Blanc SVSE 3 - Blanc - SVSE 3 - Microbiologie, immunologie, infectiologie

Role of hemostasis during influenza infections – HemoFlu

Role of hemostasis during influenza virus infections

Influenza is one of the most common infectious diseases in humans, occurring as seasonal epidemic and sporadic pandemic outbreaks. There is a need for a better understanding of the molecular mechanisms of influenza virus pathogenesis and subsequent development of new therapeutics against influenza.

To characterize the relationship between hemostasis and inflammation in the pathogenesis of IAV infections.

The hallmark of severe influenza virus infections is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. Objectives: To determine the role of platelets during influenza A virus (IAV) infections and propose new therapeutics against influenza.

Mice are infected and treated or not with agonists or antagonists PAR4 . Alternatively GPIIIa -deficient mice are infected with influenza virus. Mortality induced by influenza virus is monitored daily. Alternatively, ex vivo studies allow us to assess viral replication and inflammation.

Measurements and Main Results: Lungs of infected mice were massively infiltrated by aggregates of activated platelets. Platelet activation promoted IAV pathogenesis. Activating protease-activated receptor 4 (PAR4), a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa (GPIIIa) protected mice from death caused by influenza viruses, and treating the mice with a specific GPIIbIIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other anti-platelet compounds (antagonists of PAR4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains.

Our perspective is to test other anti-platelet compounds in lung injury and lethal infections induced by several influenza strains.

Lê VB, Schneider JG, Boergeling Y, Berri F, Ducatez M, Guerin JL, Adrian I, Errazuriz-Cerda E, Frasquilho S, Antunes L, Lina B, Bordet JC, Jandrot-Perrus M, Ludwig S, and Riteau B. Platelet activation and aggregation promote lung inflammation and influenza virus pathogenesis. Am J Respir Crit Care Med. Sous presse.

Berri F, Lê VB, Jandrot-Perrus M, Lina B, and Riteau B. Switch from protective to adverse inflammation during influenza: viral determinants and hemostasis are caught as culprits. Cell Mol Life Sci. 2013 Oct 4.


Influenza is one of the most common infectious diseases in humans, occurring as seasonal epidemic and sporadic pandemic outbreaks. Annually, influenza A viruses (IAV) cause 3-5 million clinical infections and 250000-500000 fatal cases. Thus, those viruses are of great concern to human health. The recent emergence of resistant influenza strains to the current antiviral drugs highlights the necessity for a better understanding of the molecular mechanisms of IAV pathogenesis and subsequent development of new therapeutics against influenza.

Detrimental inflammation of the lungs is a hallmark of severe influenza virus infections, although the mechanisms underlying these inflammatory processes are poorly understood. Extensive crosstalk exists between inflammation and hemostasis (ie: primary hemostasis, coagulation and fibrinolysis). Accordingly disturbance in their interplay is inevitably linked to human diseases. Numerous lines of evidence point to a link between the hemostatic system, endothelial barrier function and inappropriate inflammation in several models of injuries such as bacterial infections. Up to now, the role of hemostasis during viral infections has been mainly unexplored. The question is: do influenza viruses lead to exaggerated inflammation via inappropriate activation of hemostatic response?

Along with the deleterious host inflammatory response, significant abnormalities in hemostasis were revealed during severe IAV infections in humans. Although the clinical association between hemostasis disorders and pathogenicity of influenza virus infections has emerged, experimental evidence for the active contribution of hemostasis in the cytokine storm following influenza virus infection is still limited. Recently, our results revealed the fundamental importance of hemostatic factors in severe lung inflammation and pathogenesis of IAV infections in mice. Activation of Protease-activated-receptor 1 (PAR1), a receptor activated by the coagulation factor thrombin interacts with the fibrinolytic molecule plasminogen and plays a role in inflammation induced by IAV. Also, we found that plasminogen activation impairs fibrin deposits, which act as a physical barrier to prevent cytokine storm in the lungs upon IAV infection. Consistently, recent reports provided evidence that endothelial cells are central orchestrators of IAV-mediated lung deleterious inflammation. Altogether, crosstalk exists between the dysregulation of hemostasis and inflammation during influenza virus infection, although this remains to be fully established.

The present project aims at a better understanding of the intricate relationship between hemostasis and inflammation in the pathogenesis of IAV infections. In this project, we will first study whether hemostasis is differentially activated upon mice infection with low or highly pathogenic influenza strains and the consequence of hemostasis activation in term of IAV pathogenicity. In the second and third part of the project we will evaluate the specific contribution of protease-activated-receptors (PAR4) and protease-nexin1 to inflammation of the lungs, and outcome of influenza virus infections. Finally, the last part of our project will be dedicated to the development of new clinical and therapeutic applications. Of special interest, the protective role for commercialized drugs will be tested against a broad range of influenza strains, including those of the H5N1 (highly pathogenic) and pandemic H1N1 viruses.

Altogether, this project will represent a crucial step toward understanding the mechanism that underlie influenza cytokine storm during influenza A virus infections. It may also point at novel intervention strategies that could mitigate the host inflammatory response after infection as well as the definition of new clinical markers for severe influenza infections.

Project coordinator

Madame Béatrice RITEAU (Virologie et Pathologies Humaines)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

VirPath - UCBL Virologie et Pathologies Humaines
HBRC - INSERM Hémostase, bioingénierie et remodelage cardiovasculaire

Help of the ANR 520,000 euros
Beginning and duration of the scientific project: August 2013 - 48 Months

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