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Principal Investigator: Lothar Hennighausen
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2020
Award: $1,379,483
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Objective 1
Angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV and SARS-CoV-2, has been detected in a range of target cells, including lung epithelium, kidney and other epithelial cells. While SARS-CoV-2 infection of lung epithelium is a critical driver of disease, extrapulmonary manifestations of COVID-19 infection has been associated with direct viral damage of tissues that carry the ACE2 receptor, such as renal tissue. Deciphering the regulation of the ACE2 gene in SARS-CoV-2 target cells is a step forward in linking ACE2 levels with viral damage and COVID-19 pathology. This is relevant not only in the context of cytokine storms but also in patients with different physiological conditions, such as pregnancy and lactation. Interferons activate ACE2 expression in pneumocytes, suggesting a critical role of cytokines in SARS-CoV-2 target cells. Viral RNA was detected in breast milk in at least seven studies, raising the possibility that ACE2 is expressed in mammary tissue during lactation.
Research in our laboratory has demonstrated that that Ace2 expression in mouse mammary tissue is induced during pregnancy and lactation (Hennighausen and Lee, Cell Reports, in press, 2020)1,2. This coincides with the establishment of intronic enhancers, regulatory elements that activate genes. These enhancers are composed of the prolactin-activated transcription factor STAT5 and additional regulatory factors, including Polymerase II. Using genetic tools, we demonstrated that the ablation of Stat5a results in decommissioning of the enhancers and a more than 80% reduction of Ace2 mRNA. We also demonstrate that Ace2 expression increases during lactation in lung, but not in kidney and intestine. JAK/STAT components are present in a range of SARS-CoV-2 target cells opening the possibility that cytokines contribute to the viral load and extrapulmonary pathophysiology.
Objective 2
SARS-CoV-2 infection of lung epithelium through the receptor ACE2 is a critical driver of disease. Experiments by others have demonstrated that interferons can activate the gene for the ACE2 receptor, opening the possibility that blunting this activation process with inhibitors might be beneficial. Experiments have been initiated to investigate whether Jakinibs, molecules that inhibit the cytokine JAK/STAT signaling pathway, can blunt expression in primary human bronchial cells.
Objective 3
To investigate prevalence of ongoing activation of inflammation following asymptomatic SARS-CoV-2 infection we characterized immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals with few underlying health issues following a community superspreading event (Lee et al., submitted). Four mildly symptomatic seropositive individuals examined three weeks after infection as positive controls demonstrated immunological activation. Approximately four to six weeks following the event, the two asymptomatic groups showed no significant differences. All subjects remained in their usual state of health from event through five-month follow-up. Here, asymptomatic infection resolved without evidence of prolonged immunological activation. Inclusion of subjects with underlying genetic disease illustrated the pathophysiological importance of context on impact of immunological response.
Objective 4
With the COVID-19 pandemic extending itself into populations with underlying genetic disease, there is an urgent need to understand their immune response to SARS-CoV-2 infections. Towards this end we determined the immune transcriptome of an asymptomatic seropositive patient with Cystic Fibrosis (CF) and one with Nuclear factor-kappa B Essential Modulator (NEMO) deficiency within our study population. (Lee et al., submitted for publication). Two seropositive patients with underlying genetic disease impacting immunological activation were included (Cystic Fibrosis (CF), Nuclear factor-kappa B Essential Modulator (NEMO) deficiency). CF, but not NEMO, associated with significant immune transcriptome differences including some associated with severe SARS-CoV-2 infection (IL1B, IL17A, respective receptors).
1. Hennighausen, L. & Lee, H.K. Activation of the SARS-CoV-2 Receptor Ace2 by Cytokines Through Pan JAK-STAT Enhancers. SSRN, 3601827 (2020).
2. Hennighausen, L. & Lee, H.K. Activation of the SARS-CoV-2 receptor Ace2 by cytokines through pan JAK-STAT enhancers. bioRxiv (2020).
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