Complement regulator Factor H mediates a two-step uptake of Streptococcus pneumoniae by human cells

Area of Science:

• Microbiology
• Immunology
• Cell Biology

Background:

• Streptococcus pneumoniae recruits the complement regulator Factor H to its surface.
• The bacterial PspC protein mediates Factor H binding through specific short consensus repeats (SCRs).

Purpose of the Study:

• To elucidate the mechanism by which Factor H facilitates pneumococcal adherence and uptake by host cells.
• To identify the host cell receptors and signaling pathways involved in Factor H-mediated pneumococcal invasion.

Main Methods:

• Investigated pneumococcal adherence and uptake using glycosaminoglycans (heparin, dermatan sulfate) and monoclonal antibodies targeting Factor H SCRs.
• Utilized blocking studies with antibodies against integrin CR3 (CD11b/CD18) and the CR3 ligand Pra1.
• Examined the role of host cell actin dynamics, protein-tyrosine kinases, and phosphatidylinositol 3-kinase in pneumococcal invasion.

Main Results:

• Heparin and dermatan sulfate reduced pneumococcal adherence, while Factor H binding remained unaffected.
• Monoclonal antibodies against Factor H SCR19-20 inhibited adherence, indicating the C-terminal region mediates initial contact.
• Blocking integrin CR3 or using Pra1 significantly reduced pneumococcal interaction with epithelial cells and PMNs.
• Pra1 inhibited pneumococcal uptake but not adherence to lung epithelial cells.
• Factor H-mediated invasion required actin dynamics and was dependent on protein-tyrosine kinases and phosphatidylinositol 3-kinase.

Conclusions:

• Pneumococcal entry into host cells via Factor H is a two-step process.
• Initial contact is mediated by glycosaminoglycans on host cells binding to Factor H.
• Subsequent uptake is an integrin-mediated process dependent on host signaling pathways like phosphatidylinositol 3-kinase.