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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.

SUBMITTER: Chaguza C

PROVIDER: S-EPMC7545184 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pneumococcal conjugate vaccination has proved highly effective in eliminating vaccine-type pneumococcal carriage and disease. However, the potential adverse effects of serotype replacement remain a major concern when implementing routine childhood pneumococcal conjugate vaccination programmes. Applying a concise predictive model, we present a ready-to-use quantitative tool to investigate the implications of serotype replacement on the net effectiveness of vaccination against invasive pneumococcal disease (IPD) and to guide in the selection of optimal vaccine serotype compositions. We utilise pre-vaccination data on pneumococcal carriage and IPD and assume partial or complete elimination of vaccine-type carriage, its replacement by non-vaccine-type carriage, and stable case-to-carrier ratios (probability of IPD per carriage episode). The model predicts that the post-vaccination IPD incidences in Finland for currently available vaccine serotype compositions can eventually decrease among the target age group of children <5 years of age by 75%. However, due to replacement through herd effects, the decrease among the older population is predicted to be much less (20-40%). We introduce a sequential algorithm for the search of optimal serotype compositions and assess the robustness of inferences to uncertainties in data and assumptions about carriage and IPD. The optimal serotype composition depends on the age group of interest and some serotypes may be highly beneficial vaccine types in one age category (e.g. 6B in children), while being disadvantageous in another. The net effectiveness will be improved only if the added serotype has a higher case-to-carrier ratio than the average case-to-carrier ratio of the current non-vaccine types and the degree of improvement in effectiveness depends on the carriage incidence of the serotype. The serotype compositions of currently available pneumococcal vaccines are not optimal and the effectiveness of vaccination in the population at large could be improved by including new serotypes in the vaccine (e.g. 22 and 9N).

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

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