Variation of 46 Innate Immune Genes Evaluated for their Contribution in Pneumococcal Meningitis Susceptibility and Outcome

Abstract

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Early recognition of the pathogen and subsequent innate immune response play a vital role in disease susceptibility and outcome. Genetic variations in innate immune genes can alter the immune response and influence susceptibility and outcome of meningitis disease.Here we conducted a sequencing study of coding regions from 46 innate immune genes in 435 pneumococcal meningitis patients and 416 controls, to determine the role of genetic variation on pneumococcal meningitis susceptibility and disease outcome.Strongest signals for susceptibility were rs56078309 CXCL1 (p = 4.8e − 04) and rs2008521 in CARD8 (p = 6.1e − 04). For meningitis outcome the rs2067085 in NOD2 (p = 5.1e − 04) and rs4251552 of IRAK4 were the strongest associations with unfavorable outcome (p = 6.7e − 04). Haplotype analysis showed a haplotype block, determined by IRAK4 rs4251552, significantly associated with unfavorable outcome (p = 0.004). Cytokine measurements from cerebrospinal fluid showed that with the IRAK4 rs4251552 G risk allele had higher levels of IL-6 compared to individuals with A/A genotype (p = 0.04).We show that genetic variation within exons and flanking regions of 46 innate immunity genes does not yield significant association with pneumococcal meningitis. The strongest identified signal IRAK4 does imply a potential role of genetic variation in pneumococcal meningitis.

Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

“…Subsequently, the complement system is activated, leading to massive release of anaphylotoxins and chemotaxis and activation of neutrophils [11]. Genetic variants in complement system, TLR and IL-1R signaling pathways, and the M-TOR pathway have been identified to be associated with outcome in pneumococcal meningitis [7, 9, 12–15]. Inhibition of the final common pathway in the complement cascade has been identified as target for adjunctive treatment for experimental pneumococcal meningitis.…”

Inflammasome Genes’ Polymorphisms in Egyptian Chronic Hepatitis C Patients: Influence on Vulnerability to Infection and Response to Treatment

“…Previous studies have reported that CARD8 rs2043211 was found to be associated with susceptibility to gout [58], nodular melanoma [59], and decreased risk of ankylosing spondylitis [60]. Nonetheless, CARD8 rs2043211 could not predict the occurrence or progression of coronary artery diseases [61] or the susceptibility and outcome of meningitis [62]. The CARD8 rs2043211 (C10X) polymorphism leads to a nonfunctional truncated CARD8 and subsequently more active inflammasome and prolonged inflammation [38, 63].…”

The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infection

“…SNPs leading to a loss of the human CD22 protein have not been described so far. Systematic GWAS research on pneumococcal pneumonia susceptibility are lacking in the human, due to the difficulties in obtaining sufficient numbers of defined human subjects [24][25][26] and to the complex trait in susceptibility to infection, which is modulated by the individual's environment, age and gender [27]. Here we have described that the cd22 locus as a novel strong susceptibility locus for pneumococcal disease in mice.…”