Platelet Depletion Impairs Host Defense to Pulmonary Infection with <i>Pseudomonas aeruginosa</i> in Mice

Amison, Richard T.; O'Shaughnessy, Blaze Georgia; Arnold, Sarah Louise; Cleary, Simon J.; Nandi, Manasi; Pitchford, Simon; Bragonzi, Alessandra; Page, Clive

doi:10.1165/rcmb.2017-0083oc

Cited by 59 publications

(51 citation statements)

References 41 publications

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“…These findings support the notion that thrombocytes participate in the early immunological response to agents in the circulation [55]. This has been suggested to result from thrombocytes participating in the recruitment of neutrophils [56] and in the activation of neutrophils to release neutrophil extracellular traps (NETs) [57]. In Gram-negative sepsis with E. coli, NETs are induced by activation of TLR-4 on thrombocytes, that subsequently activates neutrophils via CD11a [58].…”

Section: Discussionsupporting

confidence: 79%

Prevention of P2 Receptor-Dependent Thrombocyte Activation by Pore-Forming Bacterial Toxins Improves Outcome in A Murine Model of Urosepsis

Christensen

Johnsen

Skals

et al. 2020

IJMS

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Urosepsis is a potentially life-threatening, systemic reaction to uropathogenic bacteria entering the bloodstream of the host. One of the hallmarks of sepsis is early thrombocyte activation with a following fall in circulating thrombocytes as a result of intravascular aggregation and sequestering of thrombocytes in the major organs. Development of a thrombocytopenic state is associated with a poorer outcome of sepsis. Uropathogenic Escherichia coli frequently produce the pore-forming, virulence factor α-haemolysin (HlyA), of which the biological effects are mediated by ATP release and subsequent activation of P2 receptors. Thus, we speculated that inhibition of thrombocyte P2Y1 and P2Y12 receptors might ameliorate the septic response to HlyA-producing E. coli. The study combined in vitro measurements of toxin-induced thrombocyte activation assessed as increased membrane abundance of P-selectin, fibronectin and CD63 and data from in vivo murine model of sepsis-induced by HlyA-producing E. coli under infusion of P2Y1 and P2Y12 antagonists. Our data show that the P2Y1 receptor antagonist almost abolishes thrombocyte activation by pore-forming bacterial toxins. Inhibition of P2Y1, by constant infusion of MRS2500, markedly increased the survival in mice with induced sepsis. Moreover, MRS2500 partially prevented the sepsis-induced depletion of circulating thrombocytes and dampened the sepsis-associated increase in proinflammatory cytokines. In contrast, P2Y12 receptor inhibition had only a marginal effect in vivo and in vitro. Taken together, inhibition of the P2Y1 receptor gives a subtle dampening of the thrombocyte activation and the cytokine response to bacteraemia, which may explain the improved survival observed by P2Y1 receptor antagonists.

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Section: Discussionsupporting

confidence: 79%

Prevention of P2 Receptor-Dependent Thrombocyte Activation by Pore-Forming Bacterial Toxins Improves Outcome in A Murine Model of Urosepsis

Christensen

Johnsen

Skals

et al. 2020

IJMS

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“…Platelets are protective against intravenous Staphylococcus aureus infection, and thrombocytopenic mice have a higher kidney bacterial burden in a DT model of thrombocytopenia [35]. In an antibody-mediated model of thrombocytopenia, mice were vulnerable to pulmonary Pseudomonas aeruginosa infection, which is coincident with higher bacterial lung CFUs [36]. Our results extend these prior studies to a medically relevant fungal pathogen.…”

Section: Discussionsupporting

confidence: 78%

Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection

et al. 2020

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Beyond their canonical roles in hemostasis and thrombosis, platelets function in the innate immune response by interacting directly with pathogens and by regulating the recruitment and activation of immune effector cells. Thrombocytopenia often coincides with neutropenia in patients with hematologic malignancies and in allogeneic hematopoietic cell transplant recipients, patient groups at high risk for invasive fungal infections. While neutropenia is well established as a major clinical risk factor for invasive fungal infections, the role of platelets in host defense against human fungal pathogens remains understudied. Here, we examined the role of platelets in murine Aspergillus fumigatus infection using two complementary approaches to induce thrombocytopenia without concurrent neutropenia. Thrombocytopenic mice were highly susceptible to A. fumigatus challenge and rapidly succumbed to infection. Although platelets regulated early conidial phagocytosis by neutrophils in a spleen tyrosine kinase (Syk)-dependent manner, platelet-regulated conidial phagocytosis was dispensable for host survival. Instead, our data indicated that platelets primarily function to maintain hemostasis and lung integrity in response to exposed fungal antigens, since thrombocytopenic mice exhibited severe hemorrhage into the airways in response to fungal challenge in the absence of overt angioinvasion. Challenge with swollen, heat-killed, conidia was lethal in thrombocytopenic hosts and could be reversed by platelet transfusion, consistent with the model that fungus-induced inflammation in platelet-depleted mice was sufficient to induce lethal hemorrhage. These data provide new insights into the role of platelets in the anti-Aspergillus host response and expand their role to host defense against filamentous molds.

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“…Although recent studies have shown that the absence of platelets impairs host defense against chronic P . aeruginosa infection[ 45 ], the immune regulatory mechanisms of platelets are not fully understood. In this study, we identified the critical role of platelets in host defense against P .…”

Section: Discussionmentioning

confidence: 99%

“…aeruginosa infection in an acute infection model. In contrast to chronic infection[ 45 ], the platelets were activated in acute infection site, and the number of platelets in blood circulation was also significantly increased during P . aeruginosa lung infection.…”

Section: Discussionmentioning

confidence: 99%

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

Yue

Pang

et al. 2018

PLoS ONE

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Platelets have been implicated in pulmonary inflammation following exposure to bacterial stimuli. The mechanisms involved in the platelet-mediated host response to respiratory bacterial infection remain incompletely understood. In this study, we demonstrate that platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) plays critical roles in a mouse model of acute bacterial pneumonia using Pseudomonas aeruginosa. Platelets are activated during P. aeruginosa infection, and mice depleted of platelets display markedly increased mortality and impaired bacterial clearance. CXCL4 deficiency impairs bacterial clearance and lung epithelial permeability, which correlate with decreased neutrophil recruitment to BALF. Interestingly, CXCL4 deficiency selectively regulates chemokine production, suggesting that CXCL4 has an impact on other chemokine expression. In addition, CXCL4 deficiency reduces platelet-neutrophil interactions in blood following P. aeruginosa infection. Further studies revealed that platelet-derived CXCL4 contributes to the P. aeruginosa-killing of neutrophils. Altogether, these findings demonstrate that CXCL4 is a vital chemokine that plays critical roles in bacterial clearance during P. aeruginosa infection through recruiting neutrophils to the lungs and intracellular bacterial killing.

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Platelet Depletion Impairs Host Defense to Pulmonary Infection with Pseudomonas aeruginosa in Mice

Cited by 59 publications

References 41 publications

Prevention of P2 Receptor-Dependent Thrombocyte Activation by Pore-Forming Bacterial Toxins Improves Outcome in A Murine Model of Urosepsis

Prevention of P2 Receptor-Dependent Thrombocyte Activation by Pore-Forming Bacterial Toxins Improves Outcome in A Murine Model of Urosepsis

Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

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