PLATELET FACTOR 4 (PF4) IMPROVES SURVIVAL IN A MURINE MODEL OF ANTIBIOTIC-SUSCEPTIBLE AND METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PERITONITIS.
PLATELET FACTOR 4 (PF4) IMPROVES SURVIVAL IN A MURINE MODEL OF ANTIBIOTIC-SUSCEPTIBLE AND METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PERITONITIS.
复制标题
血小板因子 4 (PF4) 可提高抗生素敏感且耐甲氧西林金黄色葡萄球菌腹膜炎小鼠模型的存活率。
DOI：
10.1101/2023.08.25.554865
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ugarova,TatianaP
中科院分区：
文献类型：
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作者：
Podolnikova,NatalyP;Lishko,ValeryiK;Roberson,Robert;Koh,Zhqian;Derkach,Dmitry;Richardson,David;Sheller,Michael;Ugarova,TatianaP
The complement receptor CR3, also known as integrin Mac-1 (CD11b/CD18), is one of the major phagocytic receptors on the surface of neutrophils and macrophages. We previously demonstrated that in its protein ligands, Mac-1 binds sequences enriched in basic and hydrophobic residues and strongly disfavors negatively charged sequences. The avoidance by Mac-1 of negatively charged surfaces suggests that the bacterial wall and bacterial capsule possessing net negative electrostatic charge may repel Mac-1 and that the cationic Mac-1 ligands can overcome this evasion by acting as opsonins. Indeed, we previously showed that opsonization of Gram-negativeEscherichia coliwith several cationic peptides, including PF4 (Platelet Factor 4), strongly augmented phagocytosis by macrophages. Here, we investigated the effect of recombinant PF4 (rPF4) on phagocytosis of Gram-positiveStaphylococcus aureus in vitroand examined its impact in a mouse model ofS. aureusperitonitis. Characterization of the interaction of rPF4 with nonencapsulated and encapsulatedS. aureusshowed that rPF4 localizes on the bacterial surface, thus making it available for Mac-1. Furthermore, rPF4 did not have direct bactericidal and bacteriostatic activity and was not toxic to host cells. rPF4 enhanced phagocytosis ofS. aureusbioparticles by various primary and cultured Mac-1-expressing leukocytes by several folds. It also increased phagocytosis of live nonencapsulated and encapsulated bacteria. Notably, the augmentation of phagocytosis by rPF4 did not compromise the intracellular killing ofS. aureusby macrophages. Using a murineS. aureusperitonitis model, we showed that treatment of infected mice with rPF4 caused a significant increase in the clearance of antibiotic-susceptibleS. aureusand its methicillin-resistant (MRSA) variant and markedly improved survival. These findings indicate that rPF4 binding to the bacterial surface circumvents its antiphagocytic properties, improving host defense against antibiotic-susceptible and antibiotic-resistant bacteria.
