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Joint Sequencing of Human and Pathogen Genomes Reveals the Genetics of Pneumococcal Meningitis

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Joint Sequencing of Human and Pathogen Genomes Reveals the Genetics of Pneumococcal Meningitis ARTICLE https://doi.org/10.1038/s41467-019-09976-3 OPEN Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis John A. Lees et al.# Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life- threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to 1234567890():,; what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines. Correspondence and requests for materials should be addressed to S.D.B. (email: [email protected]) or to D.v.d.B. (email: [email protected]). #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2019) 10:2176 | https://doi.org/10.1038/s41467-019-09976-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09976-3 treptococcus pneumoniae, or the pneumococcus, is the Pathogen GWASs (pGWASs) provide a way to identify S leading cause of bacterial meningitis, which is an important pneumococcal sequence variation associated with meningitis, cause of mortality and morbidity worldwide despite independent of genetic background and in an unbiased manner. advances in vaccination and treatment1,2. The case fatality rate of While GWAS is more challenging in bacteria than in humans due pneumococcal meningitis is 17–20% and unfavourable outcome to strong population structure and high levels of pan-genomic occurs in 38–50% of cases3. S. pneumoniae is also the leading variation, recent methodological advances have helped overcome cause of pneumonia and bacteremia. Invasive disease is preceded these issues18–20. by nasopharyngeal colonization3. Here, we use data and samples from Dutch adults in our Knowledge of the contribution of genetic variability of humans prospective and nationwide MeninGene cohort3. We have col- and invading pathogens to pneumococcal meningitis suscept- lected a large number of samples of both human and pathogen ibility could guide development of new vaccines preventing the DNA from culture-proven cases of pneumococcal meningitis, progression from asymptomatic carriage to invasive disease, along with detailed clinical metadata (Supplementary Tables 1 whereas genetic variation associated with disease severity may and 2). Genotyping and whole-genome sequencing of this col- guide new clinical intervention strategies during treatment4. lection allows us to undertake a combined GWASs of host However, the overall effect of human genetics on pneumococcal (hGWASs) and pathogen (pGWASs) in pneumococcal menin- meningitis is unknown—whether it affects the disease at all, and if gitis. We further include an analysis of interaction effects in a so, which specific regions of the genome cause the effect. His- joint GWAS and replicate our findings in additional cohorts of torically, genetic association studies on bacterial meningitis have invasive pneumococcal disease (IPD; Fig. 1). Our analyses define been held back by only assessing candidate genes, small sample the role of genetic variation of host and pathogen in pneumo- sizes or poorly defined phenotypes5. More recent host genome- coccal meningitis. wide association studies (hGWASs; glossary Table 1) have found associations of a protective variant in complement factor H (CFH) for children with meningococcal meningitis in Europe6, Results between a long non-coding RNA and pneumococcal meningitis Multiple bacterial loci determine pneumococcal invasiveness. in children in Kenya7 and between CA10 and self-reported bac- We first calculated the heritability of susceptibility and severity terial meningitis8. due to pneumococcal genetics using the MeninGene cohort. The In terms of pathogen variability, it is well known that the heritability corresponds to the proportion of phenotypic variation pneumococcal polysaccharide capsule, which determines its ser- explained by genetics, in this case single-nucleotide polymorph- otype, contributes to invasive propensity9,10. The pneumococcal ism (SNP) variation in the bacterial core genome. We used an genome also encodes a variety of proteins that directly interact additive binary phenotype model, which does not model any with the host, mostly to enhance colonization and avoid the host potential effects of genetic interactions (either epistatic or with immune response11. Mouse models have shown that some anti- the environment)21. Under this model, we found that additive gens such as pspC (cbpA) enhance virulence but are not essential pneumococcal genetics explained much of variation in invasive 12,13 2 in invasive isolates . While it is known that these antigens propensity (h SNP = 70%) but not meningitis disease severity 2 = have a role in colonization and disease, whether sequence varia- (h SNP 0%). We also calculated that 31% of the phenotypic tion at these loci has an effect on pathogenesis in human disease variance could be explained by the top ten principal components, remains unclear. Previous small association studies have addi- which explained 67% of the total genetic variance. This suggests tionally suggested a role for platelet binding14 and arginine that lineage effects, as in those pneumococcal strains which are synthesis15 in pneumococcal meningitis, and analysis of within- more likely to be sampled from an invaded niche, only partially host variation found that sequence variation of dlt and pde1 are account for the estimated heritability. It may therefore be possible associated with pneumococcal meningitis16,17. to find additional specific locus effects. 2 These h SNP estimates suggest that invasive propensity is highly dependent on pneumococcal genome content but that disease outcome is not determined by natural variation of pathogen Table 1 Glossary of terms genetics. The latter is not surprising as invasive disease is an evolutionary dead end for the pathogen, so adaptations affecting Term Meaning virulence over the short course of infection are unlikely to be CSF Cerebrospinal fluid selected for. This is contrary to smaller studies suggesting that IPD Invasive pneumococcal disease bacterial genotype may predict disease severity22 but consistent GWAS Genome-wide association study with a meta-analysis finding no effect of pneumococcal serotype hGWAS Host genome-wide association study on the risk ratio of death from meningitis23. In our population, pGWAS Pathogen genome-wide association study levels of antimicrobial resistance are low and rarely led to h2 Heritability (variation in phenotype explained by genetic treatment failure. In populations where resistance leads to variation) treatment failure, finding h2 > 0 for severity could be expected. OR Odds ratio LD Linkage disequilibrium The high heritability estimated here is consistent with the fact 9 MAF Minor allele frequency (of the least common allele observed in that some serotypes are rarely found in invasive disease , and the population) invasive lineages are genetically divergent from the rest of the AF Allele frequency (presence of gene or versus reference allele) population. It should also be noted that all meningitis isolates LoF Loss of function (frameshift or nonsense mutation in protein) were once carriage isolates, which by our sampling scheme are SFS Site frequency spectrum (histogram of minor allele effectively overrepresented in an invaded niche. Some of the frequencies) poorly invasive yet highly transmissible strains usually observed LMM Linear mixed model (association model used in genome-wide in carriage may also be able to cause invasive disease, potentially association study) meaning heritability is slightly underestimated. eQTL Expression quantitative trait loci (genetic association with transcript variation) Pneumococcal serotype is the current focus of vaccination. LD Linkage disequilibrium Using the same framework as for core SNPs, we calculated the proportion of variation in invasiveness that can be attributed to 2 NATURE COMMUNICATIONS | (2019) 10:2176 | https://doi.org/10.1038/s41467-019-09976-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09976-3 ARTICLE Human genotypes Netherlands Meningitis (N = 3714) Bacterial genomes eff Intersection (all) Netherlands Netherlands (N = 460) Meningitis (Neff = 2543) Meningitis (N = 1144) (pneumococcal) H. sapiens Carriage (N = 693) Meningitis (Neff = 1059) (severe) S. pneumoniae South Africa Denmark Invasive (N = 2354) Meningitis (N = 809) eff Carriage (N = 1701) Bacteremia (Neff = 2663) UK biobank Meningitis (Neff = 2662) Fig. 1 Overview of cohorts sequenced and associations performed. Left, host data; right, bacterial data; the centre represents samples with both host and pathogen sequence data. Samples in green are those collected from our
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