The Pneumococcal Surface Proteins PspA and PspC Sequester Host C4-Binding Protein To Inactivate Complement C4b on the Bacterial Surface

Abstract

Complement is a critical component of antimicrobial immunity. Various complement regulatory proteins prevent host cells from being attacked. Many pathogens have acquired the ability to sequester complement regulators from host plasma to evade complement attack. We describe here how Streptococcus pneumoniae adopts a strategy to prevent the formation of the C3 convertase C4bC2a by the rapid conversion of surface bound C4b and iC4b into C4dg, which remains bound to the bacterial surface but no longer forms a convertase complex. Noncapsular virulence factors on the pneumococcus are thought to facilitate this process by sequestering C4b-binding protein (C4BP) from host plasma. When S. pneumoniae D39 was opsonized with human serum, the larger C4 activation products C4b and iC4b were undetectable, but the bacteria were liberally decorated with C4dg and C4BP. With targeted deletions of either PspA or PspC, C4BP deposition was markedly reduced, and there was a corresponding reduction in C4dg and an increase in the deposition of C4b and iC4b. The effect was greatest when PspA and PspC were both knocked out. Infection experiments in mice indicated that the deletion of PspA and/or PspC resulted in the loss of bacterial pathogenicity. Recombinant PspA and PspC both bound serum C4BP, and both led to increased C4b and reduced C4dg deposition on S. pneumoniae D39. We conclude that PspA and PspC help the pneumococcus to evade complement attack by binding C4BP and so inactivating C4b.

Single-Cell Expression Landscape of SARS-CoV-2 Receptor ACE2 and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients

“…Cutoffs of absolute gene expression (fold-change: >1.2) and a FDR ( q -value < 0.05) were applied to select DEGs between ACE2 -expressing ( n = 607) and ACE2 -absent ( n = 26,628) AT2 cells. Among genes upregulated in ACE2 -expressing AT2 cells, we identified genes that are highly pertinent to lung epithelial biology and disease such as HHIP (lung branching and COPD [ 24 , 25 ]), FGG (fibrosis, pneumonia, and inflammation [ 26 , 27 ]), and C4BPA (complement system, pneumonia, and infection [ 28 , 29 ]) ( Figure 3 A,B). In addition, we found that ACE2 -expressing AT2 cells exhibited significantly a higher expression of scavengers such as CD36 [ 30 ], as well as DMBT1 , a pattern recognition receptor that plays crucial roles in host defense against bacterial and viral pathogens, including influenza A and human immune deficiency virus 1 (HIV-1) [ 31 ] ( Figure 3 A,B).…”

“…FGG coding for fibrinogen-gamma was shown to be induced by proinflammatory cytokines [ 27 ] and to be elevated in lung pneumonia and infection [ 26 ]. C4BPA , coding for C4BP and part of the complement system, was found to recognize and bind pneumonia-causing streptococci in the lung epithelium [ 28 , 29 ]. It is noteworthy that many patients with COVID-19 (e.g., those with severe disease) commonly display the same pathological phenotypes, namely lung inflammation, fibrosis, and pneumonia, linked to those ACE2- co-expressed genes.…”

Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism

“…Through a linear mixed model GWAS analysis, we have identified genome-wide statistically significant genetic variation differentially abundant in CNS and non-CNS isolates in genes, which encodes a surface-exposed protein (pspC or cbpA) and a hypothetical DnaQ/DinG exonuclease/helicase family gene with unknown function. The PspC protein is a multifunctional choline-binding protein, which binds to human factor H 65 , complement inhibitor C4b 66 and inhibits complement C3 deposition 67 , which promotes immune evasion and virulence 67,68 . Crucially, experimental studies have shown that interactions between PspC and the C-terminus of the lamininintegrin receptor, initiates contact with the vascular endothelium of the blood-brain barrier, which improves pneumococcal tropism to the CNS 69 , a mechanism also utilised by other respiratory bacterial pathogens 69 , neurotropic viruses [70][71][72][73] and prions 74 .…”

Streptococci and the complement system: interplay during infection, inflammation and autoimmunity

“…C4bp binding to PspC, PspA, LytA, and PepO (Pneumococcal endopeptidase O) has been demonstrated. Pneumococcal surface-bound C4bp retains its cofactor activity for factor I-mediated cleavage of C4b [72,73]. The role of LytA in complement evasion has only been recently elucidated.…”