title: Complement C1q and C3 are critical for the innate immune response to Streptococcus pneumoniae in the central nervous system.
abstract: Previous studies suggest that the complement system can contribute to limiting pneumococcal outgrowth within the CNS. In this study, we evaluated the role of the complement system in the activation of the innate immune response and the development of the prognosis-relevant intracranial complications in a murine model of pneumococcal meningitis. Thereby, we used mice deficient in C1q, lacking only the classical pathway, and C3, lacking all three complement activation pathways. At 24 h after intracisternal infection, bacterial titers in the CNS were almost 12- and 20-fold higher in C1q- and C3-deficient-mice, respectively, than in wild-type mice. Mean CSF leukocyte counts were reduced by 47 and 73% in C1q- and C3-deficient-mice, respectively. Intrathecal reconstitution with wild-type serum in C3-deficient mice restored both the ability of mice to combat pneumococcal infection of the CSF and the ability of leukocytes to egress into the CSF. The altered recruitment of leukocytes into the CSF of C3-deficient mice was paralleled by a strong reduction of the brain expression of cytokines and chemokines. The dampened immune response in C3-deficient mice was accompanied by a reduction of meningitis-induced intracranial complications, but, surprisingly, also with a worsening of short-term outcome. The latter seems to be due to more severe bacteremia (12- and 120-fold higher in C1q- and C3-deficient-mice, respectively) and, consecutively, more severe systemic complications. Thus, our study demonstrated for the first time that the complement system plays an integral role in mounting the intense host immune response to Streptococcus pneumoniae infection of the CNS.
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians-University, Munich, Germany.
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Rupprecht
authors.forename: Barbara
authors.initials: B
authors.lastname: Angele
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.forename: Juergen
authors.initials: J
authors.lastname: Heesemann
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
mesh_terms: D000818:Animals; D016470:Bacteremia; D002490:Central Nervous System / Q000276:immunology / Q000382:microbiology*; D002634:Chemotaxis, Leukocyte; D015922:Complement C1q / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology*; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007958:Leukocyte Count; D008586:Meningitis, Pneumococcal / Q000150:complications / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D003176:Complement C3; D015922:Complement C1q