key: cord-032811-sdbj26ca
authors: Hosoki, Koa; Kimata, Jason T.; Chakraborty, Abhijit; Sur, Sanjiv
title: Reply
date: 2020-09-29
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2020.09.008
sha: 
doc_id: 32811
cord_uid: sdbj26ca

nan

Reply Q 1 To the Editor:

We thank Zwaveling et al 1 for appreciating our review 2 and for their insightful correspondence. They suggest that suppression of angiotensin-converting enzyme-2 (ACE-2) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could impair the hydrolysis of des-Arg 9 -bradykinin and stimulate the bradykinin receptor type 1 (BKB1) pathway to induce leakage of fluid into the lungs. In support of their hypothesis, they stated that loss of ACE-2 in an animal model aggravated acid-induced pulmonary edema, and these effects are alleviated by administration of recombinant human ACE-2 Q 2 . 3 In addition, a report demonstrated that SARS-CoV infection downregulates the expression of ACE-2. 4 However, other studies suggest that SARS-CoV-2 may upregulate the expression of ACE-2 in patients with coronavirus disease 2019 (COVID-19) or influenza pneumonia in alveolar epithelial cells, endothelial cells, and lymphocytes in perivascular tissue than in uninfected control autopsy lung. 5 Furthermore, single-cell RNA sequencing analysis revealed that secretory cells in the upper airway epithelium have higher ACE-2 expressions in COVID-19. 6 Thus, until the effect of SARS-CoV-2 on ACE-2 levels or functionality is thoroughly addressed in peer-reviewed publications, it is difficult to precisely determine the contributory role of ACE-2 in the bradykinin pathway during SARS-CoV-2 infection.

Zwaveling bradykinin receptor type 2 (BKB2) could induce active fluid transfer through vascular pores (Fig 1  F1-4/C] , A). Another explanation for extravascular fluid leakage into the lungs in COVID-19 is secretion of proinflammatory cytokines such as TNF and IL-6 during the cytokine storm (Fig 1, A) . 7 We favor a third hypothesis, where excessive and prolonged secretion of type I and type III IFNs in the airways contributes to loss of lung epithelial barrier function during COVID-19 and other RNA virus infections (Fig  1, A) . 8, 9 To test whether entry of SARS-CoV-2 through ACE-2 is sufficient to induce type III IFNs without need for viral replication, we engineered a replication-deficient SARS-CoV-2 spike-HIV-luc pseudotype virus. Infection of Caco-2 cells, which naturally express ACE-2, with this engineered virus was sufficient to increase the mRNA expression of IFN-l2 (Fig 1, B and C) , indicating that virus replication is not required for upregulating its expression. Because IFN-l contributes to loss of lung epithelial barrier function, 8 we hypothesize that entry of SARS-CoV-2 via ACE-2 can stimulate secretion of IFN-l and induce leakage of fluid into the lungs (Fig 1, A) .

Zwaveling et al's hypothesis is most intriguing and certainly plausible. However, as acknowledged by the authors, there is no direct evidence showing increased levels of bradykinin or des-Arg 9 -bradykinin in the patients with COVID-19 at this time. Here, we provide evidence that entry of SARS-CoV-2 through ACE-2 provides an adequate signal even without viral replication to stimulate IFN-l2 mRNA expression, a cytokine that can cause damage to the epithelial barrier. Further investigations are required to test the hypotheses outlined in Figure 1 , A, which may induce leakage of fluid into the lungs in COVID-19, and identify the most important pathway(s).

Koa Hosoki, MD, PhD a * Jason T. Kimata, PhD b * Abhijit Chakraborty, PhD a Sanjiv Sur, MD a

Pulmonary edema in COVID-19: explained by bradykinin?

Molecular mechanisms and epidemiology of COVID-19 from an allergist's perspective

Angiotensin-converting enzyme 2 protects from severe acute lung failure

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Cytokine prediction of mortality in COVID19 patients

Type III interferons disrupt the lung epithelial barrier upon viral recognition

Type I and III interferons disrupt lung epithelial repair during recovery from viral infection