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

Complement Activation in Bacterial Meningitis

Pathogens that cross the blood–CNS barrier are able to multiply freely in the CSF as the effectiveness of the host defence is limited in the subarachnoid space (Mook-Kanamori et al., 2011). In non-infected healthy individuals, complement levels in the CSF are 100 to a 1000-fold lower compared to serum concentrations; too low for any significant antibacterial activity (van de Beek et al., 2016a). Historically, the CNS was considered immunologically privileged. Before the invention of antibiotics when bacterial meningitis was almost universally fatal, patients were even occasionally (and sometimes successfully) treated with intrathecally administered serum or complement to make-up for the lack of CSF bactericidal activity (M'Kenzie and Martin, 1908; Finland et al., 1938; Coleman, 1940; Domingo et al., 2019). The adjuvant use of intrathecal serum or complement in patients treated with antibacterial sulphonamides in the late 1930 to 1940s did, not, however, seem to beneficially affect the disease course and may have led to increased mortality in meningococcal meningitis patients [17% (374/2139) versus 9% (482/5221)] (Coleman, 1940; Domingo et al., 2019). Studies in the 1910–1940s that identified complement activity in the CSF of a small proportion of cases with acute inflammatory conditions thought it was the sole result of extravasation of complement components from the blood related to increased blood–CSF barrier permeability (Kolmer et al., 1918; Fothergill, 1935). However, since the 1990s, it has been known that several cells in the CNS have an immune-regulatory function, and that astrocytes, but also microglia, ependymal cells, oligodendrocytes and neurons all express complement proteins resulting in a complete and functional complement system (Morgan and Gasque, 1996; Stahel et al., 1997).

The host immune response in the CSF is activated through surface-bound or intracellular pattern recognition receptors including different Toll-like receptors (TLRs) and NOD-like receptors (NLRs) (Mook-Kanamori et al., 2011), and pattern-recognition molecules including collectins and complement component C1q, especially when pathogens die because of stress conditions (e.g. nutrient shortage, antibiotic administration) (Hajishengallis and Lambris, 2016; van de Beek et al., 2016a). The activation of these TLRs and NLRs leads to the activation of inflammatory transcription factors, in particular the nuclear factor NF-kB, which amongst others may lead to increased complement protein production through TLR-complement crosstalk, though this remains largely unexplored (Mook-Kanamori et al., 2011; Lian et al., 2015; Hajishengallis and Lambris, 2016).

Several studies included blood and/or CSF complement measurements and correlated results to disease severity and outcome (Table 2) (Greenwood et al., 1976; Whittle and Greenwood, 1977; Zwahlen et al., 1982; Stahel et al., 1997; Goonetilleke et al., 2010, 2012; Woehrl et al., 2011; Adriani et al., 2013; Brouwer et al., 2013; Lucas et al., 2013; Mook-Kanamori et al., 2014; Kasanmoentalib et al., 2017). The techniques used for measuring complement levels have varied over time and studies included different distributions of causative pathogens. Despite this heterogeneity among publications, it remains evident that massive complement system activation occurs in the CSF of patients with bacterial meningitis. Concentrations of C1q, MBL, MBL-associated serine protease 2 (MASP2), factor B, factor H, C3a, iC3b, C5a, and MAC in the CSF of the diagnostic lumbar puncture were all significantly elevated compared to control CSF (for instance of patients with thunderclap headache) (Stahel et al., 1997; Brouwer et al., 2013; Mook-Kanamori et al., 2014). Although many patients with bacterial meningitis have bacteraemia or sepsis, data on serum complement levels in bacterial meningitis patients are scarce, and only two studies have assessed paired complement levels in serum and in the CSF (Zwahlen et al., 1982; Goonetilleke et al., 2012). To date, studies including serial blood sampling to determine complement activation profiles of patients with acute bacterial meningitis are lacking. Similar to in bacterial meningitis, focus of research in sepsis shifted from the pathogenicity of the causative pathogen towards the dysregulated hosts' systemic inflammatory and immune response (Hotchkiss et al., 2016). Differences in complement activation between patients with uncomplicated sepsis and patients who eventually died were already identified over 40 years ago (McCabe, 1973). An increased degree of complement activation is also associated with unfavourable outcome in bacterial meningitis. High concentrations of C1q, MASP2, C5a and MAC in the CSF of the diagnostic puncture have been significantly associated with mortality in pneumococcal meningitis (Goonetilleke et al., 2010; Woehrl et al., 2011; Mook-Kanamori et al., 2014; Kasanmoentalib et al., 2017). High levels of C5a in the CSF were also associated with development of the detrimental complication of delayed cerebral thrombosis later in the disease course (Lucas et al., 2013). Patients with this devastating complication suddenly deteriorate after initial recovery, developing headache, fever, a decreased level of consciousness, brainstem signs, or hemiparesis due to inflammation and brain infarction (Schut et al., 2009). Low CSF C3 levels indicating complement consumption due to massive complement activation have also been associated with mortality (Zwahlen et al., 1982; Goonetilleke et al., 2010, 2012). Differences are described between causative pathogens. In contrast to pneumococcal meningitis, high MAC levels in meningococcal meningitis were associated with favourable outcome (Mook-Kanamori et al., 2014). In addition, CSF C5a and MAC levels were significantly higher in patients with pneumococcal meningitis than in patients with meningococcal meningitis, even when corrected for age, immunocompromised state, and level of consciousness (Mook-Kanamori et al., 2014).

Data on the deposition of complement components in the brain is limited as it has not been thoroughly evaluated by any of the few case series of autopsied bacterial meningitis patients (Engelen-Lee et al., 2016). Strong and specific staining of the C3a receptor was seen in astrocytes, microglia and infiltrating cells, macrophages, and neutrophils in brain tissue of bacterial meningitis patients, as was true for the C5a receptor for non-bacterial meningitis brain inflammation (Gasque et al., 1998).