key: cord-0312617-zydvo4mm
authors: Kwon, Jung Won; Quan, Hailian; Song, Juha; Chung, Hyewon; Jung, Daun; Hong, Jung Joo; Na, Yi Rang; Seok, Seung Hyeok
title: Liposomal Dexamethasone Reduces A/H1N1 Influenza-Associated Morbidity in Mice
date: 2021-08-04
journal: bioRxiv
DOI: 10.1101/2021.08.02.454850
sha: c7252d6fb7a21b30591768e14d52ab8bca5334fa
doc_id: 312617
cord_uid: zydvo4mm

Re-emerging viral threats have continued to challenge the medical and public health systems. It has become clear that a significant number of severe viral infection cases are due to an overreaction of the immune system, which leads to hyperinflammation. In this study, we aimed to demonstrate the therapeutic efficacy of the dexamethasone nanomedicine in controlling the symptoms of influenza infection. We found that the A/Wisconsin/WSLH34939/2009 (H1N1) infection induced severe pneumonia in mice with a death rate of 80%, accompanied by significant epithelial cell damage, infiltration of immune cells, and accumulation of pro-inflammatory cytokines in the airway space. Moreover, the intranasal delivery of liposomal dexamethasone during disease progression reduced the death rate by 20%. It also significantly reduced the protein level of tumor necrosis factor-alpha (TNFα), interleukin1β (IL-1β), IL-6, and the C-X-C motif chemokine ligand 2 (CXCL2) as well as the number of infiltrated immune cells in the bronchoalveolar lavage fluids as compared to the free drug. It was found that the liposomal dexamethasone was mainly distributed into the monocyte/macrophages in the lungs, suggesting its mode of action via the specific delivery of the drug into myeloid cells as a major cell population for inducing the cytokine storm. Taken together, the intranasal delivery of liposomal dexamethasone may serve as a novel promising therapeutic strategy for the treatment of influenza A-induced pneumonia. Importance Influenza A virus causes annual epidemics and sporadic pandemics of respiratory diseases. An excessive immune response, called a cytokine storm, caused by the influenza virus is the most common complication of influenza infection that is associated with high levels of morbidity and mortality. Here, we report that the liposomal dexamethasone targeting the monocytes/macrophages during disease progression reduced the death rate as well as the protein level of inflammatory cytokines and the number of immune cells. Therefore, the findings of this study may be applied to address the limitations of the current strategies for the treatment of influenza.

score improvement in the DEX/lipo group was due to the difference in viral titers between 150 groups. The viruses isolated from lungs plaqued on Madin-Darby canine kidney (MDCK) 151 cells using TCID₅₀. However, virus isolated from infected mouse lungs did not decrease in the 152 DEX/lipo group (Fig. 2E) . Collectively, these results support our hypothesis that targeting 153 macrophages using DEX/lipo has a therapeutic effect in reducing inflammation. S1 . Gating strategies to determine the cellular compositions of the lungs of mice (Related to Fig. 1) .

Molecular 432 pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene 433 expression

Influenza-induced innate immunity: regulators of viral 435

replication, respiratory tract pathology & adaptive immunity

Pathological inflammation in patients with COVID-19: a key role