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Host, Bacterial Genes Influence Meningitis Infection Susceptibility, Severity

NEW YORK (GenomeWeb) – Host genetic variants influence both susceptibility to and severity of meningitis infections, while bacterial variants only influence disease invasiveness, a new study has found.

While Streptococcus pneumoniae commonly colonizes the human throat and nose, it sometimes leads to life-threatening conditions including meningitis, which has a fatality rate between 17 percent and 20 percent.

An international team of researchers turned to sequencing data from both S. pneumoniae and people infected with the bacteria to tease out how genetic variation in each contributes to disease risk. Through a host genome-wide association study and a pathogen GWAS, the researchers uncovered genes in which variants may influence disease. These, they added, could represent targets for follow-up vaccine research.

"Our analyses define the role of genetic variation of host and pathogen in pneumococcal meningitis," researchers led by the University of Amsterdam's Diederik van de Beek wrote in their paper, which appeared this week in Nature Communications.

Using the Dutch MeninGene cohort, van de Beek and his colleagues calculated the heritability of meningitis susceptibility and severity that's due to bacterial genetics. Their model estimated that additive pneumococcal genetics account for about 70 percent of the variance in the tendency toward invasive disease, but none of the variance in disease severity. This, they said, suggests that while tendency toward invasive disease is affected by bacterial genetics, disease outcome is not.

Additionally, they noted that serotype contributes to about half of the variability in invasiveness.

The researchers also conducted a GWAS of pathogens' genetic effect on disease severity within the MeninGen cohort. As expected based on their heritability estimate, they uncovered no loci that were significantly linked with severity.

But when they then conducted a pooled analysis of carriage and invasive pneumococcal isolates — a total of 5,845 bacterial genomes — from the Dutch and a South African cohort and a meta-analysis of association studies within the individual cohorts, the researchers homed in on a number of genes linked with invasive disease, including the virulence genes pspC, dacB, and psrP.

Meanwhile, the researchers calculated that host genetics accounts for about 29 percent of the variability in meningitis susceptibility and about 49 percent of the variability in meningitis severity.

They also performed a GWAS of human hosts' contribution to disease susceptibility and severity in the Dutch cohort. They linked an intronic variant in UBE2U to disease severity and unfavorable outcomes. UBE2U, they noted, is involved in antigen presentation. Data from chromatin capture assays found that this variant further interacts with PGM1 and ROR1, while analysis using the GTex database found that this variant is linked to gene expression in a panel of tissues.

Additional association analyses in the Dutch and South African cohorts as well as using the UK Biobank further implicated a variant on chromosome 15 and an intronic SNP in CCDC33 in disease.

While CCDC33 hasn't before been linked to immunity the researchers noted that it could act at a distance on and affect the expression of ISLR2, an immunoglobulin family protein that is expressed in the brain.

Within the Dutch cohort, the researchers attempted to examine interactions between the host and pathogen genomes, but were only able to find speculative links due to the need for additional samples to boost power.

Still, the researchers noted that their approach enabled them to survey genomic variation within the host and pathogen that affect disease susceptibility and severity.

"These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines," the researchers added.

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