An Alternative Role of C1q in Bacterial Infections: FacilitatingStreptococcus pneumoniaeAdherence and Invasion of Host Cells

Abstract

Streptococcus pneumoniae (pneumococcus) is a major human pathogen, which evolved numerous successful strategies to colonize the host. In this study, we report a novel mechanism of pneumococcal–host interaction, whereby pneumococci use a host complement protein C1q, primarily involved in the host-defense mechanism, for colonization and subsequent dissemination. Using cell-culture infection assays and confocal microscopy, we observed that pneumococcal surface-bound C1q significantly enhanced pneumococcal adherence to and invasion of host epithelial and endothelial cells. Flow cytometry demonstrated a direct, Ab-independent binding of purified C1q to various clinical isolates of pneumococci. This interaction was seemingly capsule serotype independent and mediated by the bacterial surface-exposed proteins, as pretreatment of pneumococci with pronase E but not sodium periodate significantly reduced C1q binding. Moreover, similar binding was observed using C1 complex as the source of C1q. Furthermore, our data show that C1q bound to the pneumococcal surface through the globular heads and with the host cell-surface receptor(s)/glycosaminoglycans via its N-terminal collagen-like stalk, as the presence of C1q N-terminal fragment and low m.w. heparin but not the C-terminal globular heads blocked C1q-mediated pneumococcal adherence to host cells. Taken together, we demonstrate for the first time, to our knowledge, a unique function of complement protein C1q, as a molecular bridge between pneumococci and the host, which promotes bacterial cellular adherence and invasion. Nevertheless, in some conditions, this mechanism could be also beneficial for the host as it may result in uptake and clearance of the bacteria.

Binding of Streptococcus pneumoniae Endopeptidase O (PepO) to Complement Component C1q Modulates the Complement Attack and Promotes Host Cell Adherence

“…Taken together, the data suggest that C1q interacts primarily via its C-terminal globular heads with PepO. Indeed, this is in accordance with our recent finding, that C1q interacts directly in an antibodyindependent manner via its C-terminal globular heads with the pneumococcal surface-presented protein(s) and is functionally active (22). Apart from PepO, C1q will likely interact with other bacterial proteins as well as C-reactive protein and specific antibodies that both bind to the bacterial surface.…”

“…In turn, C1q functions as a molecular bridge between pneumococci and the host facilitating pneumococcal adherence and invasion (22). In the present study, we identified the multifunctional pneumococcal protein endopeptidase O (PepO) as the C1q ligand at the bacterial surface.…”

“…Inhibition of C1q-mediated Pneumococcal Adherence to Host Cells by PepO-We have recently shown that C1q facilitates pneumococcal adhesion to host cells (22). To confirm the role of PepO in this process, blocking experiments were performed.…”

“…Additionally, these virulence factors function as adhesins that either interact directly with the host cell surface receptors or utilize host proteins as a molecular bridge between the bacteria and the host to facilitate colonization. Host proteins include extracellular matrix and serum proteins such as fibronectin, thrombospondin, vitronectin, plasminogen, Factor H, C4BP, and C1q (12,18,(22)(23)(24)(25)(26)(27).…”

“…We recently reported that C1q directly interacts with protein(s) at the pneumococcal surface (22). In turn, C1q functions as a molecular bridge between pneumococci and the host facilitating pneumococcal adherence and invasion (22).…”