SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage.

PURPOSE: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. METHODS: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. RESULTS: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. CONCLUSIONS: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.

Melanosome transfer evaluation by quantitative measurement of Pmel 17 in human normal melanocyte-keratinocyte co-cultures: effect of an Alaria esculenta extract.

Numerous strategies have been proposed to evaluate melanosome transfer. Methods allowing quantitative measurements of this transfer in human normal cellular models, however, are very few and often require extremely specialized devices that are expensive and difficult to use. As a part of the melanosome-specific membrane-bound glycoprotein, Pmel 17 is released from the melanosome membrane by ectodomain shedding. We reasoned, therefore, that it should be possible to evaluate melanosome transfer by quantifying this "soluble" Pmel 17. The Pmel 17 ELISA assay developed permits a detection of 10 to 1000 ng/ml of this glycoprotein in human normal melanocyte-keratinocyte co-culture media. As expected, niacinamide, a well-known melanosome transfer inhibitor, significantly reduced the Pmel 17 quantities found in the culture media. This validated our experimental design. We then used our model to show that a whitening cosmetic active compound, i.e., an Alaria esculenta extract, can (at least in part) enable a significant decrease in the melanosome transfer to produce a lightening effect without affecting melanin production. This research provides a simple and efficient method to quantify melanosome transfer in a human normal co-culture model. It is a particularly useful tool with which to facilitate the development of new active whitening compounds.

Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV-2 infection.

Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19-ARDS+, COVID-19+ARDS+, and COVID-19+ARDS-, and compare, by high-dimensional mass cytometry, their immune landscape. A cell signature associating S100A9/calprotectin-producing CD169+ monocytes, plasmablasts, and Th1 cells is found in COVID-19+ARDS+, unlike COVID-19-ARDS+ patients. Moreover, this signature is essentially shared with COVID-19+ARDS- patients, suggesting that severe COVID-19 patients, whether or not they experience ARDS, display similar immune profiles. We show an increase in CD14+HLA-DRlow and CD14lowCD16+ monocytes correlating to the occurrence of adverse events during the ICU stay. We demonstrate that COVID-19-associated ARDS displays a specific immune profile and may benefit from personalized therapy in addition to standard ARDS management.