ABSTRACT
Introduction: The induction of regulatory T cells (Tregs) is indicated as a potential therapeutic strategy in inflammatory lung diseases including, asthma, viral-induced pneumonia, viral-induced acute lung injury (ALI), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and SARSCoV- 2-induced ALI. We previously identified that components of the bacteria Streptococcus pneumoniae (T + P) are able to increase Tregs to suppress experimental allergic airways disease, however, this mechanism of suppression and therapy has not been examined in ALI. Methods: We established a murine model of ALI using aerosolized LPS (100 μg/ml) in BALB/c mice. ALI was measured by the presence of neutrophils in the airways up to 96 hours post-exposure, and Tregs and dendritic cells were assessed by flow cytometry. To assess the therapeutic of T + P in ALI and the mechanisms involved, the combination was administered prior to LPS exposure in the absence or presence of anti-CD25. Results: Treatment with T + P significantly reduced total airway inflammation and suppressed the neutrophil chemokine C-X-C motif chemokine ligand 1 (Cxcl1) compared to Saline+LPS alone in experimental ALI. The numbers of Tregs were reduced in experimental ALI model and were restored by T + P treatment. Depletion of Tregs with anti- CD25 confirmed that the suppressive effects of T + P on ALI was through the induction of Tregs. Conclusion: Treatment with S. pneumoniae components T + P suppresses neutrophilic inflammation in ALI through immunoregulatory mechanisms that involve Tregs and may be a novel treatment for ALI including in COVID-19.
ABSTRACT
Introduction: COVID-19 is responsible for a global pandemic that is complicated by acute lung injury, and death. The virus SARS-CoV-2 requires the ACE2 receptor and serine proteases to enter airway epithelial cells. We sought to determine what factors were associated with levels of ACE2 expression and how this related to people with asthma and chronic obstructive pulmonary disease (COPD). Methods: We obtained airway epithelial cells from 146 people, aged 2 to 89 from Perth and Newcastle. The Newcastle cohort were enriched with people with asthma and COPD. Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry were assessed by quantitative PCR and immunohistochemistry. Results: Increased gene expression for ACE2 from lower airway epithelial cells was associated with older age (p=0.02) and male sex (p=0.03), but not packet years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 was lower in asthma p=0.01 (Figure). Gene expression for Furin a protease that facilitates viral endocytosis was also lower in asthma (p=0.02), while ADAM-17, a disintegrin that has been shown to cleave ACE2 from the surface was increased p=0.02. We confirmed that ACE2 protein expression was lower in endobronchial biopsies from people with asthma. Conclusions: Increased ACE2 expression is seen in older people and males. While people with asthma appear to have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism to the lower airway.
ABSTRACT
COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.