Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Abstract

Highlights:Brain tissue injury increases ACE2 levels in the lungs Brain injury induces pro-inflammatory cytokine expression in the lungs Brain injury causes parenchymal inflammation and systemic lymphopeniaAbstract Background: The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated.Methods: Mice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry.Results: Strikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1 in the lungs. Higher gene expression of cytokines IL-6 and IL-1 was found in ischemic brain hemispheres and a reduced number of Tlymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. Conclusions:We demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions.

Development of a Novel Human CD147 Transgenic NSG Mouse Model to test SARS-CoV-2 Infection and Immune Responses

“…Other models for studying SARS-CoV-2 infection in mice that are currently being optimized include models that utilize mouse-adapted virus derivations [ 40 , 41 ], immunocompromised or obese mice that lack interferon receptors [ 41 ], or utilize different animals entirely [ 42 , 43 ]. However, while these models have recapitulated some aspects of the COVID-19 disease course in infected mice, such as lung inflammation [ 44 ], cytokine storm [ 45 ], viral neuroinvasion [ 46 ], and impaired lung function [ 47 ], they fail to explain other aspects of COVID-19 such as increased thrombosis risk for affected individuals, increased risk for COVID-19 in diabetic patients [ 48 ], hemodynamic instability, and why stroke and immunosuppression may be predisposing risk factors and clinical sequelae of COVID-19 [ 49 – 51 ].…”