The airway epithelium is a critical site for binding and entry of the SARS and NL63 coronaviruses throughinteractions with their receptor angiotensin converting enzyme 2 (ACE2). ACE2, a terminal carboxypeptidase, is expressed on the apical surface of the epithelial cells that line conducting airways, as well as alveolar epithelial cells. ACE2 is released from the surface of epithelia into airway surface liquid (ASL) via cleavage by TACE (ADAM17) and other sheddases. This soluble ACE2 (sACE2) is catalytically active in ASL, although its native substrates and biologic funcfions are poorly understood. ACE2 appears to have other functions that include induction of epithelial cell signaling and defense function, and SARS-CoV S protein or SARS virus infection directly downregulate pulmonary ACE2 expression. Loss of pulmonary ACE2 function has been hypothesized to contribute to acute lung injury associated with SARS, sepsis, and acid aspiration. The overall goal of this project is to better understand how the expression and release of ACE2 is governed in ainway epithelia, using models of well-differentiated human airway epithelia and mouse models of SARS-CoV infection, and relate this to SARS-CoV pathogenesis. Our overall hypothesis is that changes in pulmonary ACE2 expression and activity contribute to SARS-CoV lung disease through reduced carboxypeptidase activity and changes in epithelial host defense signaling. There are 3 specific aims.
Aim 1. Determine how airway epithelial cell ACE2 expression is affected by SARS-CoV infection. In this aim we will investigate the hypothesis that pulmonary ACE2 expression in the vascular and epithelial compartments is regulated by cellular differentiation state, age, and mediators of infiammation and infection. We will also investigate how S-protein engagement and TACE affect sACE2 release.
Aim 2. Characterize the physiologic function of airway epithelial ACE2 during SARS-CoV infection. Here we emphasize detailed assessment of the enzymatic functions of ACE2 in the context of a local pulmonary RAS and kinin system and how they are perturbed during SARS-CoV infection and contribute to lung disease.
Aim 3. Identify enzyme activity-independent ACE2 functions that modulate host defense responses. For this aim, we focus on ACE2 function in airway epithelia independent of its receptor properties and carboxypeptidase activity. ACE2 effects that directly modulate epithelial host defenses will be studied.
SARS-CoV caused severe morbidity and mortality in humans, yet there is sfill much that we do not understand about this virus and the determinants of pulmonary pathology. The studies of this proposal will investigate the role of the virus receptor and carboxypeptidase ACE2 in lung disease pathogenesis associated with SARS.
|Canton, Javier; Fehr, Anthony R; Fernandez-Delgado, Raúl et al. (2018) MERS-CoV 4b protein interferes with the NF-?B-dependent innate immune response during infection. PLoS Pathog 14:e1006838|
|Fehr, Anthony R; Jankevicius, Gytis; Ahel, Ivan et al. (2018) Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol 26:598-610|
|Alshukairi, Abeer N; Zheng, Jian; Zhao, Jingxian et al. (2018) High Prevalence of MERS-CoV Infection in Camel Workers in Saudi Arabia. MBio 9:|
|Sodhi, Chhinder P; Wohlford-Lenane, Christine; Yamaguchi, Yukihiro et al. (2018) Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol 314:L17-L31|
|Castaño-Rodriguez, Carlos; Honrubia, Jose M; Gutiérrez-Álvarez, Javier et al. (2018) Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. MBio 9:|
|Zheng, Jian; Perlman, Stanley (2018) Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host. Curr Opin Virol 28:43-52|
|Chu, Daniel K W; Hui, Kenrie P Y; Perera, Ranawaka A P M et al. (2018) MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity. Proc Natl Acad Sci U S A 115:3144-3149|
|Galasiti Kankanamalage, Anushka C; Kim, Yunjeong; Damalanka, Vishnu C et al. (2018) Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element. Eur J Med Chem 150:334-346|
|Grunewald, Matthew E; Fehr, Anthony R; Athmer, Jeremiah et al. (2018) The coronavirus nucleocapsid protein is ADP-ribosylated. Virology 517:62-68|
|Chi, Hang; Zheng, Xuexing; Wang, Xiwen et al. (2017) DNA vaccine encoding Middle East respiratory syndrome coronavirus S1 protein induces protective immune responses in mice. Vaccine 35:2069-2075|
Showing the most recent 10 out of 111 publications