Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections

Abstract

The potential for avian influenza H5N1 outbreaks has increased in recent years. Thus, it is paramount to develop novel strategies to alleviate death rates. Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II. High serum levels of angiotensin II appear to be linked to the severity and lethality of infection, at least in some patients. In experimental mouse models, infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 (ACE2) expression in the lung and increased serum angiotensin II levels. Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice, confirming a role of ACE2 in H5N1-induced lung pathologies. Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice. Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics.

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…Such therapeutic strategies could interfere with host signalling pathways necessary for viral replication, inhibit exaggerated inflammation, or promote tissue regeneration in an effort to dampen organ dysfunction and injury [196]. Strategies that limit immune responses, for example, by inhibiting the activation of TLR4 by oxidised phospholipids [80,197], targeting the S1P receptor or the angiotensin/ACE system [124,126,197,198] or even attenuating the production of type I IFNs [107], have been shown to reduce the severity of IAV-induced mortality in murine models. Similarly, strategies that promote immune resolution or tissue regeneration, e.g.…”

“…Moreover, the pulmonary endothelium is one of the major sites of angiotensin-converting enzyme (ACE) production. ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and protects against IAV-induced ARDS [125,126]. Components of the coagulation and fibrinolysis cascades have also been associated with promotion of IAV-induced lung injury [127,128].…”

Efficacy of coupled low-volume plasma exchange with plasma filtration adsorption in treating pigs with acute liver failure: A randomised study

“…Ang-II is an important biomarker that increased with the development of ALF. Ang-II mediates vascular inflammation through the nuclear factor-κB-IL-6 signalling pathway [55,56], and high serum levels of Ang-II appear to be linked to the severity and lethality of infection in some cases [57,58]. The decrease in Ang-II level after Li-ALS treatment could indicate amelioration of the inflammatory response.…”

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…ACE2 is reported to be the receptor for the severe acute respiratory syndrome (SARS) coronavirus induced lung injury 91. More recently, compelling data suggest that ACE2 has a central role in the development and progression of the potentially lethal avian influenza viruses H5N192 and H797 93 94. Gain of function ACE1 polymorphisms are also associated with ARDS susceptibility and worse outcome 95.…”