Thrombin-activatable fibrinolysis inhibitor influences disease severity in humans and mice with pneumococcal meningitis.
BACKGROUND
Mortality and morbidity in patients with bacterial meningitis result from the proinflammatory response and dysregulation of coagulation and fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is activated by free thrombin or thrombin in complex with thrombomodulin, and plays an antifibrinolytic role during fibrin clot degradation, but also has an anti-inflammatory role by inactivating proinflammatory mediators, such as complement activation products.


OBJECTIVE
To assess the role of TAFI in pneumococcal meningitis.


METHODS
We performed a prospective nationwide genetic association study in patients with bacterial meningitis, determined TAFI and complement levels in cerebrospinal fluid (CSF), and assessed the function of TAFI in a pneumococcal meningitis mouse model by using Cpb2 (TAFI) knockout mice.


RESULTS
Polymorphisms (reference sequences: rs1926447 and rs3742264) in the CPB2 gene, coding for TAFI, were related to the development of systemic complications in patients with pneumococcal meningitis. Higher protein levels of TAFI in CSF were significantly associated with CSF complement levels (C3a, iC3b, and C5b-9) and with more systemic complications in patients with bacterial meningitis. The risk allele of rs1926447 (TT) was associated with higher levels of TAFI in CSF. In the murine model, consistent with the human data, Cpb2-deficient mice had decreased disease severity, as reflected by lower mortality, and attenuated cytokine levels and bacterial outgrowth in the systemic compartment during disease, without differences in the brain compartment, as compared with wild-type mice.


CONCLUSIONS
These findings suggest that TAFI plays an important role during pneumococcal meningitis, which is likely to be mediated through inhibition of the complement system, and influences the occurrence of systemic complications and inflammation.
Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
B B
BB
Mook-Kanamori
Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
M
M
Valls Serón
Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
M
M
Geldhoff
Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
S R
SR
Havik
Medical Microbiology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.|Netherlands Reference Laboratory for Bacterial Meningitis, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
A
A
van der Ende
Laboratory for Genome Analysis, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
F
F
Baas
Center for Experimental and Molecular Medicine, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
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T
van der Poll
Department of Experimental Vascular Medicine, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.|Department of Vascular Medicine, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
J C M
JC
Meijers
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
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B
P Morgan
Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
M C
MC
Brouwer
Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands.
D
D
van de Beek
D000328:Adult; D000368:Aged; D000818:Animals; D001925:Brain Damage, Chronic / Q000209:etiology; D025901:Carboxypeptidase B2 / Q000134:cerebrospinal fluid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002543:Cerebral Hemorrhage / Q000209:etiology; D017714:Community-Acquired Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000235:genetics; D015926:Complement C3a / Q000134:cerebrospinal fluid; D003179:Complement C3b / Q000134:cerebrospinal fluid; D015938:Complement Membrane Attack Complex / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000097:blood; D005260:Female; D005342:Fibrinolysis; D006801:Humans; D008297:Male; D008585:Meningitis, Meningococcal / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics; D008586:Meningitis, Pneumococcal / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012131:Respiratory Insufficiency / Q000209:etiology; D012772:Shock, Septic / Q000209:etiology; D016896:Treatment Outcome
D015938:Complement Membrane Attack Complex; D016207:Cytokines; D015926:Complement C3a; D003179:Complement C3b; C585364:CPB2 protein, human; D025901:Carboxypeptidase B2; C585365:Cpb2 protein, mouse
Streptococcus pneumoniae; blood coagulation; complement system proteins; pneumococcal meningitis; thrombin-activatable fibrinolysis inhibitor