Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia
Noriko Shinjyo
Wataru Kagaya
Marcela Pekna- 1Laboratory of Immune Homeostasis, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
- 2School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
- 3Department of Parasitology and Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka City University, Osaka, Japan
- 4Laboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- 5Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer’s disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., Toxoplasma gondii and Plasmodium spp.), and prion proteins activate and manipulate the complement system in the CNS. We also discuss the potential mechanisms by which the interaction between the infectious agents and the complement system can play a role in neurodegeneration and dementia.
Introduction
The Complement System
The complement system is an evolutionarily conserved proteolytic cascade, consisting of over 40 components (Schartz and Tenner, 2020). Complement plays a key role as part of the innate immunity, eliminating pathogens and damaged cells, directly killing bacteria by forming the so-called membrane attack complex (MAC), and promoting inflammatory responses via the generation of anaphylatoxins (Yanamadala and Friedlander, 2010). The activation of the complement system can be triggered via three pathways: the classical pathway, the lectin pathway, and the alternative pathway (Veerhuis et al., 2011; Figure 1).
Figure 1. The complement system: activation pathways and functions in the CNS. All three pathways converge at C3. The formation of C3 convertase [C3(H2O)Bb and C3bBb in the alternative pathway or C4b2b in the classical and lectin pathways], followed by C3 cleavage, leads to the formation of MAC, the terminal complement complex (A). C1q and iC3b also facilitate immune responses via opsonization and promoting phagocytosis through binding to the receptors (CR1 and C1qR for C1q; CR1, CR2, and CR3 for iC3b) (B). Under physiological conditions, complement activation is tightly controlled by the regulators of complement activation (RCAs) (C). C3a and C5a, the smaller fragments generated through the proteolytic activation of C3 and C5, respectively, regulate differentiation and mobilization of immune and non-immune cells through the cognate receptors C3aR and C5aR, respectively (D). C3 and C5 can be also cleaved by other proteases via the so-called extrinsic pathway. C1qR, C1q receptor; C3bBb3b, C5 convertase formed by binding of additional C3b to C3bBb (C3 convertase); C3(H2O), hydrated C3; C3(H2O)Bb, the initiating C3 convertase of alternative pathway, consisting of C3(H2O) and Bb (Factor B [FB] cleavage product); CR1, complement receptor type 1; CR2, complement receptor type 2; CR3, complement receptor type 3; CR4, complement receptor type 4; FH, complement factor H; FI, complement factor I. C4BP, C4-binding protein; C1INH, C1-inhibitor.
Each of the activation pathways leads to the formation of C3 convertase (C4bC2b or C3bBb) that cleaves the third complement component (C3) into the C3a and C3b fragments, the latter of which functions as an opsonin, forms the C3 convertase of the alternative pathway (C3bBb) and takes part in the next step of the activation cascade, i.e., proteolytic cleavage of C5. C5 activation results in the release of C5a and the formation of MAC, a.k.a. the terminal complement complex, C5b-9. C3a and C5a are peptides with anaphylatoxin properties and function as fluid-phase inflammatory mediators. They exert their biological effects mainly through the cognate membrane-bound receptors C3a receptor (C3aR) and C5a receptor (C5aR1), respectively. C5a can also bind to the second C5a-like receptor (C5L2, C5aR2). C5aR1 can propagate proinflammatory signals to induce cytokine/chemokine release and mediate the chemoattraction and activation of neutrophils and macrophages (Mathern and Heeger, 2015). C3aR signaling is immunomodulatory, exerting pro- or anti-inflammatory effects in a context-dependent manner (Coulthard and Woodruff, 2015). For example, C3aR activation enhances phagocytosis by macrophages (Wu et al., 2019) and suppresses injury-induced mobilization of neutrophils (Wu et al., 2013; Brennan et al., 2019). Besides its C3aR-mediated actions, C3a has a direct anti-microbial activity (Pasupuleti et al., 2007), indicating its multiple modes of action as an anti-infective agent. Even without antibodies, complement can neutralize pathogens (Speth et al., 2002). In addition, there are links between complement and adaptive immunity, such as the robust augmentation of antibody responses mediated by the C3d fragment (proteolytically generated from C3b) and complement receptor 2 (CR2) (Dempsey et al., 1996) and the regulation of T cell activation by C3a/C5a (Lalli et al., 2008). Thus, the complement system has crucial functions in both innate and adaptive immune responses (Mathern and Heeger, 2015). In addition, recent reports show that a number of cell types store intracellular C3 (Elvington et al., 2016), which has been proposed to have an important role in the regulation of cellular homeostasis (Liszewski et al., 2017). For example, cathepsin L-mediated intracellular C3 cleavage and C3a generation are required for homeostatic T cell survival (Liszewski et al., 2013). Airway epithelial cells can de novo synthesize C3, and intracellular C3 protects these cells from stress-induced cell death (Kulkarni et al., 2019). Intracellular C3 is also required for autophagic turnover of pancreatic β cells during diabetic stress (King et al., 2019). Notably, C3 is an evolutionarily ancient protein; it is considered to be the first element of the original complement system, whose primary role was to guard intracellular environment and homeostasis from various stimuli (Elvington et al., 2016). While complement is widely acknowledged as part of vertebrate humoral immunity, the significance of intracellular complement is less recognized. The potential role for intracellular C3 in self-defense against infection warrants further investigation.
The classical pathway is initiated by binding of C1 (C1qrs) to activators such as immune complexes, microbes, apoptotic cells, and some specific proteins including fibrillar amyloid β (Aβ) (Veerhuis et al., 2011). The lectin pathway is activated by binding of mannose-binding lectin (MBL) and ficolin to carbohydrates on microorganisms or dying cells (Veerhuis et al., 2011). The classical and lectin pathways converge at the proteolytic cleavage of C4 and C2 and the formation of C4bC2b, the C3 convertase shared by these pathways. The alternative pathway continuously generates low levels of C3-derived activation products and C3 convertase C3bBb, providing a natural immunity to microbes (Farriesa and Atkinson, 1991). The activation of alternative pathway can also occur as a result of direct interaction between C3b and pathogenic molecules, including fibrillar Aβ, further amplifying the downstream of complement cascade (Tenner, 2020). C3 and C5 can be cleaved also by MASP 1 (Matsushita and Fujita, 1995), neutrophil elastase (Yuan et al., 2015), cathepsins (Liszewski et al., 2013; Yuan et al., 2015), granulocyte proteases (Johnson et al., 1976), lysosomal enzymes, kallikrein, coagulation factors XIa, Xa, IXa, thrombin, and plasmin (Markiewski and Lambris, 2007; Amara et al., 2010). This non-convertase mode of activation is also called the extrinsic pathway.
Under physiological conditions, complement activity is tightly regulated by regulators of complement activation (RCA) to safeguard against autologous tissue injury. The RCAs that limit complement activation both in time and space include factor H (FH), factor I, C1-inhibitor, C4-binding protein, clusterin, vitronectin, CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF), and complement receptor 1 (CR1, CD35). Properdin (FP), on the other hand, acts as a positive regulator that stabilizes the alternative pathway C3-convertase (Figure 1).
The Complement System in the CNS
Although the liver is the major source of circulating soluble complement proteins (Perlmutter and Colten, 1986), it is now established that complement components are locally synthesized throughout the body, including the brain (Woodruff et al., 2010; Tenner et al., 2018). Complement proteins, including the regulatory factors and receptors, are produced by glia and neurons (Gasque et al., 1998; Ischenko et al., 1998; Nataf et al., 1999), and recent studies have revealed a range of non-immune functions of the complement system in the CNS. For example, complement deposition on synapses, followed by CR3-dependent microglial engulfment and elimination of C1q- and C3b/iC3b-tagged synapses, plays a crucial role in synaptic pruning during normal development (Schafer et al., 2012). C3aR and C5aR are expressed by neurons and glia in the brain under normal and pathological conditions (Barnum et al., 2002). C3aR signaling regulates neuronal migration during CNS development (Gorelik et al., 2017), controls neural progenitor cell proliferation (Coulthard et al., 2018), differentiation and migration in vitro (Shinjyo et al., 2009), and promotes basal as well as injury-induced neurogenesis in the adult mouse brain (Rahpeymai et al., 2006; Shinjyo et al., 2009; Stokowska and Pekna, 2018). Notably, mice lacking C3 exhibit excessive number of synapses as young adults (Stevens et al., 2007; Perez-Alcazar et al., 2014) and neuronal migration defects characteristic of autism spectrum disorder (Gorelik et al., 2017), and are protected against age-related loss of synapses in the hippocampus (Shi et al., 2015). Higher expression of C4 in the brain has been implicated in excessive loss of synapses and development of schizophrenia (Sekar et al., 2016). C3aR deficiency is associated with altered morphology of the hippocampus and amygdala, mild cognitive impairment and hyperactive behavior in unchallenged mice (Coulthard et al., 2018; Pozo-Rodrigálvarez et al., 2021) as well as reduced neural plasticity responses after ischemic brain injury (Stokowska et al., 2017). Thus, the complement system is required for the normal development and function of the CNS.
Considering the broad range of neurodevelopmental and neuroregulatory functions of complement in the brain, it is not surprising that dysfunction or aberrant activation of the complement system have been implicated in the pathogenesis of a number of brain disorders (Gasque et al., 2000; Morgan, 2015). More specifically, complement activation has been observed in human neurodegenerative diseases, such as Alzheimer’s disease (AD), prion disease, chromosome 13 dementias (Eikelenboom et al., 2002; Rostagno et al., 2002; Morgan, 2018), as well as other neurological disorders associated with the blood-brain barrier (BBB) dysfunctions such as cerebrovascular disease, multiple sclerosis (MS) (Storch et al., 1998), and meningitis (Koelman et al., 2019). In infection, while providing protection against pathogens, excessive or prolonged activation of the complement system can lead to exaggerated inflammation and unfavorable outcomes (Ross and Densen, 1984; Figure 1).
Complement and Dementia
Dementia is a broad term for conditions with progressive memory impairment, executive and behavioral anomaly, and emotional problems, affecting the ability to perform day-to-day activities. Complement activation is implicated in AD, the most prevalent form of dementia (Rubio-Perez and Morillas-Ruiz, 2012). Together with glial activation and pro-inflammatory cytokine release, complement activation occurs during the early stage of the disease progression (Aiyaz et al., 2012). As described above, amyloid proteins stimulate complement activity (Veerhuis et al., 2011; Tenner, 2020), leading to the activation of the surrounding glial cells and local chronic inflammation (Cadman and Puttfarcken, 1997; Veerhuis et al., 2011). Complement proteins are present in amyloid plaques in the brain (Aiyaz et al., 2012), and co-localize with Aβ in the brain capillaries of cerebral amyloid angiopathy (Matsuo et al., 2017), suggesting that complement activation is a key event associated with amyloid deposition. In addition, complement is likely involved in other forms of dementia, including chromosome 13 dementias (familial British dementia FBD and familial Danish dementia FDD). Similar to AD, chromosome 13 dementias are associated with neurodegeneration and amyloid deposition in the CNS. In spite of the structural differences in the disease-associated amyloid proteins (Aβ in AD, ABri in FBD, ADan in FDD), neurodegeneration and amyloid deposition, associated with glial activation and local inflammation, are the common hallmark in all of these dementias (Saul et al., 2013). Importantly, complement activation products co-localize with amyloid plaques and related deposits in FBD and FDD (Rostagno et al., 2002). ABri and ADan synthetic peptides activate classical and alternative complement pathways, leading to the formation of the terminal complex (C5b-9). These data suggest that chronic complement activation associated with amyloid deposits may be a contributing factor to dementia progression in chromosome 13 dementias as well as in AD. While experimental evidence points to the critical function of complement in Aβ clearance (Wyss-Coray et al., 2002), and C3- and CR3-dependent microglial phagocytosis appears to play a beneficial role in the elimination of foreign pathogens as well as Aβ (Fu et al., 2012), CR3 also limits Aβ clearance from the brain interstitial fluid (Czirr et al., 2017), and is involved in Aβ-induced microglia-mediated loss of synapses in AD (Hong et al., 2016). The complexity of the involvement of complement in AD type of neurodegeneration is further highlighted by findings in the C3 deficient mice carrying the AD-associated mutations in the amyloid polypeptide and presenilin 1 genes. In this model, the C3 deficiency was protective against plaque-related synapse and neuron loss as well as cognitive decline, despite higher plaque burden (Shi et al., 2017). In addition, C1q and CR3 are required for the clearance of neuronal debris by microglia, at least in the context of injury-induced neurodegeneration (Norris et al., 2018). By virtue of its proinflammatory functions, C5a plays a significant role in neurodegeneration, including AD (Landlinger et al., 2015). Jointly, these reports point to the role of the complement system in Aβ and debris clearance as well as synapse elimination, Aβ-induced neurodegeneration and dementia.
Complement and Brain Infection
In the presence of an intact BBB, circulating immune cells, such as B- and T-lymphocytes, have limited access to the CNS. As a result, the defense of brain tissue against invading pathogens is largely dependent on local innate immunity, in particular the complement system. A number of pathogens escape the peripheral immune responses and enter the CNS. The interaction between pathogens and complement can lead to the clearance of pathogens, however, it may also contribute to tissue damage. Here we summarize the interactions between complement and infectious organisms, including bacteria, viruses, fungi, and parasites (Table 1), and discuss the potential impact of these interactions on CNS function. The interactions between complement and prion proteins are also discussed.
Interactions Between Infectious Agents and Complement in the CNS
Bacteria
Genetic defects in the complement system increase the susceptibility to bacterial infection (Brouwer et al., 2009). C2, factor D (FD), and FP deficiencies are associated with predisposition to meningococcal disease (Fijen et al., 1999; Jönsson et al., 2005; Sprong et al., 2006), while single-nucleotide polymorphisms (SNPs) in MBL are associated with pneumococcal disease (Brouwer et al., 2009). FH genotype 496C/C is associated with meningococcal disease (Haralambous et al., 2006) as is a locus in the FH (CFH) region (Davila et al., 2010). C3a exhibits anti-microbial activity against Gram-negative and Gram-positive bacteria (Pasupuleti et al., 2007). These data show that complement-dependent immune response is crucial in the protection against bacterial infection.
The evidence for the involvement of the complement system in bacterial meningitis is summarized in Table 1.1. Bacterial meningitis is an acute inflammation caused by infection in the meninges that envelope and protect the brain and spinal cord. Commonly caused by Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes, bacterial meningitis is a major health threat, the morbidity and mortality of which are driven by dysregulated host immune reactions (Mook-Kanamori et al., 2011; van de Beek et al., 2016).
Table 1.1. Interactions between complement and bacteria in the CNS.
As the long-term sequelae of bacterial meningitis include cognitive impairment, infection-induced inflammation may have lasting or even permanent impact on brain function (van de Beek et al., 2004), and there is strong experimental and clinical evidence for the detrimental role of complement in meningitis. Inhibition of the classical pathway and of C5 were both protective against meningitis caused by S. pneumoniae in rodents (Zwijnenburg et al., 2007; Woehrl et al., 2011), and a single nucleotide polymorphism of C5 (rs17611, encoding V802I) was associated with poor outcome in pneumococcal meningitis patients (Woehrl et al., 2011), indicating that the activation of the classical complement pathway plays a key role in the pathogenesis. In murine bacterial meningitis model, L. monocytogenes infection caused the up-regulation of C3 and FB mRNA levels in the cerebrospinal fluid (CSF) as well as in parenchymal neurons (Stahel et al., 1997), implicating local activation of the alternative pathway in the brain during meningitis. C3aR is up-regulated in glial cells and infiltrating immune cell populations in the brain tissue autopsy from bacterial meningitis patients (Gasque et al., 1998), and C5aR deficient mice were less susceptible to meningitis development despite unaltered bacterial titers in the brain (Woehrl et al., 2011), suggesting the important roles for anaphylatoxin receptor signaling in infection-induced neuroinflammation.
FH and CD46, the negative regulators of the complement system, contribute to or even enable of bacterial dissemination into the CNS. FH binding protein (Fhb) is a meningococcal protein that binds to human FH. The interaction between Fhb and host FH enables the bacteria to evade the innate immune attack, thereby facilitating systemic dissemination. Streptococcus suis, a zoonotic bacterium causing bacterial meningitis (Dominguez-Punaro et al., 2007), expresses Fhb, which contributes to the S. suis virulence via inhibition of C3b/iC3b deposition on the bacterial surface (Pian et al., 2012). In addition, Fhb can contribute to the development of severe meningitis by enhancing the traversal of S. suis across the BBB, as suggested by in vivo and in vitro experiments (Kong et al., 2017). Similarly, CD46 acts as the entry receptor for a number of microbes, including N. meningitidis, an exclusively human pathogen. While CD46 is ubiquitously expressed in human tissues, it is only expressed in the eye and spermatozoa in mouse (Liszewski et al., 2000; Lyzogubov et al., 2014). N. meningitidis does not enter the brain in wild-type mice. However, in genetically engineered mice that express human CD46 (human CD46 transgenic), N. meningitidis traversed BBB, leading to significantly higher mortality (Johansson et al., 2003). In addition to delayed bacterial clearance from the circulation, microglial and astroglial activation was observed in the brain of CD46 transgenic mice (Johansson et al., 2005). These data suggest that N. meningitidis utilizes CD46 to facilitate its own entry into the CNS.
Systemic infection and sepsis can sensitize the brain to inflammation via complement activation, even without the bacteria entering the CNS. In preterm infants, S. epidermidis triggers cerebral inflammation, white matter injury and impaired neurodevelopment (Bi et al., 2015). While Toll-like receptor 2 (TLR2) is thought to be the major contributor to neonatal infection caused by Gram-positive bacteria, the observation that the CSF levels of C1r, C3, and C5 were rapidly increased in S. epidermidis infection-induced sepsis model in pigs (Muk et al., 2019) suggests that systemic infection may cause CNS injury via aberrant activation of the complement cascade. Bacterial lipopolysaccharide-induced long-term depression via microglial CR3 activation offers a specific mechanistic link between neuroinflammation, complement activation, synaptic dysfunction, and memory impairments (Zhang et al., 2014).
While complement protects the host against bacterial infection, excessive complement activation can contribute to CNS injury and long lasting or permanent dysfunction. In addition, several complement components and regulators are exploited by bacteria to facilitate their entry into the CNS.
Viruses
A large number of brain disease-causing viruses, including herpes viruses (human herpes virus 1 [HSV-1], human herpesvirus 6 [HHV-6], and γ-herpesviruses), HIV, measles virus, Borna disease virus (BDV), Theiler’s murine encephalitis virus (TMEV), Venezuelan equine encephalitis virus (VEEV), West Nile virus (WNV), and Zika virus (ZIKV), interact with the complement system in the CNS (Table 1.2) and this interaction may play a role in neurodegeneration. Latent HSV-1 infection is associated with increased risk for AD (Itzhaki, 2018). HHV-6A and HHV-6B are frequently found in patients with neuroinflammatory diseases including MS (Alvarez-Lafuente et al., 2006) and AD (Readhead et al., 2018). γ-herpesviruses, including human Epstein–Barr virus (EBV or HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV-8), also establish life-long latency in the host, which is associated with increased risk of diverse neurological conditions, including meningitis, encephalitis, HIV-related CNS lymphoma, and MS (Said et al., 1997; Bossolasco et al., 2006; Serafini et al., 2007). Seropositivity for EBV is associated with clinical AD (Carbone et al., 2014). In HIV patients, KSHV infection can manifest in the CNS (Andrews et al., 2011; Baldini et al., 2013; Tso et al., 2017). In addition, HIV can cause cognitive impairment, so called HIV-associated neurocognitive disorders (HAND, NeuroAIDS). Indeed, while antiretroviral therapy effectively inhibits viral replication and reduces mortality, more than 50% of HIV-positive individuals suffer from cognitive impairment (Clifford, 2017; Olivier et al., 2018). Even though antiretroviral therapy suppresses viral replication, neurotoxic HIV proteins, such as Tat, continue to be produced in the CNS, leading to persistent inflammation (Liu et al., 2014; Avalos et al., 2017). WNV is a neuroinvasive pathogen that causes significant neuronal loss, inflammation, and microglial activation (Clarke et al., 2014). WNV targets hippocampal neurons (Armah et al., 2007), and patients recovering from WNV disease often suffer from cognitive impairment (Sejvar et al., 2003; Sadek et al., 2010). ZIKV is the causative agent of Zika fever, congenital infection which leads to severe developmental neurodevelopmental defects, including neonatal microcephaly (Rasmussen et al., 2016; Russo et al., 2017). The fact that ZIKV infection in adults can lead to neurological complications such as acute myelitis, encephalomyelitis, encephalitis, meningoencephalitis, and sensory polyneuropathy (Mécharles et al., 2016; Brito Ferreira et al., 2017), further strengthens the notion that ZIKV is highly neurotropic (Souza et al., 2019). VEEV is endemic to Central and South America and periodically emerges from the enzootic cycle to cause infection in human and equid populations (Weaver and Barrett, 2004), occasionally causing severe encephalomyelitis (Weaver et al., 2004). Measles virus infects over 40 million individuals per year (McChesney and Oldstone, 1989). Acute infection can cause encephalomyelitis, the neurological sequelae of which include subacute sclerosing panencephalitis (SSPE) and measles inclusion body encephalitis (MIBE) (Griffin, 2020).
Table 1.2. Interactions between complement and viruses in the CNS.
The complement system provides the first line of defense against viruses, including HSV-1 via the lectin pathway (Bibert et al., 2019), and γ-herpesvirus, VEEV, and WNV via C3-dependent elimination mechanisms (Kapadia et al., 2002; Mehlhop et al., 2005; Brooke et al., 2012). On the other hand, the virus-induced up-regulation of complement components in the CNS may lead to BBB dysfunction and contribute to tissue damage in infection with HIV and TMEV (Speth et al., 2004; Woollard et al., 2014; Libbey et al., 2017). For example, HIV-Tat protein upregulated C3 expression in human brain microvascular endothelial cells (HBMEC) in vitro (Woollard et al., 2014), C1q is up-regulated in the brain of Simian immunodeficiency virus (SIV)-infected rhesus macaques (Speth et al., 2004; Depboylu et al., 2005) and mice after HIV-Tat injection into the cerebral cortex (Hammond et al., 2018), two in vivo models of NeuroAIDS. Increased C1q in the CSF is associated with cognitive impairment in HIV-infected individuals (McGuire et al., 2016). BDV induced local C1q mRNA expression in the hippocampus and cortex (Dietzschold et al., 1995) and ZIKV infection enhanced expression of C1q and C3, associated with microglial activation and hippocampal synaptic damage and memory impairment in a murine infection model using ZIKV intracerebroventricular infusion (Figueiredo et al., 2019). In murine model induced by intracranial infection of WNV, C1q protein colocalized with microglia adjacent to WNV-infected neurons, possibly causing synaptic terminal loss (Vasek et al., 2016). These data suggest that local complement activation may induce cognitive impairment via the disruption of neurotransmission.
Some viruses increase their virulence by manipulating complement regulatory proteins. HSV-1 infection caused the down-regulation of FH in human primary neuroglia in vitro (Hill et al., 2009), potentially leading to enhanced activity of the alternative pathway. As suggested by studies using CD46 transgenic mice, CD46 is involved in the dissemination of measles virus into the CNS, increasing the risk of measles encephalitis (Rall et al., 1997; Manchester et al., 1999; Oldstone et al., 1999; Evlashev et al., 2000). In postmortem SSPE brain tissues, strong CD46 signal was observed on cerebral endothelium throughout the brain, as well as ependymal cells lining the ventricles and choroid plexus (McQuaid and Cosby, 2002), while CD46 expression was suppressed by measles virus infection in SSPE lesions (Ogata et al., 1997; McQuaid and Cosby, 2002). In addition, CD46 expression was observed in primary human glial cells (oligodendrocytes, astrocytes, and microglia) and CD46 inhibition by anti-CD46 antibody suppressed the fusion of glia and measles virus-infected T cells in vitro, suggesting that measles virus may spread in the brain parenchyma via binding to CD46 on glia (Cassiani-Ingoni et al., 2005). In HHV-6 infection models in vitro, using neuronal and glial cell lines, CD46 also mediated HHV-6 infection-induced transactivation of Multiple Sclerosis-Associated Retrovirus (MSRV) (Charvet et al., 2018). In a murine γ-herpesviruses infection model, C3 deficiency caused higher susceptibility to viral latency in the CNS (Kapadia et al., 2002). Several γ-herpesviruses encode homologues of RCAs (Farriesa and Atkinson, 1991), to inhibit complement activation (Fodor et al., 1995; Kapadia et al., 1999, 2002) thereby preventing complement-mediated elimination (Liszewski et al., 1996; Russo et al., 1996; Virgin et al., 1997). Like bacteria, some viruses can utilize and mimic host RCA proteins for their dissemination and entry into the CNS.
Sustained complement activation is associated with neuroinflammation and neurodegeneration in a number of neurological disorders (Eikelenboom et al., 1989; Rogers et al., 1992). Of note, COVID-19 patients reportedly suffer from diverse neurological complications (Stracciari et al., 2021). Although there is no direct evidence thus far to indicate causality between SARS-CoV-2 infection and neuropathology (Maury et al., 2021), future research will show whether there is a causal link between overactivation of complement in response to SARS-CoV-2 and neurological symptoms or long-term complications of COVID-19 (Garred et al., 2021).
Fungi
Fungal infection and dissemination into the brain has been proposed to contribute to the etiology of AD (Alonso et al., 2014, 2018). Candida is one of the most common commensal fungi, and can cause systemic infections which frequently affect the CNS (Lionakis et al., 2011; Alonso et al., 2014, 2018). Mice with invasive candidiasis exhibit microglial activation and local inflammation (Lionakis et al., 2011). Aspergillus and Cryptococcus are also fungal species that can cause invasive CNS infection, especially in immunocompromised individuals (Panackal and Williamson, 2015). Similarly, cerebral aspergillosis is caused by Aspergillus spp. that mainly affect immunocompromised individuals, such as AIDS patients and those under immunosuppressive treatment regimens (Ruhnke et al., 2007). Cryptococcosis, caused by the encapsulated fungus Cryptococcus neoformans, frequently occurs in AIDS, organ transplant recipients and cancer patients, and is the leading cause of mortality in immunocompromised individuals (Rajasingham et al., 2017). These fungal species can also cause meningoencephalitis (Gottfredsson and Perfect, 2000; Góralska et al., 2018), suggesting that fungal infection-induced local inflammation and meningoencephalitis may lead to long-term sequelae including cognitive dysfunction.
The complement system plays pivotal roles in the susceptibility to fungal CNS infection and infection-induced neuropathology (Table 1.3). A study using murine Candida albican infection models showed that C5 could be a major determinant of CNS infection susceptibility (Tuite et al., 2005). Neutrophils play a major protective role against dissemination of C. neoformans (Lovchik and Lipscomb, 1993; Graybill et al., 1997), and C5aR signaling is required for infection-induced neutrophil recruitment to the brain as suggested by data obtained in a murine infection model using C5 deficiency and inhibitory anti-C5aR antibodies (Sun et al., 2016). C5 and its cleavage product C5a are required for pulmonary accumulation of neutrophils upon infection and intravascular clearance of C. neoformans (Lovchik and Lipscomb, 1993; Sun et al., 2016), further confirming the crucial roles for C5 and C5a in neutrophil-mediated killing of C. neoformans. Jointly, these data suggest that complement activation and C5aR signaling are protective against C. neoformans-induced meningoencephalitis. In postmortem brain tissues from subjects with cerebral aspergillosis, C1q, C4, C3, and C5 were up-regulated in the brain, and co-localized with neurons, astrocytes, oligodendrocytes, and infiltrating macrophages (Rambach et al., 2008).
Table 1.3. Interactions between complement and fungi in the CNS.
While the specific mechanistic links between fungal infection and dementia remain to be elucidated (Alonso et al., 2014, 2018), complement may be protective against neurodegenerative disorders via limiting fungal invasion into the CNS.
Parasites
Protozoan parasites including Toxoplasma gondii and Plasmodium spp. are obligate intracellular organisms that can potentially cause dysfunction and parenchymal injury in the brain. While T. gondii infects all nucleated cells of warm-blooded vertebrates, erythrocytes are the main target in Plasmodium infection in vertebrates. Host immune responses to these eukaryotes are very complex (Ivanova et al., 2019). The interactions between the complement system and these protozoa, with relevance for brain pathologies and the potential links to dementia, are summarized in Table 1.4.
Table 1.4. Interactions between complement and parasites in the CNS.
Plasmodium
Plasmodium spp. are the agents causing malaria, one of the deadliest infectious diseases worldwide. Cerebral malaria (CM), caused by P. falciparum, is the most severe and life-threatening condition characterized by diffuse encephalopathy. CM is frequently accompanied by seizures and coma, and accounts for the majority of childhood deaths from malaria in endemic regions (Schmutzhard and Gerstenbrand, 1984; Idro et al., 2010; Riggle et al., 2020). In addition, more than 10% of children who survive CM have persistent neurological sequelae, including those affecting cognition and behavior (Frevert and Nacer, 2014). Among the features of CM is the adherence of Plasmodium-infected red blood cells (iRBCs) to brain vascular endothelium and BBB dysfunction (Yusuf et al., 2017; Pais and Penha-Gonçalves, 2019). Several mechanisms were suggested to explain the severe endothelial damage and vascular leakage in CM, and the proposed hypotheses include hemodynamic hypothesis (Van der Heyde et al., 2006; Wassmer and Grau, 2017), inflammation hypothesis (Silamut et al., 1999; Van der Heyde et al., 2006; Wassmer et al., 2006; Dunst et al., 2017), coagulation dysfunction hypothesis (Grau et al., 2003; Francischetti, 2008; Bridges et al., 2010; OSullivan et al., 2016), and innate immune hypothesis (Pais and Penha-Gonçalves, 2019). However, the exact mechanism remains elusive.
There is evidence suggesting that the complement system plays a significant role in CM pathogenesis. In an early study using murine CM model with P. berghei ANKA (Finley et al., 1982), T cell-deficient (nu/nu) mice were protected against CM compared to nu/+ mice, despite comparable parasitemia. The rapid decrease in serum C3 and concomitant increase in serum immune complexes observed in wildtype mice were absent in nu/nu mice, indicating the interaction between the complement system and cellular immunity in CM (Finley et al., 1982). C1q and C5 protein levels were also significantly higher in the brain of CM mice compared to non-CM mice, suggesting the activation of the classical pathway (Lackner et al., 2008). The roles for the complement system in CM were further examined using genetically modified mice, including mice deficient in C5 (Patel et al., 2008; Ramos et al., 2011; Buckingham et al., 2014), C5aR (Ramos et al., 2011; Kim et al., 2014; McDonald et al., 2015), C3 (Ramos et al., 2012), C4 (Ramos et al., 2012), FB (Ramos et al., 2012), and C3aR (Ramos et al., 2011). Notably, C5 deficient mice were fully protected from CM and CM-associated seizures (Ramos et al., 2011; Buckingham et al., 2014), while C5aR deficient mice were only moderately protected (Ramos et al., 2011; Kim et al., 2014). Mice lacking FB, C4, or C3aR showed outcomes comparable to wildtype mice (Ramos et al., 2011, 2012). In addition, C9 deposits were observed in the CNS during CM, and C9 inhibition (neutralizing anti-C9 antibody injection) significantly delayed CM development (Ramos et al., 2011). Results from clinical studies also show complement activation during CM. Serum C5a levels were significantly higher in children with CM compared to those without CM (Kim et al., 2014). Postmortem CM frontal lobes exhibited activation of complement, the coagulation cascade, and platelets (Kumar et al., 2018). These data suggest that MAC formation plays a critical role in CM pathogenesis. In addition, persistent cognitive deficits caused in the offspring by in utero exposure to malaria were dependent on maternal C5a-C5aR signaling (McDonald et al., 2015). These findings point to the role of C5a in the initiation of neuroinflammation together with the dysregulation of angiogenesis and synaptogenesis (McDonald et al., 2013). Surprisingly, the formation of conventional C5 convertase via C3 activation was not required for CM progression (Ramos et al., 2012), which suggests that C5 was activated by coagulation factors or other non-complement proteases (Ramos et al., 2012; Figure 2). These observations support the role for the complement system as a link between immune responses and dysregulated coagulation during CM.
Figure 2. Known and potential interactions between complement proteins and infectious agents. Infectious agents can modulate the expression or activity of complement proteins and receptors in the brain parenchyma, CSF, and BBB. Highlighted are the core complement components/positive regulators (red) and negative regulators (RCAs) (blue), which are potentially affected by infectious agents. Infection-induced activation of the coagulation cascade can also lead to C3 and C5 cleavage via the extrinsic pathway. Pathogens known to interact with the respective complement proteins are presented in the boxes to the right or below the pathway diagram. B, bacteria; V, viruses; F, fungi; P, parasites; PrP, prion proteins.
The interactions between Plasmodium and the complement system are possibly even more intricate (Schmidt et al., 2015; Kennedy et al., 2016, 2017; Rosa et al., 2016). Blood stage P. falciparum (free merozoites as well as intraerythrocytic schizonts) evades complement-mediated destruction by recruiting FH, a major negative regulator of complement activation, on the cell surface (Kennedy et al., 2016; Rosa et al., 2016). As mentioned above, several other pathogens, including Neisseria meningitidis (Granoff et al., 2009; Schneider et al., 2009) and Borrelia burgdorferi (Kraiczy et al., 2001), use FH for the same purpose, suggesting that it is an evolutionarily conserved strategy to circumvent complement-mediated elimination. Plasmodium utilizes another complement regulatory protein CR1 as a receptor for red blood cell invasion (Tham et al., 2010; Spadafora et al., 2010). In addition, mobilization of CR1 on the surface of Plasmodium-infected red blood cells is required for rosetting (Rowe et al., 1997), a process implicated in vascular obstruction during severe malaria (Carlson, 1993). CR1 polymorphisms could explain the association between altered efficiency of rosetting and malaria severity (Cockburn et al., 2004; Schmidt et al., 2015).
In conclusion, overactivation of complement cascade triggered by the parasite conceivably contributes to CM pathogenesis, and the inhibition of the complement cascade at the level or downstream of C5 activation, and/or the inhibition of CR1 could be a beneficial treatment strategy for CM.
Toxoplasma gondii
Toxoplasma gondii infects approximately one-third of the world population. It is an opportunistic infection that in individuals with immunodeficiency can cause severe diseases, including Toxoplasma encephalitis (Marra, 2018). Infection during pregnancy can lead to congenital toxoplasmosis, the severity of which depends on the stage of pregnancy (Bigna et al., 2020). While Toxoplasma rarely causes symptoms in healthy individuals with effective immunity, it can establish latent infection in the brain and other tissues (Pittman and Knoll, 2015). It is also notable that the virulence can vary depending on Toxoplasma genotype (Howe and Sibley, 1995; Behnke et al., 2011; Pomares et al., 2018; Taniguchi et al., 2018). Once disseminated into the brain, the parasite transforms into bradyzoite form (cyst) and establishes a life-long infection in neurons and glia (Ólafsson and Barragan, 2020). The presence of Toxoplasma cysts in the CNS has been linked to various neuropsychiatric disorders, such as schizophrenia (Elsheikha et al., 2016; Del Grande et al., 2017; Fuglewicz et al., 2017; Fond et al., 2018; Stepanova et al., 2019; Tyebji et al., 2019a, b), possibly via the direct modulation of dopaminergic/serotonergic signaling as well as neuroinflammation (Henriquez et al., 2009; Mahmoud et al., 2017). T cells and type II interferon (IFN-γ)-dependent immune responses are an essential part of the host defense against Toxoplasma infection (Sasai et al., 2018). Type I interferons (IFNs) also play an important regulatory role in the innate immune response during protozoan infection, including toxoplasmosis (Silva-Barrios and Stäger, 2017).
Toxoplasma is classified into three groups: virulent type I, which causes acute infection, and avirulent type II and type III, which are responsible for chronic infection. Several studies have suggested the involvement of the complement system during acute Toxoplasma (type I) infection. Toxoplasma lytic activity of human sera was dependent on classical pathway components (C1q, C2, C4, C5, C6, C7, and C8) in a study using a virulent Toxoplasma strain in vitro (Schreiber and Feldman, 1980). Animal sera (pig, rabbit, and dog), with the exception of cat serum, effectively killed Toxoplasma tachyzoites of a virulent strain via C1q and natural IgM-dependent complement activation (Kaneko et al., 2004). Toxoplasma tachyzoites of the same strain were resistant to complement-mediated lysis via the formation of iC3b, the inactive form of C3b (Fuhrman and Joiner, 1989). Toxoplasma tachyzoites of both virulent and avirulent strains mobilized complement regulatory proteins (FH and C4BP) on their surface to evade complement-mediated parasite killing in vitro, whereas C3 deficient mice suffered higher parasite burden in the brain and other organs in vivo, suggesting complex host-parasite interactions (Sikorski et al., 2020). Of note, C5 deficiency rendered either protection or enhanced mortality depending on the genetic background of the murine host (Araujo et al., 1975). These data suggest that, while the complement system plays a pivotal role in the protection against acute Toxoplasma infection, the parasite has evolved strategies to manipulate the complement system to survive and propagate in the host.
The interaction between Toxoplasma and the complement system in the brain has recently been elucidated. In murine Toxoplasma infection models, cerebral C1q is upregulated during chronic infection with virulent and avirulent strains (Xiao et al., 2016), and persistent infection with a virulent Toxoplasma strain led to the upregulation of C1q, C1r, C3, and C4 mRNA levels and deposition of complement component proteins (C1q and C3) in the brain. These changes were associated with neurodegeneration (Li et al., 2019). An avirulent Toxoplasma strain also caused upregulation of complement proteins, including C3, C4b, and C1q, in the mouse brain (Huang et al., 2019). Furthermore, mRNAs for FB and FP, C3aR, and C5aR were up-regulated in the brain of mice chronically infected with an avirulent Toxoplasma strain (Shinjyo et al., 2021), suggesting that the alternative pathway is activated in the brain during chronic infection. The Toxoplasma infection-induced up-regulation of FB, FP, and C5aR mRNAs occurred in primary murine glial cells in vitro in a microglia-dependent manner (Shinjyo et al., 2021). These data suggest that, while complement-dependent clearance is essential in the initial, peripheral phase of infection, chronic Toxoplasma infection can cause persistent complement activation in the CNS.
Prion Proteins
Transmissible spongiform encephalopathies (TSEs, prion diseases) are fatal neurodegenerative diseases, which include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goat, Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome in humans (Prusiner et al., 1998; Prusiner, 1998). Most neurodegenerative diseases, including prion diseases and AD, share two common features: the accumulation and self-propagation of misfolded proteins (Gomez-Gutierrez and Morales, 2020). TSE-causing infectious prion proteins (PrPSc) transmit the disease-associated conformation to normal prion proteins (PrPC), leading to further propagation of PrPSc. Following peripheral exposure and prior to neuroinvasion, PrPSc accumulates in lymphoid tissues, including lymph nodes and Peyer’s patches. Early PrPSc accumulation occurs within the germinal center on follicular dendritic cells (FDCs) (Brown et al., 1999) as well as within tingible body macrophages (McGovern and Jeffrey, 2007). From the lymphoid tissues, transmission to the CNS occurs via the peripheral nervous system (Glatzel et al., 2001). The central event in prion disease progression is the accumulation of PrPSc in the CNS accompanied by neuronal loss and spongiform neuropils, suggesting aggressive destruction of neural networks (Budka, 2000).
The involvement of the complement system in prion-induced neuropathology has been observed in different types of prion diseases (Bonifati and Kishore, 2007; Table 1.5). In scrapie-infected rodents, total complement activity in the brain was significantly increased at the terminal stage (Lv et al., 2014). In addition, C1q upregulation (Dandoy-Dron et al., 1998, 2000; Carroll et al., 2018), C3 upregulation and colocalization with neurons, and MAC deposition on neurons were observed in infected human brain (Kovacs et al., 2004) as well as in scrapie model in mice (Lv et al., 2014), suggesting the activation of the classical and terminal pathways. C1q also colocalized with infected neurons in vitro, and throughout the brain C1q distribution overlapped with PrP (Hasebe et al., 2012). In addition, FB and FP levels significantly increased in the brain of scrapie-infected mice, while FB and C3 colocalized with neurons and activated microglia (Chen et al., 2020), suggesting the activation of the alternative pathway and microglia. Notably, mice deficient in C1q or FB/C2 were protected against encephalopathy after intraperitoneal prion exposure, but C3 deficiency was not protective (Klein et al., 2001). Interestingly, reactive astrocytes in prion diseases are characterized by C3 up-regulation and mixed A1/A2 phenotype (Hartmann et al., 2019) distinct from neurotoxic astrocytes observed in other neurodegenerative diseases (Kwon and Koh, 2020). The abolishment of C3-positive astrocytes led to prion disease acceleration (Hartmann et al., 2019). These data suggest that C3 plays multiple roles in prion disease progression, depending on the context. In contrast, complement hemolytic activity was significantly lower in the CSF of CJD patients, particularly in genetic CJD cases (Chen et al., 2016). In addition, the protein levels of some complement components, including C3, C4, and C9, decreased in the CSF of sporadic CJD (sCJD) patients compared to non-CJD group (Chen et al., 2016). While the explanation conceivably lies in the increased consumption of complement in the brain parenchyma, the neuropathologic implications of these findings are currently elusive.
Table 1.5. Interactions between complement and prion proteins in the CNS.
Given that FH deficiency was protective against PrP propagation (Kane et al., 2017), prion proteins may escape complement-mediated clearance by manipulating FH-dependent complement inhibition, possibly via direct interaction between PrPSc and FH (Kane et al., 2017). Thus, RCAs seem important target molecules exploited by infectious agents, including prion proteins, to evade innate immunity and propagate throughout the body including the CNS.
Complement: A Double Edge Sword in the Infected Brain
The consequences of local complement activation by infectious agents for brain tissue integrity and function are highly context dependent. Complement has a role in the regulation of normal neuronal functioning and homeostasis. It may be neuroprotective and play a critical role in the elimination of various pathogens, but can also be a major mediator of neurodegeneration and tissue damage. The complement system can also be hijacked by some pathogens and play a complicit role in their dissemination. Figure 2 illustrates the potential interactions between the complement system and infectious agents, and Table 2 summarizes the responses of selected complement proteins to the individual pathogens, including up- or down-regulation, deposition, and the impact of genetic polymorphism or genetic manipulations.
Table 2. The functions of specific complement proteins and in CNS infection.
In the CNS, C1q plays potentially harmful roles in bacterial (S. pneumoniae-induced bacterial meningitis) (Zwijnenburg et al., 2007), viral (HIV-associated cognitive impairment) (McGuire et al., 2016), parasite (Plasmodium, CM) (Lackner et al., 2008), and prion (Klein et al., 2001) infections, while it may be protective during the initial phase of prion disease (Flores-Langarica et al., 2009). Jointly these findings indicate the deleterious consequences of overactivation of the classical pathway. The lectin pathway is protective against herpes simplex virus encephalitis by inhibiting viral dissemination into the CNS (Bibert et al., 2019). While C3-mediated pathogen clearance is beneficial in the periphery (Mehlhop et al., 2005; Brooke et al., 2012; Sun et al., 2016), C3d deposition on synaptic terminals may facilitate synaptic loss in WNV infection (Vasek et al., 2016). Likewise, the net outcome of downstream complement activation seems to be context-dependent. C5 is important for fungal clearance in the vasculature (Sun et al., 2016) and inhibits fungal dissemination into the CNS (Tuite et al., 2005). In contrast, in the Plasmodium infection, C5 deficiency is protective against CM (Patel et al., 2008; Ramos et al., 2011; Buckingham et al., 2014). Inhibition of MAC formation was also protective against CM (Ramos et al., 2011), confirming the crucial role of terminal complement pathway in CM pathogenesis. C3aR was up-regulated in the brain upon viral infection (Libbey et al., 2017) and C3aR deficiency was protective against viral infection-induced synaptic loss (Vasek et al., 2016). C5aR deficiency was also protective against CM development (Patel et al., 2008; Kim et al., 2014; McDonald et al., 2015), as well as bacterial meningitis (Woehrl et al., 2011). However, neither C3aR deficiency nor C5aR deficiency were protective against prion-induced neuropathology (Carroll et al., 2018), indicating pathogen-specific roles of anaphylatoxin receptors in the CNS.
CD46, a negative regulator of the classical and lectin pathways, aids in the dissemination of bacteria (N. meningitidis) (Johansson et al., 2003, 2005) and viruses [Measles virus (Rall et al., 1997; Manchester et al., 1999; Oldstone et al., 1999; Evlashev et al., 2000) and HHV-6 (Cassiani-Ingoni et al., 2005)] into the CNS, leading to meningitis and encephalitis, respectively. While the use of CD46 by these pathogens could be an evasion strategy from the classical or lectin pathway-mediated clearance, CD46-dependent facilitation of immune cell infiltration into the CNS (Manchester et al., 1999; Oldstone et al., 1999) and cell-cell fusion of infected lymphocytes and glial cells (Cassiani-Ingoni et al., 2005) suggest higher mechanistic complexity of the interactions between complement and infectious agents. FH, a negative regulator of the alternative pathway, is also engaged in the dissemination of pathogens in bacterial (S. suis) (Kong et al., 2017) and prion infections (Kane et al., 2017), indicating that these infectious agents manipulate the alternative complement pathway for their propagation in the brain. The fact that a viral RCA homolog plays a facilitatory role in viral dissemination via the inhibition of C3-dependent host defense (Kapadia et al., 2002) suggests that infectious agents have evolved diverse molecular mechanisms to escape complement-mediated killing.
Discussion
Potential Link Between Infection-Induced Complement Activation and Dementia
Considering the link between cognitive impairment and aberrant complement activation in the CNS (Aiyaz et al., 2012; Rubio-Perez and Morillas-Ruiz, 2012), the most simplified view is that CNS infection could lead to dementia via the complement activation (Figure 3A: dotted rectangle). However, as discussed above, the mechanistic links between infectious agents, complement, and neurodegeneration are far more complex. Due to the multiple neurodevelopmental and homeostatic functions that the complement system and its individual components play in the brain (Figure 1), complement activation by infectious agents can cause an imbalance in the intricate web of interactions between complement proteins and the nervous system with deleterious consequences for CNS tissue integrity and function (Figure 3B: solid rectangle). This could explain the unpredictable and sometimes inconsistent observations in different studies in human patients as well as in animal models of CNS infection. The multiple functions of the complement system in the CNS together with the complexity of immune responses to infection call for well-informed and highly selective approaches when manipulating the complement system for therapeutic benefit. For example, inhibiting the down-stream of complement cascade (C5 and MAC) and/or C5aR could protect the brain from Plasmodium infection-induced tissue damage (Patel et al., 2008; Ramos et al., 2011; Buckingham et al., 2014; Kim et al., 2014), whereas inhibition restricted to the upstream components (C1q, C2, and FB) could be beneficial in prion diseases (Klein et al., 2001), as shown in animal models. However, these studies were conducted using constitutive inactivation of specific genes. As the complement system plays multiple roles in the CNS, roles which are distinct from those in the periphery, it is imperative to investigate CNS-specific roles of the complement system in the context of an infection by a specific pathogen. Furthermore, while complement proteins are locally produced in the brain, it is less clear which cell types are responsible, how complement protein production and responses are regulated, and how are these processes influenced by various stimuli under physiological and pathological conditions, including CNS infection. Of particular interest in this respect are the potential functions of intracellular C3 (Elvington et al., 2016), not only with regard to the interactions between infectious agents and the brain-resident cells but also the role of intracellular C3 in neurodegeneration. Considering the diverse roles of glial cells (astrocytes and microglia, the brain-resident macrophages) in the maintenance of CNS homeostasis, further studies are required to elucidate how infectious agents modulate complement generation in glial cells and how, in turn, it might affect the phenotypes of these cells.
Figure 3. Infection-induced complement activation in the CNS and potential links to neurodegeneration and dementia. (A) The most simplified view of how CNS infection can lead to neurodegeneration and dementia is enclosed in the dotted rectangle. Infection-induced complement activation products may contribute to neurodegeneration and dementia via interaction with amyloid deposits and enhanced neuroinflammation. (B) A more detailed schematic representation of specific interactions between infectious agents and the complement system as a potential mechanistic link between CNS infection, neurodegeneration and dementia. The consequences of complement activation may be context-dependent. For example, MAC plays a role in pathogen elimination but can also contribute to tissue damage. C3a and C5a can support tissue repair and adaptive neural plasticity, but also promote potentially detrimental inflammation and leukocyte recruitment. Opsonization and phagocytosis are needed for clearance of pathogens, but the same mechanisms are involved in synapse elimination as the first step in neurodegeneration.
Conclusion
Of the approximately 50 million people with dementia worldwide, about 50% live in low- and middle-income countries (WHO, 2019). Considering higher risk of infection and infection-induced brain disorders in those countries (Fernandes and Caramelli, 2019; Singh et al., 2020), understanding of the potential mechanistic links between infection and neurodegenerative disorders including dementia, will inform the development of preventive and therapeutic strategies. While amyloidogenesis is widely accepted as the underlying cause of AD and other forms of neurodegenerative diseases, Aβ-targeting drug development has been so far unsuccessful (Robakis, 2020). Given that the presence of amyloid plaques does not necessarily indicate cognitive decline (Skaper, 2012; Robakis, 2020), alternative culprits and theories are needed. Indeed, there is a growing body of evidence showing that innate immunity and neuroinflammation play a pivotal role in dementia development (Leng and Edison, 2020).
Separated from the other parts of the body by the BBB and CSF barrier, the CNS is uniquely protected by special immune components, including the complement system and glial cells. While locally produced complement components play crucial homeostatic roles in the CNS, dysregulated complement activity could be detrimental to the function of the CNS. As the key element of brain-resident innate immunity, the complement system plays both protective and destructive roles in neurodegeneration (Kolev et al., 2009). Whereas aberrant complement activation is frequently associated with neuroinflammation and neurodegenerative disorders, the complement system exerts homeostatic functions via eliminating apoptotic cells, cell debris, and toxic substances, and supports plasticity and tissue repair. A broad range of infectious agents can potentially interact with the complement system in the brain and the net outcome of these interactions appears to depend on the specific pathogens, the target components, and the mode of interaction. It is therefore conceivable that pathogen-triggered and persistent activation of the complement system represents the missing mechanistic link between infection, in particular infection affecting the CNS, and neurodegeneration. We are fully aware that the simplified view presented in Figure 3 does not capture every aspect of the involvement of the complement system in infection-induced neuropathology and neurodegeneration, but only highlights the key components of the interplay between pathogens and complement activation induced–neurodegenerative processes that may lead to dementia. While the specific mechanistic links between CNS infection, neurodegeneration and dementia are still unclear, the involvement of the complement system and the pathogen- and disease stage-specific roles of the individual complement proteins warrant further intense investigation.
Author Contributions
NS wrote the first draft of the manuscript. MP and WK critically assessed the content. NS and MP jointly revised and finalized the manuscript. All the authors contributed to the article and approved the submitted version.
Funding
MP’s research was supported by the Swedish Research Council (2017-00991), Hjärnfonden/The Swedish Brain Foundation, the Swedish state under the agreement between the Swedish Government and the county councils, the ALF agreement (716591), E. Jacobson’s Foundation, and R. and U. Amlöv’s Foundation. NS’s research was supported by JSPS KAKENHI Grant No. 19K07839.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
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Keywords: complement, infection, dementia, Alzheimer’s disease, inflammation
Citation: Shinjyo N, Kagaya W and Pekna M (2021) Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia. Front. Cell. Neurosci. 15:710390. doi: 10.3389/fncel.2021.710390
Received: 16 May 2021; Accepted: 09 July 2021;
Published: 02 August 2021.
Edited by:
Marco Bacigaluppi, San Raffaele Scientific Institute (IRCCS), ItalyReviewed by:
Faith H. Brennan, The Ohio State University, United StatesJudith Fraussen, Hasselt University, Belgium
Copyright © 2021 Shinjyo, Kagaya and Pekna. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Noriko Shinjyo, nshinjyo@ifrec.osaka-u.ac.jp