Genetic Dissection of the Regulatory Mechanisms of Ace2 in the Infected Mouse Lung

Abstract

Acute lung injury (ALI) is an important cause of morbidity and mortality after viral infections, including influenza A virus H1N1, SARS-CoV, MERS-CoV, and SARS-CoV-2. The angiotensin I converting enzyme 2 (ACE2) is a key host membrane-bound protein that modulates ALI induced by viral infection, pulmonary acid aspiration, and sepsis. However, the contributions of ACE2 sequence variants to individual differences in disease risk and severity after viral infection are not understood. In this study, we quantified H1N1 influenza-infected lung transcriptomes across a family of 41 BXD recombinant inbred strains of mice and both parents—C57BL/6J and DBA/2J. In response to infection Ace2 mRNA levels decreased significantly for both parental strains and the expression levels was associated with disease severity (body weight loss) and viral load (expression levels of viral NA segment) across the BXD family members. Pulmonary RNA-seq for 43 lines was analyzed using weighted gene co-expression network analysis (WGCNA) and Bayesian network approaches. Ace2 not only participated in virus-induced ALI by interacting with TNF, MAPK, and NOTCH signaling pathways, but was also linked with high confidence to gene products that have important functions in the pulmonary epithelium, including Rnf128, Muc5b, and Tmprss2. Comparable sets of transcripts were also highlighted in parallel studies of human SARS-CoV-infected primary human airway epithelial cells. Using conventional mapping methods, we determined that weight loss at two and three days after viral infection maps to chromosome X—the location of Ace2. This finding motivated the hierarchical Bayesian network analysis, which defined molecular endophenotypes of lung infection linked to Ace2 expression and to a key disease outcome. Core members of this Bayesian network include Ace2, Atf4, Csf2, Cxcl2, Lif, Maml3, Muc5b, Reg3g, Ripk3, and Traf3. Collectively, these findings define a causally-rooted Ace2 modulatory network relevant to host response to viral infection and identify potential therapeutic targets for virus-induced respiratory diseases, including those caused by influenza and coronaviruses.

Differing susceptibility of C57BL/6J and DBA/2J mice—parents of the murine BXD family, to severe acute respiratory syndrome coronavirus infection

“…To determine whether the BXD family is suitable as a diversity model to define causal molecular networks modulating SARS pathogenesis and disease severity, we investigated whether the two founders, B6 and D2, differ significantly in susceptibility to MA15 infection. We first examined our existing transcriptomic data on the B6 and D2 parents and found that basal pulmonary levels of viral entry receptor Ace2 transcript are well matched [ 8 ], ruling out the possibility of pre-infection Ace2 expression as a confounding factor. We then challenged groups of 10-week old B6 ( n = 26) and D2 ( n = 28) via the intranasal route with 10 5 TCID 50 of MA15 virus (diluted in 50-μl phosphate-buffered saline, PBS), and monitored weight changes for 9 days.…”

Acute Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Pregnancy Is Associated with Placental Angiotensin-Converting Enzyme 2 Shedding

“…Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 7, 8 . This receptor’s inducibility and variability are proposed to be an essential element for viral tropism, infectivity, and COVID-19 disease progression and outcomes [9] , [10] , [11] , [12] , [13] , [14] . ACE2, a vital member of the renin-angiotensin system (RAS), is a monocarboxyl peptidase and type I transmembrane protein 15 .…”

Assemblies of JAG1 and JAG2 determine tracheobronchial cell fate in mucosecretory lung disease

“…These agents damage the ciliated cell, often resulting in cell death and ciliated cell hypoplasia. Notch pathway components were identified as susceptibility genes for lung damage ( 16 ), viral entry ( 17 ), and hyperinflammation ( 18 ). Consequently, treatments that specifically target Notch pathway components have the potential to normalize ciliated and goblet cell frequency, restore mucociliary clearance, and improve the health of people with chronic lung disease.…”