Monocytes, dendritic cells and myeloid-derived suppressor cells in blood and airways across COVID-19 and influenza severity

<p dir="ltr">Respiratory viral infections including influenza and COVID-19 continue to cause substantial morbidity and mortality globally. Although several risk factors for severe disease are known, and include older age and underlying diseases, it is not fully known why certain individuals develop severe disease.</p><p dir="ltr">Monocytes and dendritic cells (DC) are positioned in mucosal surfaces and also circulate in blood, and are important sensors and responders to these viruses. Importantly, DCs efficiently activate T cells that are typically needed to clear viral infection. Although epithelial cells in the upper respiratory tract are the primary site of infection for these viruses, and early events at this site are likely important for subsequent disease severity, most studies focus on blood samples. Moreover, monocytes and DCs differ in distribution and function depending on their anatomical location, and it is therefore important to sample the mucosa in addition to blood. While monocytes and DCs can initiate an inflammatory response upon viral infection, myeloid-derived suppressor cells (MDSC) are instead suppressors of T cell responses. Monocytic MDSCs (M-MDSC) are phenotypically similar to monocytes, and likely represent an altered monocyte state. These cells have mostly been studied in chronic inflammatory conditions such as cancer, but are also present in sepsis. The role of MDSC in influenza and COVID-19, however, is less clear.</p><p dir="ltr">In this thesis, we focused on the role of monocytes, DCs and M-MDSC in influenza and COVID-19 patients, and investigate how these cells may influence disease severity. We collected longitudinal samples from the airways, including nasopharyngeal aspirates (NPA) and endotracheal aspirates (ETA), along with blood samples from two cohorts of patients with ongoing influenza or COVID-19 with varying degree of disease severity.</p><p dir="ltr">We found an early recruitment of monocytes and DCs to the nasopharynx during influenza, while DCs instead decreased in blood. By separating patients based on severity, we found that lower DC levels in blood and decreased DC recruitment to the nasopharynx associated with more severe influenza. Similarly, we found that COVID-19 patients displayed substantial monocyte recruitment to the trachea, whereas DCs were not recruited. In blood, DCs were depleted and both monocytes and DCs displayed decreased maturation.</p><p dir="ltr">In patients with COVID-19, we found a severity-dependent increase in levels of M-MDSC. These cells were capable of suppressing T cell proliferation in vitro. Moreover, levels of arginase 1, which is produced by M-MDSC, were increased in plasma of patients with more severe disease. Cells with the same phenotype were also increased in the blood of influenza patients.</p><p dir="ltr">Comparing different sampling methods to study monocytes and DCs in the upper airways during respiratory viral infection, we found that NPA generated significantly higher cell yield as compared to nasal curettes and nostril swabs. In addition, NPA was not associated with more blood contamination or increased patient discomfort. NPA could also be used for longitudinal sampling, allowing temporal assessment of monocytes and DCs during acute infection and convalescence.</p><p dir="ltr">Collectively, this thesis points out a recruitment of DCs to the airways in mild influenza, whereas DCs were less recruited in patients with more severe influenza and COVID-19. Instead, the most severe COVID-19 patients were characterized by airway recruitment of monocytes and high levels of circulating M-MDSC. We also establish NPA as a useful method to study monocytes and DCs longitudinally in the upper airways during ongoing infection.</p><h3>List of scientific papers</h3><p dir="ltr">I. Vangeti S, <b>Falck-Jones S,</b> Yu M, Österberg B, Liu S, Asghar M, Sonden K, Paterson C, Whitley P, Albert J, Johansson N, Färnert A, Smed-Sörensen A. Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx. Elife. 2023 Feb 8;12:e77345. <a href="https://doi.org/10.7554/elife.77345" rel="noreferrer" target="_blank">https://doi.org/10.7554/elife.77345</a></p><p dir="ltr">II. <b>Falck-Jones S,</b> Vangeti S, Yu M, Falck-Jones R, Cagigi A, Badolati I, Österberg B, Lautenbach MJ, Åhlberg E, Lin A, Lepzien R, Szurgot I, Lenart K, Hellgren F, Maecker H, Sälde J, Albert J, Johansson N, Bell M, Loré K, Färnert A, Smed-Sörensen A. Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity. Journal of Clinical Investigation. 2021 Mar 15;131(6): e144734. <a href="https://doi.org/10.1172/jci144734" rel="noreferrer" target="_blank">https://doi.org/10.1172/jci144734</a></p><p dir="ltr">III. Österberg B*, <b>Falck-Jones S*</b>, Vangeti S, Åhlberg E, Yu M, Granja D, Snik ME, Falck-Jones R, Barros G W F, Charles A, Lepzien R, Johansson N, Holmes TH, Maecker H, Czarnewski P, Bell M, Färnert A, Smed-Sörensen A. *Equal contribution. Decreased levels and function of dendritic cells in blood and airways predict COVID-19 severity. Clinical and Translational Immunology. 2025 Mar 3;14(3):e70026. <a href="https://doi.org/10.1002/cti2.70026" rel="noreferrer" target="_blank">https://doi.org/10.1002/cti2.70026</a></p><p dir="ltr">IV. <b>Falck-Jones S*</b>, Österberg B*, Åhlberg E, Padhi A, Joshua V, Grundström J, Svensson J, Charles A, Yu M, Falck-Jones R, Bell M, Bergqvist L, Färnert A, Smed-Sörensen A. * Equal contribution. Temporal dynamics of dendritic cells in the upper airways distinguish influenza patients requiring hospitalization. [Manuscript]</p>