Pneumococcal immune evasion: ZmpC inhibits neutrophil influx

Abstract

SummaryNeutrophil recruitment is essential in clearing pneumococcal infections. The first step in neutrophil extravasation involves the interaction between P-selectin on activated endothelium and P-Selectin Glycoprotein 1 (PSGL-1) on neutrophils. Here, we identify pneumococcal Zinc metalloproteinase C as a potent inhibitor of PSGL-1. ZmpC degrades the N-terminal domain of PSGL-1, thereby disrupting the initial rolling of neutrophils on activated human umbilical vein endothelial cells. Furthermore, mice infected with wild-type strain in the model of pneumococcal pneumonia showed lower lungs neutrophil infiltration compare to animals infected with ZmpC mutant. In addition, we confirmed the association of zmpC with serotype 8 and 11A and found it to be associated with serotype 33F as well. In conclusion, we report PSGL-1 as a novel target for ZmpC and show that ZmpC inhibits neutrophil extravasation during pneumococcal pneumonia.

Neutrophils and Bacterial Immune Evasion

“…Streptococcus pneumoniae employs a slightly different mechanism to block neutrophil recruitment. This pathogen produces pneumococcal zinc metalloproteinase C (ZmpC), which targets the initial rolling step of neutrophil extravasation by cleavage of the N-terminal domain of P-selectin glycoprotein 1 (PSGL-1) [13]. …”

Review: Current and new generation pneumococcal vaccines

“…139 In the latter setting, ZmpC was found to cleave the N-terminal domain of the glycoprotein endothelial adhesion molecule, P-selectin (PSGL-1), interfering with initial events in neutrophil transendothelial migration. 139 NET formation is a strategy used not only by activated neutrophils, but also eosinophils and monocytes/macrophages, to immobilise and kill microbial pathogens by ensnaring and exposing them extracellularly to an array of antimicrobial granule proteins immersed in a web of citrullinated histones and DNA. 140 Enolase, as well as IgA and IgG antibodies of undetermined specificity, have been reported to induce NET formation.…”

Malnutrition, Immunodeficiency, and Mucosal Infection

“…These discoveries reveal host defense mechanisms. For example, Streptococcus pneumoniae (pneumococcus), the most common bacterial respiratory pathogen that causes invasive pneumococcal disease, secretes metalloproteases (Zmp), one of which blocks neutrophil extravasation from blood and influx into the lung (Surewaard et al, 2013), showing that this host defense mechanism is zinc dependent. Zinc, the most common trace mineral after iron in the human body, is involved in enzyme structure and function, epigenetic processes, and is a regulator of gene expression, leading to effects on cell signaling.…”