Using Neisseria meningitidis genomic diversity to inform outbreak strain identification

Meningococcal disease is a life-threatening illness caused by the human-restricted bacterium Neisseria meningitidis. Outbreaks in the USA involve at least two cases in an organization or community caused by the same serogroup within three months. Genome comparisons, including phylogenetic analysis and quantification of genome distances can provide confirmatory evidence of pathogen transmission during an outbreak. Interpreting genome distances depends on understanding their distribution both among isolates from outbreaks and among those not from outbreaks. Here, we identify outbreak strains based on phylogenetic relationships among 141 N. meningitidis isolates collected from 28 outbreaks in the USA during 2010–2017 and 1516 non-outbreak isolates collected through contemporaneous meningococcal surveillance. We show that genome distance thresholds based on the maximum SNPs and allele distances among isolates in the phylogenetically defined outbreak strains are sufficient to separate most pairs of non-outbreak isolates into separate strains. Non-outbreak isolate pairs that could not be distinguished from each other based on genetic distances were concentrated in the clonal complexes CC11, CC103, and CC32. Within each of these clonal complexes, phylodynamic analysis identified a group of isolates with extremely low diversity, collected over several years and multiple states. Clusters of isolates with low genetic diversity could indicate increased pathogen transmission, potentially resulting in local outbreaks or nationwide clonal expansions.
Author summary Meningococcal disease is a life-threatening illness caused by the bacterium Neisseria meningitidis. Meningococcal disease outbreaks occur when the same serogroup of N. meningitidis causes multiple cases of disease over a short time period in a population such as a community, college, or prison. As with many other pathogens, genome sequencing can reveal genetic relationships among N. meningitidis based on genomic changes that accumulated as the bacteria were transmitted from person to person. Here, we review 28 outbreaks that occurred over eight years in the United States and identify outbreak strains based on how the N. meningitidis isolated from these outbreaks relate to each other and to N. meningitidis isolated from hundreds of other cases from across the country. We show that pairs of isolates from the same outbreak strain have much higher genome similarity than is typical for pairs of isolates that are not from outbreaks; therefore, genome similarity can help delimit outbreak strains during future outbreak investigations. We also identify groups of N. meningitidis that had similar genomes despite being collected over several years and in multiple states; illustrating how changes in meningococcal disease epidemiology could be affected by the spread of these bacteria.