Complement factor H contributes to mortality in humans and mice with bacterial meningitis

Area of Science:

• Immunology
• Neuroscience
• Genetics

Background:

• The complement system is crucial in the inflammatory response to bacterial meningitis.
• Complement factor H (FH) regulates the alternative pathway but is exploited by pathogens like *Streptococcus pneumoniae* for immune evasion.
• Previous studies suggest blocking complement improves outcomes in experimental meningitis.

Purpose of the Study:

• To investigate the influence of genetic variations in *CFH* on FH levels and disease severity in bacterial meningitis.
• To elucidate the role of FH in pneumococcal meningitis using a mouse model.
• To evaluate the therapeutic potential of human FH (hFH) in treating pneumococcal meningitis.

Main Methods:

• A prospective cohort study of 1009 community-acquired bacterial meningitis episodes.
• Analysis of genetic variations in *CFH* and their association with FH cerebrospinal fluid levels and mortality.
• Utilized *Cfh* knockout and wild-type mice in a pneumococcal meningitis model.
• Conducted a randomized, blinded trial of adjuvant hFH treatment in mice.

Main Results:

• A specific *CFH* single nucleotide polymorphism (rs6677604, major allele G) correlated with low FH cerebrospinal fluid levels and increased mortality.
• FH levels were elevated during meningitis in patients and mice.
• *Cfh* knockout mice exhibited higher mortality than wild-type mice due to C3 depletion.
• Adjuvant hFH treatment inhibited complement but increased bacterial outgrowth, leading to similar disease outcomes.

Conclusions:

• Low FH levels are a significant contributor to mortality in pneumococcal meningitis.
• Therapeutic administration of FH at a clinically relevant time point did not demonstrate a beneficial effect on disease outcome.