Scientists worldwide are investigating the mechanism behind COVID-19 infection and the pneumonia and lung damage that sometimes accompany it. Researchers* at Charité, the Berlin Institute of Health at Charité (BIH), the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Robert Koch Institute, and Freie Universität Berlin have now analyzed how SARS-CoV-2 viruses replicate in human lungs and activate the immune response. To this end, they have focused on the cells of the human alveoli, also called alveoli, as well as the alveolar macrophages. These scavenger cells of our innate immune system destroy foreign particles, including infectious agents such as viruses and bacteria, and thus ensure that the lungs are cleansed.
No direct tissue damage from SARS-CoV-2
Under the leadership of Prof. Dr. Andreas Hocke of Charité's Department of Infectious Diseases and Respiratory Medicine, the research team has found that SARS-CoV-2 infects only a very small number of epithelial cells lining the surface of the alveoli and thus causes very little direct tissue damage. This represents a decisive difference to MERS coronaviruses or influenza viruses, for example. At the same time, the scientists were able to prove that the ACE2 receptor required for SARS-CoV-2, which serves as an entry portal for the viruses, is detectable in only very few alveolar epithelial cells. This was revealed by extensive analysis using spectral microscopy.
"We were able to show the direct dependence of SARS-CoV-2 on its receptor in human lungs as well as in lung organoids - which are models of human alveoli that we obtained from stem cells of lung tissue - and thus rule out other, alternative receptors," explains the study's first author Dr. Katja Hönzke from the Department of Medicine with a focus on infectious diseases and pneumology. According to the study, if large amounts of viruses enter the alveoli from the upper respiratory tract, they do not multiply to a high degree in the resident epithelial cells of the lung, as is often the case with other severe viral infections, but are taken up directly by the phagocytes.
Phagocytes take up the viruses
"We saw with detailed bioinformatics analyses, as well as using autopsy tissue from individuals who died from COVID-19, that the phagocytes change as a result of the uptake of the coronaviruses," says the study's second first author, Dr. Benedikt Obermayer-Wasserscheid of BIH. The phagocytes release inflammatory messengers and can sometimes trigger very strong inflammatory cascades. The researchers also observed that the virus does not multiply in the phagocytes of the immune system.
Prof. Hocke classifies the results: "Our study suggests that severe lung damage in COVID-19 is more likely due to immune activation triggered by macrophages than to direct destruction of the alveoli by the virus. Thus, it contributes significantly to our understanding of how COVID-19 develops in the early phase of potential pneumonia and demonstrates why SARS-CoV-2, in contrast to MERS coronaviruses, has a more moderate course in the majority of cases." The scientists* assume that in the vast majority of cases, local immune mechanisms in the respiratory tissues efficiently clear the SARS-CoV-2 viruses and limit the inflammatory response. If this does not happen, which may be influenced by individual risk factors, severe and fatal courses can result in rare cases.
Lung models as an alternative to animal testing
Prof. Hocke continues, "The lung models we used are an excellent demonstration of how alternatives to animal models based on human cells can be used, particularly in research into zoonotic diseases. We achieved this in close collaboration with Charité 3R, our facility for developing alternatives to animal testing."
The scientists now want to study patient-specific organoid models to find out how general risk factors such as age, gender, concomitant diseases and other medications influence the activation of the inflammatory response. This knowledge could be used to identify potential therapeutic approaches that target the immune system.
About this study
This research received funding from the German Research Foundation (DFG) as part of the Collaborative Research Center SFB-TR84 ‘Innate Immunity of the Lung’. Additional funding was provided by the Einstein Foundation Berlin (Einstein Center 3R), as well as the ‘Organ-specific Stratification in COVID-19’ (Organo-Strat) research collaboration, which is funded by the Federal Ministry of Education and Research (BMBF). This research collaboration was conducted under the auspices of the NUM, an academic research network initiated and coordinated by Charité. The NUM brings together the combined strength of Germany’s 36 university hospitals.
*Hönzke K, Obermayer B, Mache C, et al. Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages. European Respiratory Journal (2022). doi: 10.1183/13993003.02725-2021