The human complement regulator factor H binds pneumococcal surface protein PspC via short consensus repeats 13 to 15

Area of Science:

• Microbiology
• Immunology
• Structural Biology

Background:

• Streptococcus pneumoniae evades complement-mediated immunity by binding complement regulatory proteins.
• Factor H (fH) is a key regulator of the alternative complement pathway, and its interaction with pathogens is vital for immune evasion.
• Pneumococcal surface protein C (PspC) is known to bind fH, but the precise binding site remains uncharacterized.

Purpose of the Study:

• To map the specific short consensus repeats (SCRs) on factor H responsible for binding to pneumococcal surface protein C (PspC).
• To elucidate the nature of the interaction between PspC and factor H.

Main Methods:

• Utilized isogenic PspC-negative pneumococcal mutants to confirm PspC-dependent fH binding.
• Employed recombinant PspC variants (PspCDeltaPro) to assess the role of specific protein regions.
• Conducted inhibition assays with heparin, C3b, and NaCl to characterize the binding interaction.
• Constructed and tested SCR deletion/fusion proteins of factor H to identify binding domains.

Main Results:

• Factor H binding to Streptococcus pneumoniae was confirmed to be dependent on PspC.
• The proline-rich region of PspC is important for efficient factor H binding.
• The interaction between PspC and factor H is largely hydrophobic and does not involve fH's heparin or C3b binding sites.
• Factor H's SCRs 8 to 15 mediate binding to PspC, with SCRs 13 and 15 being critical for full binding.

Conclusions:

• The study precisely maps the factor H binding site for PspC to SCRs 8-15, highlighting SCRs 13 and 15.
• Understanding this interaction provides insights into Streptococcus pneumoniae's complement evasion mechanisms.
• This detailed mapping can inform the development of novel therapeutic strategies targeting bacterial immune evasion.