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Role of alarmins and opsonophagocytosis in innate immunity in critically ill patients

English title Role of alarmins and opsonophagocytosis in innate immunity in critically ill patients
Applicant Pugin Jérôme
Number 122034
Funding scheme Project funding (Div. I-III)
Research institution Division des Soins Intensifs de Médecine Département de Médecine Hôpital Cantonal - HUG
Institution of higher education University of Geneva - GE
Main discipline Clinical Immunology and Immunopathology
Start/End 01.04.2009 - 31.03.2012
Approved amount 415'000.00
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Keywords (7)

criticaly ill patients; sepsis; phagocytosis; opsonins; alarmins; toll-like receptors; Innate immunity

Lay Summary (English)

Lead
Lay summary
A functional innate immunity is of foremost importance to fight bacterial infections. This system relies on both soluble proteins and cells expressing pattern-recognition receptors such as CD14, and Toll-like receptors expressed at the surface of immune cells. These receptors not only mediate immune cell activation by bacterial molecules, they also recognize and bind a recently recognized set of host molecules called "alarmins". This system is a way for immunity to sense danger, and modulate immune responses to bacteria associated with tissue injury. Although candidate alarmins have been recently identified, a thorough search for such host proteins has not been performed yet. It is the ambition of this proposal to: 1) test what are the relevant alarmin(s) in the context of tissue injury, and 2) discover new alarmin(s) in an in vitro model of tissue injury. Dysfunctional innate immunity is observed in many critically ill adults and infants, and is a major reason for those patients for either acquiring secondary severe bacterial infections (nosocomial infections) or failing to clear a primary bacterial infection. Opsonophagocytosis is a key feature of innate immunity. It is a complex process involving innate soluble opsonins binding to bacteria, signaling the presence of non-self microorganisms to immune effector cells, facilitating their phagocytosis. It is a goal of this proposal to study the capacity of plasma opsonins to mediate phagocytosis in adult critically ill patients, and in premature infants, in whom obvious immune defects exist. A significant proportion of circulating polymorphonuclear neutrophils are immature in patients with severe sepsis and septic shock. It is also one aim of this proposal to determine the capacity of immature neutrophils to mediate key innate immune functions, such as chemotaxis and phagocytosis of bacteria. This proposal will be divided into two projects, a basic research project on alarmins (project A) and a translational research project on opsonophagocytosis (project B).
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ.
Tissières Pierre, Ochoda Agnieszka, Dunn-Siegrist Irène, Drifte Geneviève, Morales Michel, Pfister Riccardo, Berner Michel, Pugin Jérôme (2012), Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ., in PloS one, 7(3), 32863-32863.
Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide.
Charles Pierre-Emmanuel, Tissières Pierre, Barbar Saber Davide, Croisier Delphine, Dufour Julien, Dunn-Siegrist Irène, Chavanet Pascal, Pugin Jérôme (2011), Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide., in Critical care (London, England), 15(4), 181-181.
Cooperation between PU.1 and CAAT/enhancer-binding protein beta is necessary to induce the expression of the MD-2 gene.
Tissières Pierre, Araud Tanguy, Ochoda Agnieszka, Drifte Geneviève, Dunn-Siegrist Irène, Pugin Jérôme (2009), Cooperation between PU.1 and CAAT/enhancer-binding protein beta is necessary to induce the expression of the MD-2 gene., in The Journal of biological chemistry, 284(39), 26261-72.
The role of MD-2 in the opsonophagocytosis of Gram-negative bacteria.
Tissières Pierre, Pugin Jérôme (2009), The role of MD-2 in the opsonophagocytosis of Gram-negative bacteria., in Current opinion in infectious diseases, 22(3), 286-91.
Role of proinflammatory activity contained in gastric juice from intensive care unit patients to induce lung injury in a rabbit aspiration model.
Brégeon Fabienne, Papazian Laurent, Delpierre Stéphane, Kajikawa Osamu, Payan Marie-José, Martin Thomas R, Kipson Nathalie, Pugin Jérôme (2008), Role of proinflammatory activity contained in gastric juice from intensive care unit patients to induce lung injury in a rabbit aspiration model., in Critical care medicine, 36(12), 3205-12.
How tissue injury alarms the immune system and causes a systemic inflammatory response syndrome
Pugin Jérôme, How tissue injury alarms the immune system and causes a systemic inflammatory response syndrome, in Annals of Intensive Care, in press.
Toll-like receptor activation of human cells by synthetic triacylated lipid A-like molecules.
Dunn-Siegrist Irène, Tissières Pierre, Drifte Geneviève, Bauer Jacques, Moutel Stéphane, Pugin Jérôme, Toll-like receptor activation of human cells by synthetic triacylated lipid A-like molecules., in The Journal of biological chemistry, in press.

Associated projects

Number Title Start Funding scheme
141143 Alarmins as mediators of aseptic inflammatory responses and sepsis 01.07.2012 Project funding (Div. I-III)
141143 Alarmins as mediators of aseptic inflammatory responses and sepsis 01.07.2012 Project funding (Div. I-III)
141143 Alarmins as mediators of aseptic inflammatory responses and sepsis 01.07.2012 Project funding (Div. I-III)
105770 Role of MD-2 during sepsis 01.10.2005 Project funding (Div. I-III)

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