Targeting the Complement System in Bacterial Meningitis

Diederik L.H. Koelman; Matthijs C. Brouwer; Diederik van de Beek


Brain. 2019;142(11):3325-3337. 

In This Article

Abstract and Introduction


Bacterial meningitis is most commonly caused by Streptococcus pneumoniae and Neisseria meningitidis and continues to pose a major public health threat. Morbidity and mortality of meningitis are driven by an uncontrolled host inflammatory response. This comprehensive update evaluates the role of the complement system in upregulating and maintaining the inflammatory response in bacterial meningitis. Genetic variation studies, complement level measurements in blood and CSF, and experimental work have together led to the identification of anaphylatoxin C5a as a promising treatment target in bacterial meningitis. In animals and patients with pneumococcal meningitis, the accumulation of neutrophils in the CSF was mainly driven by C5-derived chemotactic activity and correlated positively with disease severity and outcome. In murine pneumococcal meningitis, adjunctive treatment with C5 antibodies prevented brain damage and death. Several recently developed therapeutics target C5 conversion, C5a, or its receptor C5aR. Caution is warranted because treatment with C5 antibodies such as eculizumab also inhibits the formation of the membrane attack complex, which may result in decreased meningococcal killing and increased meningococcal disease susceptibility. The use of C5a or C5aR antagonists to specifically target the harmful anaphylatoxins-induced effects, therefore, are most promising and present opportunities for a phase 2 clinical trial.


Bacterial meningitis is a life-threatening infection of the CNS. Bacteria enter the CSF in the subarachnoid space either by crossing the blood–CNS barrier (either the blood–brain barrier through the brain parenchymal microvasculature or the blood–CSF barrier through the choroid plexus or the pial or arachnoidal microvasculature) or from a contiguous site of infection (Mook-Kanamori et al., 2011; Coureuil et al., 2017). Bacterial pathogen-associated molecular patterns and the resulting damage-associated molecular patterns in the CSF provoke a massive and often uncontrolled inflammatory response leading to high rates of complications, morbidity, and mortality in patients (Mook-Kanamori et al., 2011; van de Beek et al., 2016a).

Most common pathogens causing community-acquired bacterial meningitis are currently Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes, accounting for 70%, 10%, and 5% of cases, respectively (van de Beek et al., 2004b; Bijlsma et al., 2016). Pneumococcal meningitis is also one of the most common forms, after listerial meningitis, the form with the highest mortality rate (12–18%) (van de Beek et al., 2006; Bijlsma et al., 2016; Polkowska et al., 2017). The introduction of pneumococcal conjugate vaccination has resulted in a decline in incidence as reported by cohorts from several geographical areas (Hsu et al., 2009; Alari et al., 2016; Bijlsma et al., 2016; Ruiz-Contreras et al., 2017). Nevertheless, reported effectiveness of the 7- and 13-valent pneumococcal conjugate vaccines differed per region, and subsequent increase of invasive pneumococcal disease due to non-vaccine pneumococcal serotypes has been reported (Weinberger et al., 2011; Gladstone et al., 2015; Weiss et al., 2015; Brouwer and van de Beek, 2018; Vadlamudi et al., 2019). It is therefore likely that pneumococcal meningitis will remain a major health challenge (Koelman et al., 2019).

Over the past 15 years, the implementation of anti-inflammatory treatment with adjunctive dexamethasone therapy to dampen the inflammatory response has resulted in an absolute decrease of mortality by 10% (de Gans et al., 2002; van de Beek et al., 2004a; Brouwer et al., 2010). Nevertheless, mortality and morbidity are still too high with death occurring in ~20% of patients, inability to live an independent life in 20%, and (neuro)psychological sequelae in 50% (Schmidt et al., 2006; Hoogman et al., 2007; Bijlsma et al., 2016; Lucas et al., 2016). Therefore, new adjunctive therapies are needed (Davis and Greenlee, 2003; van de Beek, 2012). Further, dampening the host inflammatory response with such new adjunctive treatments is the promising approach in bacterial meningitis (van de Beek et al., 2012).

The complement system plays a key role in the innate immune system, through facilitating the clearing of pathogens and damaged cells by immune cells, direct bacterial killing by the pore-forming membrane attack complex (MAC), but also by promoting the inflammatory response through the production of anaphylatoxins (Murphy and Weaver, 2017). Diseases directly linked with the complement system include paroxysmal nocturnal haemoglobinuria (PNH), age-related macular degeneration, atypical haemolytic uraemic syndrome (aHUS), hereditary angioedema, and C3-glomerulopathies (Morgan and Harris, 2015). The complement system also appears to play an important role in the pathogenesis of multiple neurological diseases, resulting in a strong increase in pathophysiological studies and clinical trials investigating complement system intervention over the past 15 years (Morgan, 2015). Because of the multiplicity of complement system activation routes and the various components, proteases, convertases, anaphylactic peptides and receptors involved, the complement system includes numerous points to intervene (Figure 1) (Morgan and Harris, 2015). Bacterial meningitis is one of the diseases in which the complement anaphylatoxin-induced cellular immune response seems to have profound detrimental effects on the brain and blood compartment.

Figure 1.

Complement system and therapeutic targets in bacterial meningitis. The complement system is activated via multiple pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway starts with binding of C1q to immune complexes such as non-specific IgM that binds to the pneumococcal C polysaccharide. The lectin pathway is activated through direct binding of collectins, such as mannose-binding lectin (MBL) and ficolins, to sugars on the bacterial surface. This results in the binding with the corresponding serine proteases [C1r and C1s, and MBL-associated serine proteases (MASP), respectively], to form complexes that facilitate cleavage of C2 and C4. This forms C3-convertase (C4bC2b), which catalyses the conversion of C3 to C3a and C3b. The alternative pathway is activated when C3b, either produced due to spontaneous hydrolysis or initiating pathway activation, binds to a microbe. This allows C3b to bind with factor B. Subsequently, factor B is cleaved into Ba and Bb by factor D. Bb remains bound to C3 and forms a complex (C3bBb). The serum protein properdin binds this complex to make it more stable. C3bBb(P) acts as another C3-convertase further promoting C3 conversion, thus amplifying complement system activation. There are several natural inhibitors of the alternative pathway including complement receptor 1, factor H and complement protease complement factor I. C3b is an opsonin that facilitates phagocytosis. When C3b binds with the C4b2b complex or to a C3bBb complex, it forms C5 convertase (C4b2b3b and C3bBb3b respectively). Because of the catalysing activity of C5 convertase, C5 is cleaved to C5a and C5b. C5b is the first complement component of the MAC complex. Simplified, C5b consecutively binds C6, C7, C8, which induced the binding and subsequent polymerization of 10 to 16 C9 molecules, creating the pore-forming structure known as the MAC. The pores formed by the MAC complex enable molecules to diffuse freely in and out of the cell. If enough pores form, the cell will no longer be viable. C3a and C5a are anaphylatoxins that are produced during complement system activation both in order of production (from early to late) as in order of potency (from weak to active). Anaphylatoxins upregulate the inflammatory response by binding to its specific receptor C5aR, which are mainly expressed by immune cells, and result in increased blood–CSF barrier permeability and the accumulation of polymorphonuclear leucocytes in the CSF. Various complement therapeutics are available targeting C1s [TNNNT009 (True North), C1q (ANX005 (Annexon)], MASP-2 and 3 [OMS-721 and OMS906, respectively (Omeros)], C2 [PRO-02 (Prothix/Broteio)], C3b [H17 (Elusys); S77 (Genentech), factor B (bikaciomab (Novelmed)], factor D [lampalizumab (Genentech); ACH-4471 (Achillion)], properdin [CLG561 (Novartis)], C3 [compstatin family: AMY-101 (Amyndas), APL-1 and APL-2 (Apellis)], C5 [soliris/eculizumab (Alexion); ALXN1210 (Alexion); tesidolumab/LFG316 (Novartins/Morphosys); SKY59/RO7112689 (Chugai and Roche); REGN3918 (Regeneron); ABP 959 (Amgen); Coversin (Akari); Zilucoplan/RA101495 (Ra Pharma); Zimura (Ophtotech); ALN-CC5 (Alnylam)], C5a [IFX-1 (InflaRx); ALXN1007 (Alexion)], and C5aR [Avacopan/CCX168 (Chemocentryx); IPH5401 (Innate Pharma)].

In this comprehensive update, we will systematically evaluate evidence gained from genetic variation studies, complement level measurements in blood and CSF, and experimental work that have together identified the complement system as a promising treatment target in bacterial meningitis. We will conclude with an up-to-date summary of the therapeutic options available to move complement system intervention forward to clinical translation in bacterial meningitis.