Targeting the capsule of Klebsiella pneumoniae with a cationic CR3-binding protein enhances phagocytosis and promotes bacterial clearance and survival in a mouse sepsis model.
- 1From the School of Life Sciences, Arizona State University, Tempe, AZ, United States.
- 2bioSyntagma Inc., Tempe, AZ, United States.
Abstract
Platelet Factor 4 (PF4), a cationic antimicrobial peptide, serves as a ligand for the myeloid-specific phagocytic receptor CR3 (Mac-1, CD11b/CD18). We previously demonstrated that recombinant dimeric PF4 (rPF4) functions as a bacterial opsonin, enhancing phagocytosis of Gram-positive Staphylococcus aureus and facilitating clearance of both antibiotic-susceptible and methicillin-resistant S. aureus in a mouse model of infectious peritonitis. In this study, we examined whether rPF4 is pathogen-agnostic by assessing its effect on phagocytosis of Gram-negative encapsulated Klebsiella pneumoniae, a WHO Bacterial Priority Pathogen. We demonstrate that rPF4 enhances CR3-mediated phagocytosis of both live and heat-inactivated high-virulence K2 and low-virulence K3 strains of K. pneumoniae by various mouse and human macrophage cell lines, as well as primary neutrophils and macrophages. It also increased phagocytosis of carbapenem-resistant K. pneumoniae. rPF4 did not directly kill bacteria but acted as an opsonin, binding to the negatively charged bacterial capsule and creating recognition sites for CR3 on leukocytes. In a mouse sepsis model, a single dose of rPF4 significantly enhanced bacterial clearance from the lungs, liver, and peritoneum and reduced bacteremia. Histological analyses showed that rPF4 provided substantial protection to lung and liver tissues against K. pneumoniae-induced damage. Consistent with these findings, rPF4 treatment increased the survival rates of infected mice. These results show that rPF4 effectively targets the capsule, a key virulence factor of K. pneumoniae, thereby reducing the bacterium's ability to evade the host immune response. Overall, the data suggest a common mechanism in which cationic rPF4, by binding to the negatively charged surfaces of both Gram-negative and Gram-positive bacteria, diminishes their antiphagocytic properties.
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BibTeX
@article{podolnikova2026targeting,
title = {{Targeting the capsule of Klebsiella pneumoniae with a cationic CR3-binding protein enhances phagocytosis and promotes bacterial clearance and survival in a mouse sepsis model.}},
author = {Nataly P Podolnikova and Iryna Klymenko and James Alagna and Cyrus Diercksmeier and Arnat Balabiyev and David Richardson and Tatiana P Ugarova},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1934439},
url = {https://europepmc.org/article/MED/42890606},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting the capsule of Klebsiella pneumoniae with a cationic CR3-binding protein enhances phagocytosis and promotes bacterial clearance and survival in a mouse sepsis model.
AU - Nataly P Podolnikova
AU - Iryna Klymenko
AU - James Alagna
AU - Cyrus Diercksmeier
AU - Arnat Balabiyev
AU - David Richardson
AU - Tatiana P Ugarova
PY - 2026
DA - 2026/10/02
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1934439
UR - https://europepmc.org/article/MED/42890606
AB - Platelet Factor 4 (PF4), a cationic antimicrobial peptide, serves as a ligand for the myeloid-specific phagocytic receptor CR3 (Mac-1, CD11b/CD18). We previously demonstrated that recombinant dimeric PF4 (rPF4) functions as a bacterial opsonin, enhancing phagocytosis of Gram-positive Staphylococcus aureus and facilitating clearance of both antibiotic-susceptible and methicillin-resistant S. aureus in a mouse model of infectious peritonitis. In this study, we examined whether rPF4 is pathogen-agnostic by assessing its effect on phagocytosis of Gram-negative encapsulated Klebsiella pneumoniae, a WHO Bacterial Priority Pathogen. We demonstrate that rPF4 enhances CR3-mediated phagocytosis of both live and heat-inactivated high-virulence K2 and low-virulence K3 strains of K. pneumoniae by various mouse and human macrophage cell lines, as well as primary neutrophils and macrophages. It also increased phagocytosis of carbapenem-resistant K. pneumoniae. rPF4 did not directly kill bacteria but acted as an opsonin, binding to the negatively charged bacterial capsule and creating recognition sites for CR3 on leukocytes. In a mouse sepsis model, a single dose of rPF4 significantly enhanced bacterial clearance from the lungs, liver, and peritoneum and reduced bacteremia. Histological analyses showed that rPF4 provided substantial protection to lung and liver tissues against K. pneumoniae-induced damage. Consistent with these findings, rPF4 treatment increased the survival rates of infected mice. These results show that rPF4 effectively targets the capsule, a key virulence factor of K. pneumoniae, thereby reducing the bacterium's ability to evade the host immune response. Overall, the data suggest a common mechanism in which cationic rPF4, by binding to the negatively charged surfaces of both Gram-negative and Gram-positive bacteria, diminishes their antiphagocytic properties.
SN - 1664-3224
ER -