Immuno-paralysis following severe infections or trauma
Systemic Inflammatory Response Syndrome (SIRS) is a common condition associated with systemic or severe infections, trauma, burns or haemorrhage. It is characterised by the release of inflammatory cytokines whose main function is to activate the innate and acquired immune system to fight infection and/or to limit and repair tissue damage. Paradoxically, this enhanced state of responsiveness is often followed by a period of immunosuppression that can last for several weeks, long after resolution of the infection or trauma that triggered SIRS. The immunosuppressed patients are at risk of suffering secondary or opportunistic infections, which are the main cause of death in patients hospitalized in intensive care units. Malaria infection can also cause SIRS and immunosuppression, probably contributing to the poor efficacy of vaccination against malaria and other pathogens, and to high incidence of Burkitt’s lymphoma, in malaria-endemic areas. Impairment of dendritic cells (DC), the primary initiators of T cell immunity, plays a prominent role in this immunosuppression post-SIRS. There is an unmet medical need to characterise the mechanisms that impair DC function following SIRS and to prevent and/or overcome the onset of this state of DC paralysis. Our groundwork indicates that SIRS induces long-term changes in the environment where DC develop, causing sustained formation of paralysed DC with impaired antigen capture, processing and/or presentation function.
In this project we will use models of infection with malaria, viruses or bacteria, or trauma, to characterise the mechanisms that cause DC paralysis and to develop therapies to prevent or reduce the impact of DC paralysis in human patients.
Professor Jose Villadangos
Professor William Heath (Peter Doherty Institute)
Dr Justine Mintern (University of Melbourne)
Dr Antoine Roquilly (University Hospital of Nantes, France)
Professor Gordon Smyth (The Walter and Eliza Hall Institute)
Wilson NS, Behrens GM, Lundie RJ, Smith CM, Waithman J, Young L, Forehan SP, Mount A, Steptoe RJ, Shortman KD, de Koning-Ward TF, Belz GT, Carbone FR, Crabb BS, Heath WR, Villadangos JA. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat Immunol 2006; 7: 165-172.
Young LJ, Wilson NS, Schnorrer P, Mount A, Lundie La Gruta NL, Crabb BS, Belz GT, Heath WR, Villadangos JA. Dendritic cell pre-activation impairs MHC II presentation of vaccines and endogenous viral antigens. Proc. Natl. Acad. Sci. USA 2007; 104: 17753-17758.
Lundie RJ, Young LJ, Davey G, Villadangos JA, Carbone FR, Heath WR, Crabb BS. Blood-stage Plasmodium berghei infection leads to short-lived parasite-associated antigen presentation by dendritic cell. Eur J Immunol 2010; 40: 1674-1681
Sutherland RM, Londrigan SL, Brady JL, Azher H, Carrngton EM, Zhan Y, Vega-Ramos J, Villadango JA, Lew M. Shutdown of immunological priming and presentation after in vivo administration of adenovirus. Gene Ther 2012; 19:1095-1100.
Vega-Ramos J, Roquilly A, Zhan Y, Young LJ, Mintern JD, Villadangos JA. Inflammation conditions mature dendritic cells to retain the capacity to present new antigens but with altered cytokine secretion function. J Immunol 2014; 193: 3851-3859.
Roquilly A, Broquet AC, Jacqueline D, Masson D, Segain JP, Braudeau C, Vourc'h MJ, Caillon J, Altare F, Josien R, Retière C, Villadangos JA, Asehnoune K. Hydrocortisone prevents immunosuppression by interleukin-10+ natural killer cells after trauma-hemorrhage. Crit Care Med 2014; 42: e752-61.
Vega-Ramos J, Roquilly A, Asehnoune K, Villadangos JA. Modulation of dendritic cell antigen presentation by pathogens, tissue damage and secondary inflammatory signals. Curr Opin Pharmacol 2014; 17: 64-70.
Roquilly R, Villadangos JA. The role of dendritic cell alterations in susceptibility to hospital-acquired infections during critical-illness related immunosuppression. Mol Immunol 2015; 68: 120-123.
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