Platelets are the chief effector cells in hemostasis. However, recent evidence suggests that platelets have multiple roles in host defense against infection. Reports by us and others showed that platelets functionally contribute to protection against Staphylococcus aureus (S. aureus) infection. In the current study, the capacity of mouse platelets to participate in host defense against S. aureus infection was determined by assessing two possibilities. First, we determined the ability of platelets to kill S. aureus directly; and second, we tested the possibility that platelets enhance macrophage phagocytosis and intracellular killing of S. aureus. We report here evidence in support of both mechanisms. Platelets effectively killed two different strains of S. aureus. A clinical isolate of methicillin resistant S. aureus (MRSA) was killed by platelets (>40% killing in 2 h) in a thrombin-dependent manner while a methicillin sensitive strain (MSSA) was killed to equal extent but did not require thrombin. Interestingly, thrombin-stimulated platelets also significantly enhanced peritoneal macrophage phagocytosis of both MRSA and MSSA by >70%, and restricted intracellular growth by >40%. Enhancement of macrophage anti-S. aureus activities is independent of contact with platelets but is mediated through releasable products, namely IL-1β. These data confirm our hypothesis that platelets participate in host defense against S. aureus both through direct killing of S. aureus and enhancing the antimicrobial function of macrophages in protection against S. aureus infection.

Platelets are critical to hemostatic and immunological function, and are key players in cancer progression, metastasis, and cancer-related thrombosis. Platelets interact with immune cells to stimulate anti-tumor responses and can be activated by immune cells and tumor cells. Platelet activation can lead to complex interactions between platelets and tumor cells. Platelets facilitate cancer progression and metastasis by: (1) forming aggregates with tumor cells; (2) inducing tumor growth, epithelial-mesenchymal transition, and invasion; (3) shielding circulating tumor cells from immune surveillance and killing; (4) facilitating tethering and arrest of circulating tumor cells; and (5) promoting angiogenesis and tumor cell establishment at distant sites. Tumor cell-activated platelets also predispose cancer patients to thrombotic events. Tumor cells and tumor-derived microparticles lead to thrombosis by secreting procoagulant factors, resulting in platelet activation and clotting. Platelets play a critical role in cancer progression and thrombosis, and markers of platelet-tumor cell interaction are candidates as biomarkers for cancer progression and thrombosis risk.

Background Platelets are critical cells for maintaining vascular hemostasis but their activities in other processes are becoming apparent. Specifically, the ability of platelets to recognize and respond to infectious agents is an important area of investigation. To understand the physiological roles of platelets in vivo, most researchers have used antibody-mediated platelet depletion, which has certain limitations. Objective To develop an optimal system to study the contribution of platelets to protection from S. aureus blood infection. Methods Here we describe a novel experimental model of conditional platelet depletion based on the Cre-recombinase cell ablation system. Using this technology, the simian diphtheria toxin receptor was expressed in platelet factor 4 (PF4) positive cells (megakaryocytes and platelets). Results Systemic administration of diphtheria toxin (DT) every 48 hours results in reduced platelet numbers that become undetectable after six days. While platelets are depleted, no other blood cells are affected. Using this newly-developed model, the functional contributions of platelets in protection against Staphylococcus aureus (S. aureus) bacteremia was examined. Platelet-depleted mice succumbed to infection more rapidly than wild-type (WT) mice and contained significantly higher bacterial burden in kidneys, increased serum markers of kidney damage and elevated levels of cytokines indicative of septic shock. Conclusions Here we illustrate a new mouse model for conditional platelet depletion and implicate platelets as important participants of the immune response to bacterial blood infections.

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Background:The glucocorticoid receptor ␤ (GR␤) is a positive regulator of growth. Results: GR␤ suppression of PTEN resulted in enhanced phosphorylation of Akt and growth. Conclusion: GR␤ enhances insulin-induced proliferation by suppressing PTEN and activating Akt1. Significance: GR␤ suppression of PTEN indicates that it has an important role in growth factor signaling and potentially cancer.