The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide. As of 2024, the SARS-CoV-2 Omicron variant is the predominant strain circulating within the population, generally causing mild upper respiratory tract infections. However, hospitalizations and case fatalities due to COVID-19 continue, and there is a high probability that a new human coronavirus will emerge in the future. Understanding the pathophysiology of severe COVID-19 remains highly relevant, as its mechanisms may be comparable to those of other respiratory viral infections. SARS-CoV-2 infects human cells primarily by binding to angiotensin-converting enzyme 2 (ACE2) and type 2 transmembrane serine protease (TMPRSS2) receptors, which are both expressed in alveolar epithelial type II cells, through the virus' spike protein. In a later stage, the replication of SARS-CoV-2 and activation of resident immune cells lead to the infiltration and activation of large numbers of innate immune cells. Consequently, this results in an excessive pro-inflammatory immune response, including increased production of IL-6, a hallmark cytokine of severe COVID-19. Eventually, the excessive inflammation results in microthrombus formation and pulmonary edema. Further studies have indicated that SARS-CoV-2 spike-specific antibodies, along with alveolar macrophages, play a pivotal role in the pathophysiology of severe COVID-19. Alveolar macrophages, which reside in the lung alveoli, are typically the first immune cells to sense pulmonary pathogens. However, these cells can also bind IgG antibodies through their Fc-receptor, leading to cellular activation. When stimulated with both a viral stimulus and anti-SARS-CoV-2 IgG antibodies from severe COVID-19 patients (a situation similar to that in the lungs of these patients) alveolar macrophages elicit a significant proinflammatory response. This response aligns with the observed post-seral conversion deterioration in COVID-19 patients. Obesity is a significant risk factor for developing severe COVID-19, but the underlying mechanism is not well understood. Previous studies report that macrophages in obese patients are skewed towards a pro-inflammatory phenotype due to altered fatty acid contents, particularly increased saturated fatty acids. Using our in vitro obesity model, which incorporates higher saturated fatty acid contents, the investigators already demonstrated that SARS-CoV-2 antibody-mediated inflammation of alveolar macrophages is increased (unpublished data). Thus, this may explain why obese patients are more likely to develop severe COVID-19. To validate these in vitro findings, the investigators aim to confirm these results in monocyte-derived macrophages isolated from individuals with and without obesity. Additionally, the investigators will investigate the underlying mechanisms involved in detail. This study will provide valuable insights into the role of obesity in severe COVID-19 and potentially inform therapeutic strategies for at-risk populations.