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

Experimental Rationale for Complement System Targets

The effects of complement system intervention on bacterial killing and spurring inflammation have been investigated in various experimental studies. Intervening early in the complement cascade by targeting the initiating pathways has the potential benefit of limiting the production of anaphylatoxin C3a, but may impair its opsonophagocytic function. This is illustrated by various in vitro opsonophagocytosis assays, showing reduced opsonization and phagocytosis of S. pneumoniae in classical (C1q) and lectin pathway (MASP-2) deficient mice and human serum, and may lead to increased bacterial outgrowth in in vivo models (Brown et al., 2002; Yuste et al., 2008; Ali et al., 2012). Targeting the alternative pathway does not alter opsonization as significantly. Opsonization of S. pneumoniae was less intense for sera of factor B-deficient mice (Brown et al., 2002), and only limited for some S. pneumoniae strains in human factor B-depleted serum resulting in only mild impairment of phagocytosis (Yuste et al., 2008). Properdin to stabilize C3-convertase significantly improved opsonization of both S. pneumoniae and N. meningitidis in serum (Ali et al., 2014). Targeting C3 itself, as illustrated in rats and rabbits that were enzymatically depleted of C3 following intraperitoneal injection of cobra venom factor, a proteolytic activator of C3 and C5, almost completely abolishes opsonizing function resulting in an increased bacterial outgrowth (Crosson et al., 1976; Tuomanen et al., 1986). Targeting C5 conversion, C5a, or the C5a receptor has the benefit of not limiting opsonization, while still targeting the production of the most potent anaphylatoxin C5a. The chemotactic activity of C5a in the accumulation of polymorphonuclear leucocytes has been recognized for a long time (Ernst et al., 1984). Intrathecally administered human C5a in rabbits resulted in a rapid leucocytosis (Kadurugamuwa et al., 1989).

Several models of experimental bacterial meningitis have been used, either investigating the difference between wild-type and complement-deficient mice (Rupprecht et al., 2007; Woehrl et al., 2011; Kasanmoentalib et al., 2017), or using adjunctive complement-targeted therapies (Table 3) (Crosson et al., 1976; Tuomanen et al., 1986; Zwijnenburg et al., 2007; Woehrl et al., 2011; Kasanmoentalib et al., 2015, 2017; Klein et al., 2018). Most models investigated pneumococcal meningitis. The development of experimental meningococcal meningitis models has been hindered by the exclusivity of this pathogen to humans. Classical pathway deficiency (C1q) was associated with lower rates of intracranial complications and lower CSF leucocyte count, but higher mortality rates due to increased bacterial outgrowth and septicaemia (Rupprecht et al., 2007). Adjunctive treatment with a classical pathway inhibitor (C1-INH, inhibitor of C1r and C1s) also attenuated CSF leucocyte count and cytokine and chemokine response and reduced clinical illness measures (Zwijnenburg et al., 2007). Surprisingly, C1-INH treated rats and mice had reduced bacterial outgrowth, possibly related to increased CR3-receptor expression, improving phagocytic function in spite of impaired opsonization. Lectin pathway deficiency (MASP-2) improved survival, and adjunctive treatment with MASP-2 antibodies in adjunction to standard care with dexamethasone and antibiotics significantly reduced progression of clinical severity scores and non-significantly lowered mortality rates (Kasanmoentalib et al., 2017). C3-deficient mice had increased bacterial outgrowth and increased mortality (Rupprecht et al., 2007). Whilst different from treatment in meningitis, C3-inhibition by compstatin in a baboon E. coli sepsis model had organ-protective effects, even when administered after sepsis induction (Silasi-Mansat et al., 2010; Mastellos et al., 2015). Most clear is the evidence resulting from experimental models investigating targeting C5a. Mice with C5a receptor deficiency had reduced inflammation and improved clinical scores (Woehrl et al., 2011). Adjunctive treatment with C5-antibody therapy, preventing C5 conversion to C5a, was significantly associated with decreased mortality, improved neuroscore and clinical score, and less frequent cerebral haemorrhages (Woehrl et al., 2011). A subsequent investigator-blinded experimental model showed that combined treatment with dexamethasone and C5 antibodies significantly reduced mortality when compared to placebo, and also when compared with dexamethasone and C5-antibody therapy alone (Kasanmoentalib et al., 2015). A recently published experimental pneumococcal meningitis model comparing the use of ceftriaxone with different combinations of dexamethasone, daptomycin, IL1-antibody, roscovitine and C5a antibodies in mice, showed most favourable results for the combination of daptomycin and anti-C5 antibody (Klein et al., 2018). Mice treated with adjunctive dexamethasone and C5-antibody had similar clinical scores and survival (all mice survived), but had higher hearing thresholds and CSF leucocyte count (Klein et al., 2018). An experimental study comparing different complement interventions in the same model has not been performed, while this would overcome the limitation of comparing heterogeneous models, using different bacterial strains with varying pathogenicity (for instance S. pneumoniae strain ATCC 6303 has shown to be more lethal than D39 in wild-type mice) (Kostyukova et al., 1995; Lim et al., 2007).