AUTHOR=Bénard Alan , Hansen Frederik J. , Uhle Florian , Klösch Bettina , Czubayko Franziska , Mittelstädt Anke , Jacobsen Anne , David Paul , Podolska Malgorzata J. , Anthuber Anna , Swierzy Izabela , Schaack Dominik , Mühl-Zürbes Petra , Steinkasserer Alexander , Weyand Michael , Weigand Markus A. , Brenner Thorsten , Krautz Christian , Grützmann Robert , Weber Georg F. TITLE=Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1140630 DOI=10.3389/fimmu.2023.1140630 ISSN=1664-3224 ABSTRACT=Rationale

Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive.

Objectives

To investigate the role of IL-3 during viral pneumonia in sepsis.

Methods

We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections).

Measurements and main results

Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections.

Conclusion

Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.