Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis.

Philip H C Kremer,John A Lees,Bart Ferwerda,Arie Van De Ende,Diederik Van De Beek,Stephen D Bentley,Matthijs C Brouwer

doi:10.3389/fmed.2020.594769

Abstract

Neisseria meningitidis causes sepsis and meningitis in humans. It has been suggested that pathogen genetic variation determines variance in disease severity. Here we report results of a genome-wide association study of 486 N. meningitidis genomes from meningococcal meningitis patients and their association with disease severity. Of 369 meningococcal meningitis patients for whom clinical data was available, 44 (12%) had unfavorable outcome and 24 (7%) died. To increase power, thrombocyte count was used as proxy marker for disease severity. Bacterial genetic variants were called as k-mers, SNPs, insertions and deletions and clusters of orthologous genes (COGs). Population-level meningococcal genetic variation did not explain variance in disease severity (unfavorable outcome or thrombocyte count) in this cohort (h2 = 0.0%; 95% confidence interval: 0.0–0.9). Genetic variants in the bacterial uppS gene represented the top signal associated with thrombocyte count (p-value = 9.96e-07) but this did not reach statistical significance. We did not find an association between previously published variants in lpxL1, fHbp, and tps genes and unfavorable outcome or thrombocyte count. A power analysis based on simulated phenotypes based on real genetic data from 880 N. meningitidis genomes showed that we would be able to detect a continuous phenotype with h2 > = 0.5 with the population size available in this study. This rules out a major contribution of pathogen genetic variation to disease severity in meningococcal meningitis, and shows that much larger sample sizes are required to find specific low-effect genetic variants modulating disease outcome in meningococcal meningitis.

Highlights

Neisseria meningitidis is a commensal to the human nasopharynx [1]
To increase the power to identify genetic variations associated with disease severity we investigated whether blood thrombocyte count on admission was a predictor of unfavorable outcome
N, number; c-reactive protein (CRP), C-reactive protein; IQR, interquartile range; CSF, cerebrospinal fluid; mg, milligrams; mL, milliliter; g, grams; N.S., not significant Numbers do not add up to total number of patients because of missing values. &Wald test p-value; %multivariate logistic regression corrected for thrombocyte count. In this pathogen genome-wide association analysis, we could not detect genetic loci in the meningococcal genome predictive of blood thrombocyte count as a proxy for disease severity

Summary

Introduction

Neisseria meningitidis is a commensal to the human nasopharynx [1]. Rarely, it crosses the mucosal barrier to cause invasive meningococcal disease, which can manifest as bacteremia, fulminant septicemia and meningitis [2]. Patients present with severe septic shock and no clinical signs of meningitis. Patients with meningococcal meningitis have lower concentrations of meningococci and endotoxin in blood, but higher concentrations in cerebrospinal fluid (CSF) [5, 6]. Mortality rate is lower, around 3%; and 10% of patients have neurological sequelae after disease [8]. Unfavorable outcome in patients with meningococcal meningitis is the result of neurological or systemic disease complications such as multi-organ failure complicating bacteremia, peripheral vasculopathy and peripheral ischemia [9]. Excessive activation of the coagulation system can result in disseminated intravascular coagulation (DIC) This leads to low blood thrombocyte counts through consumption. Low blood thrombocyte counts are associated with severe meningococcal disease and unfavorable outcome [11]

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Results

Conclusion