Tracing the origin and spread of Neisseria meningitidis CC4821 in China

Neisseria meningitidis is one of the important pathogens that cause purulent meningitis, and invasive meningococcal disease (IMD) has a high mortality rate. In this study, we used cerebrospinal fluid metagenomic sequencing to assist in the diagnosis of 4 cases of IMD in 2019.At the same time, we assembled the complete genome sequences of these 4 N. meningitidis from the reads measured by mNGS. The N. meningitidis isolated from these 4 patients belonged to ST4821-serotype C. In order to investigate the phylogeny of CC4821, we also included 37 CC4821 N. meningitidis genome downloaded from the PubMLST Neisseria genome database from 1972 to 2017.Atimed phylogeny was estimated from the core genome alignment of CC4821 using Bayesian method. The core genome has accumulated variation at a rate of 1.45 * 10-7 substitutions per nucleotide site per year [95% highest probability density (HPD), 1.05 * 10-7 to 1.89 * 10-7]. Phylogeny showed that CC4821 differentiated into 2 sub-lineages during evolution, named sub-lineage A& B. In the process of evolving from sub-lineageA(early stage) to sub-lineage B (late stage), the ST type and serotype of CC4821 were in converge, mainly ST4821-serotype C clone. Compared with sub-lineageA, most strains of sub-lineage B were isolated from IMD, and the resistance to quinolones was increased. The selective pressure of quinolones was the main reason for the converge evolution of CC4821. The phylogeographic analysis showed that CC4821 originated in Shanghai in 1902 (95% HPD 1869 ~ 1935), and then spread to other cities in China and other countries. In conclusion, the selective pressure of quinolones caused CC4821 to converge evolution, which is more invasive and spreading.