Nature Communications | Di Qian’s team uncovers how PM2.5 exposure enhances SARS-CoV-2 infection

SARS-CoV-2 has posed a profound and lasting threat to global public health. Beyond acute infection, the virus is associated with increased risks of hospitalization and mortality, as well as long-term complications, recurrent infections, and persistent health burdens. Meanwhile, fine particulate matter (PM_2.5), one of the leading environmental risk factors worldwide, originates from fuel combustion, traffic emissions, industrial activities, and complex atmospheric chemical processes. PM_2.5 exposure has been linked to a wide range of adverse effects on the respiratory, cardiovascular, and nervous systems. As both SARS-CoV-2 infection and PM_2.5 exposure represent major threats to human health, understanding how environmental factors influence viral susceptibility has become a critical scientific question in the post-pandemic era.

In recent years, accumulating epidemiological evidence has suggested that PM_2.5 exposure is associated with adverse COVID-19 outcomes, including increased risks of infection, hospitalization, and mortality. Previous studies have further indicated that PM_2.5 may impair respiratory function, induce immune and inflammatory responses, and even act as a carrier that increases viral load and facilitates viral entry and replication. However, despite the well-recognized association between PM_2.5 exposure and elevated SARS-CoV-2 risk at the population level, the underlying molecular mechanisms remain poorly understood. In particular, the cellular pathways, key regulatory genes, and gene–environment interactions mediating this effect have yet to be systematically elucidated.

On March 30, 2026, Associate Professor Di Qian from the Vanke School of Public Health, Tsinghua University, Professor Liu Sijin and Associate Professor Dong Zheng from the Medical Science and Technology Innovation Center, Shandong First Medical University (Shandong Academy of Medical Sciences), published an online research article entitled “AI-guided multi-omics analysis identifies NPC1-modulated susceptibility to SARS-CoV-2 infection under PM_2.5 exposure” in Nature Communications. In this work, the authors developed an AI-driven multi-omics integrative framework to systematically investigate how PM_2.5 exposure influences susceptibility to SARS-CoV-2 infection.

Specifically, the researchers first applied a fine-tuned foundation model for single-cell transcriptomic data to identify shared transcriptional signatures and pathways between PM_2.5 exposure and SARS-CoV-2 infection. They then performed epidemiological analyses using data from the UK Biobank, confirming a positive association between PM_2.5 exposure and increased risk of SARS-CoV-2 infection. Through genome-wide association studies (GWAS) and functional genomics analyses, the study further identified key genetic loci near NPC1 and RMC1, highlighting NPC1 as a critical regulatory factor. In vitro experiments demonstrated that virus-laden PM_2.5 enhances infection efficiency, whereas suppressing NPC1 expression or disrupting relevant regulatory variants significantly reduces viral replication. Collectively, these findings suggest that PM_2.5 may act as a viral carrier, facilitating receptor-independent endocytic entry and promoting infection through an NPC1-regulated endo-lysosomal pathway.

A major strength of this study lies in its construction of a comprehensive evidence chain spanning molecular, cellular, genetic, and population levels, moving beyond correlation to mechanistic insight. First, the study introduces AI foundation models into the investigation of environmental exposure and viral infection, providing a powerful tool for extracting key biological signals from complex transcriptomic data. Second, it integrates single-cell omics, epidemiology, GWAS, eQTL analysis, Mendelian randomization, and in vitro functional validation to achieve cross-scale validation. Third, it proposes an NPC1-mediated gene–environment interaction mechanism, offering a novel molecular framework to explain how air pollution increases viral susceptibility. Finally, the findings highlight that air quality management is not only essential for chronic disease prevention but may also play an important role in preparedness for future respiratory infectious diseases and public health risk assessment.

In summary, this study leverages AI-assisted multi-omics integration to systematically uncover a molecular mechanism by which PM_2.5 enhances susceptibility to SARS-CoV-2 infection through an NPC1-modulated endo-lysosomal pathway.

The study was co-corresponded by Associate Professor Di Qian from Tsinghua University and Associate Professor Dong Zheng from Shandong First Medical University. Ph.D. candidate Feng Guoqing from the School of Biomedical Engineering, Tsinghua University, is the first author of this study.