Abstract:Novel coronavirus disease 2019 (COVID-19) severity is highly variable, with pediatric patients typically experiencing less severe infection than adults and especially the elderly. The basis for this difference is unclear. We find that mRNA and protein expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, increases with advancing age in distal lung epithelial cells. However, in humans, ACE2 e… Show more
“…In contrast, alveolar regions were characterized by widespread infection but little cleaved caspase-3. These differences in apoptotic activity are consistent with reports that murine airway epithelial cells are more primed for apoptosis than alveolar epithelial cells in basal states ( 41 ).…”
COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
“…In contrast, alveolar regions were characterized by widespread infection but little cleaved caspase-3. These differences in apoptotic activity are consistent with reports that murine airway epithelial cells are more primed for apoptosis than alveolar epithelial cells in basal states ( 41 ).…”
COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
“…Lastly, IL-6 and IL-10 are among two of the interleukins secreted after inflammasome activation, one of the shared mechanisms between these pathologies, and their increased expression has been shown to be predictive of COVID-19 severity [14] . Furthermore, the interaction between two other proteins (i.e., DDIT3 and BCL2L11) involved in the regulation of apoptosis is also suggested as a common mechanism across these indications [ 18 , 26 ]. Fig.…”
Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center ‘Lean European Open Survey on SARS-CoV-2-infected patients’ (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.
“…As the first step of gene expression, the production of ACE2 mRNA has been reported to be positively correlated with the increased susceptibility to SARS-CoV-2 infection and severity of COVID-19 symptoms. 19 , 20 The alterations of ACE2 transcription and expression can be a result of genetic factors such as age 21 and race, 22 but nongenetic factors such as chemical exposure can also impact virus receptor, transcription, translation, and so forth. Work to date has not looked at how these exogenous chemicals impact virus receptor transcription or expression, which deserve further research.…”
Virus receptors are highly involved
in mediating the entrance of
infectious viruses into host cells. Here, we found that typical chemical
exposure caused the upregulation of virus receptor mRNA levels. Chemicals
with the same structural characteristics can affect the transcription
of angiotensin-converting enzyme 2 (
ACE2
), a dominant
receptor of SARS-CoV-2. Some chemicals can also regulate the transcription
of
ACE2
by similar regulatory mechanisms, such as
multilayer biological responses and the crucial role of TATA-box binding
protein associated factor 6. The abovementioned finding suggested
that chemical mixtures may have a joint effect on the
ACE2
mRNA level in the real scenario, where humans are exposed to numerous
chemicals simultaneously in daily life. Chemically regulated virus
receptor transcription was in a tissue-dependent manner, with the
highest sensitivity in pulmonary epithelial cells. Therefore, in addition
to genetic factors, exogenous chemical exposure can be an emerging
nongenetic factor that stimulates the transcription of virus receptor
abundance and may elevate the protein expression. These alterations
could ultimately give rise to the susceptibility to virus infection
and disease severity. This finding highlights new requirements for
sufficient epidemiological data about exposomes on pathogen receptors
in the host.
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