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.
Highlights
Hyper-virulent Streptococcus pneumoniae serotype 1 strains are endemic in Sub-Saharan Africa and frequently cause lethal meningitis outbreaks
We identified 34 sequence types (ST) inferred from whole-genome sequences using the multilocus sequence typing (MLST)[54], which belonged to the hyper-virulent African clonal complex (CC) 217 lineage[50,51]
Despite the rollout of 13-valent pneumococcal conjugate vaccine (PCV) in Sub-Saharan Africa[8,9], serotype 1 pneumococci remain a significant cause of lifethreatening invasive pneumococcal diseases including meningitis[7,12,64]
Summary
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, meningitis. Serotype 1 strains may be genetically adapted to be more prone at invading their hosts, it remains unknown whether they possess genetic variations other than the capsule biosynthesis genes, which modulates their tissue tropism[25,26] Such genotypic variants may have a higher ability to migrate and survive in given tissues, such as the cerebrospinal fluid (CSF), where they can cause central nervous system (CNS) pathologies. Absence of genes and single-nucleotide polymorphisms (SNPs) and insertions/deletions, which may contribute to the pathogen virulence to causing certain invasive diseases
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