Sani Ousmane; Gerd Pluschke; Jean Marc Collard; Betuel Sigaùque; Neil French; Keith P. Klugman; Robert S. Heyderman; Lesley McGee; Martin Antonio; Robert F. Breiman; Anne von Gottberg; Dean B. Everett; Aras Kadioglu; Stephen D. Bentley

doi:10.1038/s42003-020-01290-9

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

Chrispin Chaguza, Marie Yang, Jennifer E. Cornick, Mignon du Plessis, Rebecca A. Gladstone, Brenda A. Kwambana-Adams, Stephanie W. Lo, Chinelo Ebruke, Gerry Tonkin-Hill, Chikondi Peno, Madikay Senghore, Stephen K. Obaro, Sani Ousmane, Gerd Pluschke, Jean Marc Collard, Betuel Sigaùque, Neil French, Keith P. Klugman, Robert S. Heyderman, Lesley McGeeMartin Antonio, Robert F. Breiman, Anne von Gottberg, Dean B. Everett, Aras Kadioglu, Stephen D. Bentley

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	559
Journal	Communications biology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-01290-9
State	Published - Dec 1 2020

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Medicine (miscellaneous)
Medicine(all)

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Chaguza, C., Yang, M., Cornick, J. E., du Plessis, M., Gladstone, R. A., Kwambana-Adams, B. A., Lo, S. W., Ebruke, C., Tonkin-Hill, G., Peno, C., Senghore, M., Obaro, S. K., Ousmane, S., Pluschke, G., Collard, J. M., Sigaùque, B., French, N., Klugman, K. P., Heyderman, R. S., ... Bentley, S. D. (2020). Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism. Communications biology, 3(1), [559]. https://doi.org/10.1038/s42003-020-01290-9

Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism. / Chaguza, Chrispin; Yang, Marie; Cornick, Jennifer E.; du Plessis, Mignon; Gladstone, Rebecca A.; Kwambana-Adams, Brenda A.; Lo, Stephanie W.; Ebruke, Chinelo; Tonkin-Hill, Gerry; Peno, Chikondi; Senghore, Madikay; Obaro, Stephen K.; Ousmane, Sani; Pluschke, Gerd; Collard, Jean Marc; Sigaùque, Betuel; French, Neil; Klugman, Keith P.; Heyderman, Robert S.; McGee, Lesley; Antonio, Martin; Breiman, Robert F.; von Gottberg, Anne; Everett, Dean B.; Kadioglu, Aras; Bentley, Stephen D.

In: Communications biology, Vol. 3, No. 1, 559, 01.12.2020.

Research output: Contribution to journal › Article › peer-review

Chaguza, C, Yang, M, Cornick, JE, du Plessis, M, Gladstone, RA, Kwambana-Adams, BA, Lo, SW, Ebruke, C, Tonkin-Hill, G, Peno, C, Senghore, M, Obaro, SK, Ousmane, S, Pluschke, G, Collard, JM, Sigaùque, B, French, N, Klugman, KP, Heyderman, RS, McGee, L, Antonio, M, Breiman, RF, von Gottberg, A, Everett, DB, Kadioglu, A & Bentley, SD 2020, 'Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism', Communications biology, vol. 3, no. 1, 559. https://doi.org/10.1038/s42003-020-01290-9

Chaguza, Chrispin ; Yang, Marie ; Cornick, Jennifer E. ; du Plessis, Mignon ; Gladstone, Rebecca A. ; Kwambana-Adams, Brenda A. ; Lo, Stephanie W. ; Ebruke, Chinelo ; Tonkin-Hill, Gerry ; Peno, Chikondi ; Senghore, Madikay ; Obaro, Stephen K. ; Ousmane, Sani ; Pluschke, Gerd ; Collard, Jean Marc ; Sigaùque, Betuel ; French, Neil ; Klugman, Keith P. ; Heyderman, Robert S. ; McGee, Lesley ; Antonio, Martin ; Breiman, Robert F. ; von Gottberg, Anne ; Everett, Dean B. ; Kadioglu, Aras ; Bentley, Stephen D. / Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism. In: Communications biology. 2020 ; Vol. 3, No. 1.

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

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.",

author = "Chrispin Chaguza and Marie Yang and Cornick, {Jennifer E.} and {du Plessis}, Mignon and Gladstone, {Rebecca A.} and Kwambana-Adams, {Brenda A.} and Lo, {Stephanie W.} and Chinelo Ebruke and Gerry Tonkin-Hill and Chikondi Peno and Madikay Senghore and Obaro, {Stephen K.} and Sani Ousmane and Gerd Pluschke and Collard, {Jean Marc} and Betuel Siga{\`u}que and Neil French and Klugman, {Keith P.} and Heyderman, {Robert S.} and Lesley McGee and Martin Antonio and Breiman, {Robert F.} and {von Gottberg}, Anne and Everett, {Dean B.} and Aras Kadioglu and Bentley, {Stephen D.}",

note = "Funding Information: We thank the clinical and laboratory teams at the collaborating institutions, and the sequencing and informatics teams at the Wellcome Sanger Institute. We are also grateful for the insightful feedback on the manuscript provided by Dr. Bernard Beall and Dr. Allen S. Craig at the Centers for Disease Control and Prevention (CDC) in the US. 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.",

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AU - Chaguza, Chrispin

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AU - Cornick, Jennifer E.

AU - du Plessis, Mignon

AU - Gladstone, Rebecca A.

AU - Kwambana-Adams, Brenda A.

AU - Lo, Stephanie W.

AU - Ebruke, Chinelo

AU - Tonkin-Hill, Gerry

AU - Peno, Chikondi

AU - Senghore, Madikay

AU - Obaro, Stephen K.

AU - Ousmane, Sani

AU - Pluschke, Gerd

AU - Collard, Jean Marc

AU - Sigaùque, Betuel

AU - French, Neil

AU - Klugman, Keith P.

AU - Heyderman, Robert S.

AU - McGee, Lesley

AU - Antonio, Martin

AU - Breiman, Robert F.

AU - von Gottberg, Anne

AU - Everett, Dean B.

AU - Kadioglu, Aras

AU - Bentley, Stephen D.

N1 - Funding Information: We thank the clinical and laboratory teams at the collaborating institutions, and the sequencing and informatics teams at the Wellcome Sanger Institute. We are also grateful for the insightful feedback on the manuscript provided by Dr. Bernard Beall and Dr. Allen S. Craig at the Centers for Disease Control and Prevention (CDC) in the US. 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.

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N2 - 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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