A groundbreaking study conducted by researchers from the LMU Hospital in Germany, the Institute of Lung Health and Immunity at Helmholtz Zentrum München, and Ludwig-Maximilians-Universität in Munich has revealed a new mechanism of SARS-CoV-2 infection. The study focuses on the role of the cell surface glucose-regulated protein 78 (csGRP78) on monocytes, shedding light on how the virus can infect cells independently of the ACE2/TMPRSS2 pathway that is commonly known. This discovery has significant implications for understanding the dynamics of SARS-CoV-2 infection and could potentially lead to targeted therapies to modulate the hyperinflammatory response seen in severe COVID-19 cases.
Previous research has shown that SARS-CoV-2 primarily enters respiratory epithelial cells through the ACE2 receptor, facilitated by TMPRSS2. However, monocytes and macrophages, which are important players in severe COVID-19 cases, express low levels of ACE2, suggesting alternative entry routes for these immune cells. The researchers hypothesized that csGRP78, a protein expressed on monocytes and macrophages, could serve as a potential receptor for SARS-CoV-2.
To investigate this hypothesis, the researchers analyzed hospitalized COVID-19 patients and compared their pro-inflammatory state and csGRP78 expression on monocytes to healthy controls. They also conducted transcriptome analyses, bioinformatic re-analyses of bronchoalveolar lavage fluid datasets, and immunohistocytochemistry on post-mortem lung tissues. In addition, cell culture experiments were performed to validate the interaction between csGRP78 and the SARS-CoV-2 spike protein, and to determine the role of csGRP78 in ACE2-independent virus entry into monocytes.
The results of the study showed that COVID-19 patients exhibited a distinct pro-inflammatory state, with increased levels of cytokines and higher expression of csGRP78 on peripheral blood and lung monocytes/macrophages. The researchers confirmed that pro-inflammatory cytokines were associated with csGRP78 upregulation. In vitro analyses demonstrated a strong interaction between csGRP78 and the SARS-CoV-2 spike protein, indicating that csGRP78 can act as a receptor for the virus. Furthermore, infection rate analyses showed increased uptake of the virus in monocytes, highlighting the role of csGRP78 in ACE2-independent SARS-CoV-2 entry.
This groundbreaking research challenges the conventional understanding of SARS-CoV-2 entry and reveals csGRP78 as a crucial receptor for the virus on monocytes. The study suggests that the enhanced expression of csGRP78, driven by pro-inflammatory cytokines, mediates ACE2-independent virus entry into monocytes, contributing to the hyperinflammation observed in severe COVID-19 cases. Targeting csGRP78 could be a potential therapeutic strategy to mitigate the hyperinflammatory response and improve patient outcomes.
The research provides a comprehensive approach, integrating clinical data with in vitro experiments and bioinformatic analyses. By confirming csGRP78 upregulation in COVID-19 patients and establishing its interaction with the SARS-CoV-2 spike protein, the study bridges the gap between clinical observations and molecular mechanisms. This discovery offers new insights into COVID-19 pathogenesis and highlights csGRP78 as a promising target for drug development.
The identification of csGRP78 as a key player in SARS-CoV-2 entry has significant implications for understanding the dynamics of infection, particularly in immune cells like monocytes. Targeted therapies that modulate the hyperinflammatory response by disrupting csGRP78 upregulation, such as small molecule inhibitors like BOLD-100, present promising avenues for further investigation and clinical trials.
In conclusion, this study represents a paradigm shift in our understanding of SARS-CoV-2 entry into host cells. The discovery of csGRP78 as a receptor for the virus on monocytes opens up new possibilities for therapeutic interventions in severe COVID-19 cases. Further research and clinical trials are needed to explore the potential of targeting csGRP78, particularly using small molecule inhibitors, as a viable strategy in the fight against COVID-19. This breakthrough not only enhances our knowledge of the virus’s pathogenesis but also provides a promising direction for the development of targeted antiviral therapies. The study findings were published in the peer-reviewed journal eBioMedicine.