Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

Abstract

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

“…After identification by the Netherlands Reference Laboratory for Bacterial Meningitis (Academic Medical Center, Amsterdam) patients >16 y of age and with a positive CSF culture were enrolled between March 2006 and June 2011 in a nationwide prospective cohort study (54). The study was approved by the medical ethics committee of the University of Amsterdam.…”

Роль Генетичних Модифікацій Факторів Природного Імунітету При Менінгіті

“…Як показали експериментальні й клінічні дослідження, знижений рівень компонента C5 у сиро-ватці крові й СМР, обумовлений SNP у гені (С5), асоці-юється з несприятливим результатом менінгококового й пневмококового М [39]. Недолік компонента C6 вияв-лено у пацієнтів з генералізованою і рецидивною менін-гококовою інфекцією.…”

Méningites purulentes et méningoencéphalites graves (à l’exclusion des patients immunodéprimés)

“…Les facteurs de risque de méningites, notamment à S. pneumoniae sont bien connus [2] et ne seront pas rappelés ici. Plus originaux et récents sont la mise en évidence de polymorphismes génétiques semblant favoriser les complications vasculaires et le décès au cours des méningites tant à pneumocoques (fraction C5 du complément) [3] qu'à méningocoques (gènes codant pour PAI et SERPINE I) [4]. Les taux de mortalité des méningites à S. pneumoniae à N. meningitidis et à L. monocytogenes de l'adulte sont respectivement de 17, 10,4 et 20,5 %.…”

“…Il s'agit de patients âgés (mé-diane 75 ans) et fréquemment porteurs de comorbidités. Le LCR est franchement infl ammatoire avec une médiane de 150 éléments/mm 3 , et il existe une hypoglycorachie dans 40 % des cas [27]. Dans une série de 30 patients, en majorité des adultes, 19 étaient immunocompétents.…”