Parasites and Microbes Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Darwin College, University of Cambridge, Silver Street, Cambridge, UK.
Commun Biol. 2020 Oct 8;3(1):559. doi: 10.1038/s42003-020-01290-9.
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) and helicase proteins (P = 1.32 × 10) 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.
高毒力肺炎链球菌 1 型血清型在撒哈拉以南非洲流行，经常导致致命性脑膜炎暴发。目前尚不清楚 1 型菌株的遗传变异是否调节向脑脊液的亲嗜性，从而导致中枢神经系统（CNS）感染，特别是脑膜炎。在这里，我们通过对从 CNS 和非 CNS 人体样本中收集的 909 株非洲肺炎链球菌 1 型分离株进行大规模线性混合模型全基因组关联研究来解决这个问题。通过控制宿主年龄、地理位置和菌株群体结构，我们在表面暴露的胆碱结合（P=5.00×10）和螺旋酶蛋白（P=1.32×10）中鉴定到与入侵、免疫逃逸和肺炎链球菌向 CNS 亲嗜性相关的全基因组统计学显著的基因型-表型关联，这些蛋白对入侵、免疫逃避和肺炎链球菌向中枢神经系统的亲嗜性很重要。小的效应大小和可忽略的遗传力表明，CNS 感染的因果关系需要反映复杂的多基因病因的多个遗传和其他因素。我们的研究结果表明，某些病原体的遗传变异调节肺炎链球菌在中枢神经系统组织中的存活和亲嗜性，因此，对脑膜炎的毒力。
