Exogenous Chemicals Impact Virus Receptor Gene Transcription: Insights from Deep Learning.

Despite the fact that coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been disrupting human life and health worldwide since the outbreak in late 2019, the impact of exogenous substance exposure on the viral infection remains unclear. It is well-known that, during viral infection, organism receptors play a significant role in mediating the entry of viruses to enter host cells. A major receptor of SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2). This study proposes a deep learning model based on the graph convolutional network (GCN) that enables, for the first time, the prediction of exogenous substances that affect the transcriptional expression of the ACE2 gene. It outperforms other machine learning models, achieving an area under receiver operating characteristic curve (AUROC) of 0.712 and 0.703 on the validation and internal test set, respectively. In addition, quantitative polymerase chain reaction (qPCR) experiments provided additional supporting evidence for indoor air pollutants identified by the GCN model. More broadly, the proposed methodology can be applied to predict the effect of environmental chemicals on the gene transcription of other virus receptors as well. In contrast to typical deep learning models that are of black box nature, we further highlight the interpretability of the proposed GCN model and how it facilitates deeper understanding of gene change at the structural level.

Exogenous Chemical Exposure Increased Transcription Levels of the Host Virus Receptor Involving Coronavirus Infection.

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.