Reciprocal enhancement of SARS-CoV-2 and influenza virus replication in human pluripotent stem cell-derived lung organoids1.

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (FLUAV) coinfections were associated with severe respiratory failure and more deaths. Here, we developed a model for studying SARS-CoV-2 and FLUAV coinfection using human pluripotent stem cell-induced alveolar type II organoids (hiAT2). hiAT2 organoids were susceptible to infection by both viruses and had features of severe lung damage. A single virus markedly enhanced the susceptibility to other virus infections. SARS-CoV-2 delta variants upregulated α-2-3-linked sialic acid, while FLUAV upregulated angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Moreover, coinfection by SARS-CoV-2 and FLUAV caused hyperactivation of proinflammatory and immune-related signaling pathways and cellular damage compared to a respective single virus in hiAT2 organoids. This study provides insight into molecular mechanisms underlying enhanced infectivity and severity in patients with co-infection of SARS-CoV-2 and FLUAV, which may aid in the development of therapeutics for such co-infection cases.

Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Medical Use of Military Hospitals in Korea.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic began in December 2019. While it has not yet ended, COVID-19 has already created transitions in health care, one of which is a decrease in medical use for health-related issues other than COVID-19 infection. Korean soldiers are relatively homogeneous in terms of age and physical condition. They show a similar disease distribution pattern every year and are directly affected by changes in government attempts to control COVID-19 with nonpharmaceutical interventions. This study aimed to identify the changes in patterns of outpatient visits and admissions to military hospitals for a range of disease types during a pandemic. METHODS: Outpatient attendance and admission data from all military hospitals in South Korea from January 2016 to December 2020 were analyzed. Only active enlisted soldiers aged 18-32 years were included. Outpatient visits where there was a diagnosis of pneumonia, acute upper respiratory tract infection, infectious conjunctivitis, infectious enteritis, asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, and fractures were analyzed. Admissions for pneumonia, acute enteritis, and fractures were also analyzed. All outpatient visits and admissions in 2020 for each disease were counted on a weekly basis and compared with the average number of visits over the same period of each year from 2016 to 2019. The corrected value was calculated by dividing the ratio of total weekly number of outpatient visits or admissions to the corresponding medical department in 2020 to the average in 2016-2019. RESULTS: A total of 5,813,304 cases of outpatient care and 143,022 cases of admission were analyzed. For pneumonia, the observed and corrected numbers of outpatient visits and admissions in 2020 decreased significantly compared with the average of other years (P < 0.001). The results were similar for outpatient visits for acute upper respiratory tract infection and infectious conjunctivitis (P < 0.001), while the corrected number of outpatient visits for infectious enteritis showed a significant increase in 2020 (P = 0.005). The corrected number of outpatient visits for asthma in 2020 did not differ from the average of the previous 4 years but the number of visits for the other allergic diseases increased significantly (P < 0.001). For fractures, the observed and corrected numbers of outpatient visits and admissions in 2020 decreased significantly compared with the average of other years (P < 0.001). CONCLUSION: During the COVID-19 pandemic, outpatient visits to military hospitals for respiratory and conjunctival infections and fractures decreased, whereas visits for allergic diseases did not change or increased only slightly. Admissions for pneumonia decreased significantly in 2020, while those for acute enteritis and fractures also decreased, but showed an increased proportion compared with previous years. These results are important because they illustrate the changing patterns in lifestyle as a result of public encouragement to adopt nonpharmaceutical interventions during the pandemic and their effect on medical needs for both infectious and noninfectious diseases in a select group.

Diesel Particulate Matter 2.5 Induces Epithelial-to-Mesenchymal Transition and Upregulation of SARS-CoV-2 Receptor during Human Pluripotent Stem Cell-Derived Alveolar Organoid Development.

Growing evidence links prenatal exposure to particulate matter (PM2.5) with reduced lung function and incidence of pulmonary diseases in infancy and childhood. However, the underlying biological mechanisms of how prenatal PM2.5 exposure affects the lungs are incompletely understood, which explains the lack of an ideal in vitro lung development model. Human pluripotent stem cells (hPSCs) have been successfully employed for in vitro developmental toxicity evaluations due to their unique ability to differentiate into any type of cell in the body. In this study, we investigated the developmental toxicity of diesel fine PM (dPM2.5) exposure during hPSC-derived alveolar epithelial cell (AEC) differentiation and three-dimensional (3D) multicellular alveolar organoid (AO) development. We found that dPM2.5 (50 and 100 µg/mL) treatment disturbed the AEC differentiation, accompanied by upregulation of nicotinamide adenine dinucleotide phosphate oxidases and inflammation. Exposure to dPM2.5 also promoted epithelial-to-mesenchymal transition during AEC and AO development via activation of extracellular signal-regulated kinase signaling, while dPM2.5 had no effect on surfactant protein C expression in hPSC-derived AECs. Notably, we provided evidence, for the first time, that angiotensin-converting enzyme 2, a receptor to mediate the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) entry into target cells, and the cofactor transmembrane protease serine 2 were significantly upregulated in both hPSC-AECs and AOs treated with dPM2.5. In conclusion, we demonstrated the potential alveolar development toxicity and the increase of SARS-Cov-2 susceptibility of PM2.5. Our findings suggest that an hPSC-based 2D and 3D alveolar induction system could be a useful in vitro platform for evaluating the adverse effects of environmental toxins and for virus research.