TABLE 2.
The functions of specific complement proteins and in CNS infection.
| Pathogen | Observation | Function | References | |
| Classical pathway | ||||
| Bacteria | ||||
| 1 | Staphylococcus epidermidis | C1r is up-regulated in CSF. | Unknown | Muk et al., 2019 |
| 2 | Streptococcus pneumoniae | C1 inhibitor is protective against meningitis. | Harmful | Zwijnenburg et al., 2007 |
| Viruses | ||||
| 1 | BDV | C1q is up-regulated in the brain. | Unknown | Dietzschold et al., 1995 |
| 2 | HIV (Tat protein) | C1q is up-regulated in the brain (corpus callosum), however, C1q deficiency does not prevent HIV-induced synaptic loss and microgliosis. | Not harmful | Hammond et al., 2018 |
| 3 | HIV | CSF C1q is associated with cognitive impairment. | Potentially harmful | McGuire et al., 2016 |
| 4 | HIV | C1q is up-regulated and colocalizes with microglia/macrophages in the infected brain. | Unknown | Depboylu et al., 2005 |
| 5 | HIV | C1q is up-regulated in astrocytes, microglia, and neuron, expressed in infiltrating immune cells, and deposited on the membrane of neurons. | Unknown | Speth et al., 2004 |
| 6 | WNV | C1q deposition on microglial processes adjacent to WNV-positive neurons, which may facilitate synaptic loss. | Unknown | Vasek et al., 2016 |
| 7 | ZIKV | C1q is up-regulated in the CNS, which is associated with microglial activation. | Unknown | Figueiredo et al., 2019 |
| Fungi | ||||
| 1 | Aspergillus spp. | C1q is up-regulated in the postmortem brain from cerebral aspergillosis subjects. Complement proteins co-localized with neurons, astrocytes, oligodendrocytes, and infiltrating macrophages. Higher levels in the surrounding fibrous layer. | Unknown | Rambach et al., 2008 |
| Parasites | ||||
| 1 | Plasmodium falciparum | C1q is up-regulated in the frontal lobe of cerebral malaria patients. | Unknown | Kumar et al., 2018 |
| 2 | Plasmodium spp. | C1q is up-regulated in the brain of cerebral malaria, correlation with clinical severity. | Potentially harmful | Lackner et al., 2008 |
| 3 | Toxoplasma gondii | C1q is up-regulated in the cerebral cortex and glial cells. | Unknown | Shinjyo et al., 2021 |
| 4 | Toxoplasma gondii | C1q is up-regulated in the brain. | Unknown | Huang et al., 2019 |
| 5 | Toxoplasma gondii | C1q and C1r are up-regulated in the brain with high cyst burden. | Unknown | Li et al., 2019 |
| 6 | Toxoplasma gondii | C1q is up-regulated in the brain. | Unknown | Xiao et al., 2016 |
| Prion proteins | ||||
| 1 | Prion (scrapie) | C1q is up-regulated in the brain. | Unknown | Carroll et al., 2018 |
| 2 | Prion (scrapie) | C1q is up-regulated in the brain. | Unknown | Lv et al., 2014 |
| 3 | Prion (scrapie) | C1q and complement receptor mediate PrPSc uptake by cDCs in the periphery | Potentially beneficial in the initial phase. | Flores-Langarica et al., 2009 |
| 4 | Prion (scrapie) | C1q colocalized with PrP in neurons. | Unknown | Kovacs et al., 2004 |
| 5 | Prion (scrapie) | C1q deficiency is protective against hippocampal neuropathogenesis. | Harmful | Klein et al., 2001 |
| 6 | Prion (BSE and scrapie) | C1q is up-regulated in the brain. | Unknown | Dandoy-Dron et al., 2000 |
| 7 | Prion (scrapie) | C1q is up-regulated in the brain. | Unknown | Dandoy-Dron et al., 1998 |
| Lectin pathway | ||||
| Viruses | ||||
| 1 | HSV-1 | Defects in the lectin pathway (MBL and MASP) can cause higher viral burden in the brain and susceptibility to adult Herpes simplex virus encephalitis. | Beneficial | Bibert et al., 2019 |
| Classical pathway or Lectin pathway | ||||
| Viruses | ||||
| 1 | TMEV | C4b is up-regulated in the CNS. | Unknown | Libbey et al., 2017 |
| Parasites | ||||
| 1 | Toxoplasma gondii | C4b is up-regulated in the brain. | Unknown | Huang et al., 2019 |
| 2 | Toxoplasma gondii | C4 is up-regulated in the brain with high cyst burden. | Unknown | Li et al., 2019 |
| Proteins | ||||
| 1 | Prion (scrapie) | C4b is up-regulated in the brain. | Unknown | Carroll et al., 2018 |
| 2 | Prion (scrapie) | C2 contributes to hippocampal neuropathogenesis. | Harmful | Klein et al., 2001 |
| Alternative pathway | ||||
| Bacteria | ||||
| 1 | Listeria monocytogenes | FB is up-regulated in CSF and neurons. | Unknown | Stahel et al., 1997 |
| 2 | Streptococcus suis | Bacterial Factor H binding protein (Fhb) facilitates BBB traversal. | Potentially complicit | Kong et al., 2017 |
| Parasites | ||||
| 1 | Toxoplasma gondii | FB and FP are up-regulated in the cerebral cortex and glial cells. | Unknown | Shinjyo et al., 2021 |
| Proteins | ||||
| 1 | Prion (scrapie) | FB and FP are up-regulated in the brain. | Unknown | Chen et al., 2020 |
| 2 | Prion (scrapie) | FB facilitates hippocampal neuropathogenesis. | Harmful | Klein et al., 2001 |
| C3 | ||||
| Bacteria | ||||
| 1 | Staphylococcus epidermidis | C3 is up-regulated in CSF. | Unknown | Muk et al., 2019 |
| 2 | Listeria monocytogenes | C3 is up-regulated in CSF and neurons. | Unknown | Stahel et al., 1997 |
| Viruses | ||||
| 1 | γ-herpesvirus | C3 prevents viral latency in the CNS. | Beneficial | Kapadia et al., 2002 |
| 2 | HIV | C3 is up-regulated in the brain (corpus callosum). | Unknown | Hammond et al., 2018 |
| 3 | HIV (Tat protein) | C3 and C3b are up-regulated in BBB endothelial cells. | Unknown | Woollard et al., 2014 |
| 4 | HIV | C1q is up-regulated in astrocytes, microglia, and neuron, expressed in infiltrating immune cells, and deposited on the membrane of neurons. | Unknown | Speth et al., 2004 |
| 5 | TMEV | C3 is up-regulated in the CNS. | Unknown | Libbey et al., 2017 |
| 6 | VEEV | C3-dependent viral clearance in the periphery is protective against VEEV-induced encephalitis. | Beneficial | Brooke et al., 2012 |
| 7 | WNV | C3d deposition on synaptic terminals, which may facilitate synaptic loss. | Potentially harmful | Vasek et al., 2016 |
| 8 | WNV | C3 is protective against WNV dissemination in the CNS. C3 plays a role in WNV-specific antibody development. | Beneficial | Mehlhop et al., 2005 |
| 9 | ZIKV | C3 is up-regulated in the CNS, association with microglial activation. | Unknown | Figueiredo et al., 2019 |
| Fungi | ||||
| 1 | Aspergillus spp. | C3 is up-regulated in the postmortem brain from cerebral aspergillosis subjects. Co-localized with neurons, astrocytes, oligodendrocytes, and infiltrating macrophages. Higher levels in the surrounding fibrous layer. | Unknown | Rambach et al., 2008 |
| 2 | Cryptococcus neoformans | C3 facilitates the intravascular clearance of C. neoformans. | Beneficial | Sun et al., 2016 |
| Parasites | ||||
| 1 | Toxoplasma gondii | C3 is up-regulated in the brain. | Unknown | Huang et al., 2019 |
| 2 | Toxoplasma gondii | C3 is up-regulated in the cerebral cortex and glial cells. | Unknown | Shinjyo et al., 2021 |
| 3 | Toxoplasma gondii | C3 is up-regulated in the brain with high cyst burden. | Unknown | Li et al., 2019 |
| Proteins | ||||
| 1 | Prion (scrapie and human sCJD) | C3 is up-regulated in A1/A2-mixed astrocytes in the brain. | Unknown | Hartmann et al., 2019 |
| 2 | Prion (scrapie) | C3 is up-regulated and colocalized with neurons and glia in the brain. | Unknown | Lv et al., 2014 |
| 3 | Prion (scrapie) | C3b colocalized with PrP in neurons. | Unknown | Kovacs et al., 2004 |
| 4 | Prion (scrapie) | C3 deficiency is NOT protective against prion-induced hippocampal neuropathogenesis. | Not harmful | Klein et al., 2001 |
| C5 | ||||
| Bacteria | ||||
| 1 | Staphylococcus epidermidis | C5 up-regulation in CSF. | Unknown | Muk et al., 2019 |
| 2 | Streptococcus pneumoniae | C5 inhibition is protective against meningitis. | Potentially harmful | Woehrl et al., 2011 |
| Fungi | ||||
| 1 | Aspergillus spp. | C3 is up-regulated in the postmortem brain from cerebral aspergillosis subjects. Complement co-localized with neurons, astrocytes, oligodendrocytes, and infiltrating macrophages. Higher levels in the surrounding fibrous layer. | Unknown | Rambach et al., 2008 |
| 2 | Candida albicans | C5 deficiency is associated with fungal dissemination, including in the brain. | Beneficial | Tuite et al., 2005 |
| 3 | Cryptococcus neoformans | C5 facilitates the intravascular clearance of C. neoformans. | Beneficial | Sun et al., 2016 |
| Parasites | ||||
| 1 | Plasmodium spp. | C5 deficiency is protective against infection-induced seizures. | Harmful | Buckingham et al., 2014 |
| 2 | Plasmodium spp. | C5 deficiency is protective against cerebral malaria development. | Harmful | Ramos et al., 2011 |
| 3 | Plasmodium spp. | C5 deficiency is protective against cerebral malaria development. | Harmful | Patel et al., 2008 |
| 4 | Plasmodium spp. | C5 is up-regulated in the brain of cerebral malaria, correlates with clinical severity. | Unknown | Lackner et al., 2008 |
| 5 | Taenia solium | C5 polymorphism is associated with the risk of developing neurocysticercosis. | Unknown | Villegas et al., 2019 |
| MAC | ||||
| Parasites | ||||
| 1 | Plasmodium spp. | C9 deposits throughout the cortex of cerebral malaria, frequently colocalizing with blood vessels. Anti-C9 antibody treatment delayed the progress of cerebral malaria. | Harmful | Ramos et al., 2011 |
| 2 | Prion (scrapie) | MAC deposits and colocalized with neurons in the brain. | Unknown | Lv et al., 2014 |
| 3 | Prion (scrapie) | MAC formation is correlated with severity of neuropathology. | Potentially harmful | Kovacs et al., 2004 |
| C3aR | ||||
| Bacteria | ||||
| 1 | Meningitis causing bacteria | Up-regulated in reactive astrocytes, microglia, and infiltrating immune cells. | Unknown | Gasque et al., 1998 |
| Viruses | ||||
| 1 | TMEV | C3aR is up-regulated in the CNS. | Unknown | Libbey et al., 2017 |
| 2 | WNV | C3aR deficiency is protective against WNV-induced synaptic loss. | Harmful | Vasek et al., 2016 |
| Parasites | ||||
| 1 | Toxoplasma gondii | C3aR is up-regulated in the cerebral cortex. | Unknown | Shinjyo et al., 2021 |
| Proteins | ||||
| 2 | Prion (scrapie) | C3aR is up-regulated in the brain. C3aR deficiency was not protective against neuropathology. | Not harmful | Carroll et al., 2018 |
| C5aR | ||||
| Bacteria | ||||
| 1 | Streptococcus pneumoniae | C5aR deficiency is protective against meningitis, while conferring no impact on bacterial titer. | Potentially harmful | Woehrl et al., 2011 |
| Viruses | ||||
| 1 | TMEV | C5aR is up-regulated in the CNS. | Unknown | Libbey et al., 2017 |
| Fungi | ||||
| 1 | Cryptococcus neoformans | C5aR-dependent neutrophil recruitment mediates intravascular clearance of C. neoformans. | Beneficial | Sun et al., 2016 |
| Parasites | ||||
| 1 | Plasmodium spp. | C5aR mediates in utero malaria exposure-induced persistent neurocognitive deficits. | Harmful | McDonald et al., 2015 |
| 2 | Plasmodium spp. | C5a is up-regulated C5aR deficiency was protective against in cerebral malaria. | Harmful | Kim et al., 2014 |
| 3 | Plasmodium spp. | C5aR blockade was protective against cerebral malaria. | Harmful | Patel et al., 2008 |
| 4 | Toxoplasma gondii | C5aR is up-regulated in the cerebral cortex and glial cells. | Unknown | Shinjyo et al., 2021 |
| Proteins | ||||
| 1 | Prion (scrapie) | C5aR is up-regulated in the brain. C5aR deficiency was not protective against neuropathology. | Not harmful | Carroll et al., 2018 |
| Regulators of complement activation (RCAs) | ||||
| CR1/CR2 (CD35/CD21) | ||||
| Viruses | ||||
| 1 | West Nile virus (WNV) | CR1/CR2 is protective against WNV dissemination in the CNS. CR1/CR2 plays a role in WNV-specific antibody development. | Beneficial | Mehlhop et al., 2005 |
| CD46 | ||||
| Bacteria | ||||
| 1 | Neisseria meningitidis | Human CD46 mediates meningitis development. | Complicit | Johansson et al., 2005 |
| 2 | Neisseria meningitidis | Human CD46 mediates BBB traversal. | Complicit | Johansson et al., 2003 |
| Viruses | ||||
| 1 | HHV-6A | Human CD46 mediates HHV-6A induced transactivation of MSRV-Env, which leads to TLR4 activation. | Unknown | Charvet et al., 2018 |
| 2 | HHV-6 | Human CD46 facilitates viral dissemination into the CNS via mediating cell-cell fusion of infected lymphocytes and glial cells. | Complicit | Cassiani-Ingoni et al., 2005 |
| 3 | Measles virus | Human CD46 is down-regulated in the postmortem brain of Measles virus-induced subacute sclerosing panencephalitis subjects. | Unknown | McQuaid and Cosby, 2002 |
| 4 | Measles virus | Human CD46 mediates progressive viral dissemination and the development of encephalitis. | Complicit | Evlashev et al., 2000 |
| 5 | Measles virus | Human CD46 causes the suppression of immune responses caused by viral infection, and facilitates viral dissemination into the CNS, leading to glial activation and T cell infiltration. | Complicit Eventually harmful | Oldstone et al., 1999 |
| 6 | Measles virus | Human CD46 expression in neurons facilitates viral replication in the brain, and causes the infiltration of immune cells into the CNS and lethality. | Complicit Eventually harmful | Manchester et al., 1999 |
| 7 | Measles virus | CD46 is down-regulated in the heavily infected brain lesions of SSPE patients. | Unknown | Ogata et al., 1997 |
| 8 | Measles virus | Human CD46 expression in neurons facilitates viral dissemination in the brain (hippocampus and cortex). | Complicit | Rall et al., 1997 |
| FH | ||||
| Bacteria | ||||
| 1 | Streptococcus suis | Bacterial Factor H binding protein (Fhb) facilitates BBB traversal. | Potentially complicit | Kong et al., 2017 |
| Viruses | ||||
| 1 | HSV-1 | FH is down-regulated in infected neural cells. | Unknown | Hill et al., 2009 |
| Proteins | ||||
| 1 | Prion (scrapie) | FH directly interacts with PrPSc. FH facilitates disease propagation. | Potentially complicit | Kane et al., 2017 |
| RCA homolog | ||||
| Viruses | ||||
| 1 | γ-herpesvirus | Viral RCA homologue increases viral virulence via inhibiting C3-dependent host defense. | Manipulated | Kapadia et al., 2002 |
The relevant complement proteins are highlighted in bold.