Role of pro-inflammatory response and antiviral dysfunction as a target of butyrate in murine and human macrophages exposed to cigarette smoke and infected with SARS-CoV-2: Relevance to exacerbation of chronic obstructive pulmonary disease

• Grant number: 23/11973-1
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Flávio Aimbire Soares de Carvalho
• Grantee: Flávio Aimbire Soares de Carvalho
• Host Institution: Instituto de Ciência e Tecnologia (ICT). Universidade Federal de São Paulo (UNIFESP). Campus São José dos Campos. São José dos Campos , SP, Brazil
• Associated researchers: Alexandre de Castro Keller

Abstract

The present project aims to investigate the effect of sodium butyrate on exacerbating the pro-inflammatory response and dysfunction of the antiviral response in murine and human macrophages exposed to cigarette smoke and infected with SARS-CoV-2. This approach is plausible due to the fact that individuals with COVID-19, particularly those affected by its most severe form, severe acute respiratory syndrome (SARS), exhibit intense inflammation of the airways, alveolar edema, and progressive pulmonary fibrosis, culminating in reduced respiratory capacity and death. For this reason, COVID-19 exacerbates inflammation in individuals with smoking-induced chronic obstructive pulmonary disease (COPD), and there is no effective treatment for COPD exacerbation. In fact, among chronic inflammatory diseases, COPD is classified as a risk group for COVID-19. It is important to note that pulmonary inflammatory response is exacerbated in individuals with COPD and infected with SARS-CoV-2, as both COPD and COVID-19 induce inflammatory signaling resulting in intense secretion of pro-inflammatory cytokines and chemokines in the pulmonary microenvironment. Additionally, individuals with COPD exhibit dysfunction in the antiviral immune response. On the other hand, this condition in COPD is due to the fact that protein receptors responsible for virus recognition in cells of the innate immune system, such as macrophages, have impaired signaling responsible for the production of antiviral IFN-1. Thus, individuals with COPD and infected with SARS-CoV-2 exhibit exacerbation of the pulmonary inflammatory response and dysfunction of the antiviral immune response. The pharmacological treatment to attenuate the exacerbation of pulmonary inflammation induced by COVID-19 in COPD patients is the use of corticosteroids. However, individuals with COPD are resistant to corticosteroid therapy, and furthermore, corticosteroids are restricted depending on the timing of SARS-CoV-2 infection, and also cause significant side effects. In this scenario, the study of new therapies capable of attenuating the exacerbation of pulmonary inflammation induced by COVID-19 in COPD deserves attention. Among the new therapies, short-chain fatty acids, especially butyrate, present in the diet with butter, fruits, oats, whole grains, and legumes, fulfill this prerequisite. In fact, butyrate has anti-inflammatory activity in asthma and COPD, and evidence points to the effect of butyrate against SARS-CoV-2 infections. Therefore, it is reasonable to investigate the effect of butyrate on the exacerbation of COPD in murine and human macrophages infected with SARS-CoV-2. The immunomodulatory effects of butyrate are attributed to the activation of the GPR43 membrane receptor in cells of the innate immune system. In fact, some authors show that inhibition of this receptor reduces the anti-inflammatory and immune effect of butyrate in various inflammatory conditions. In this sense, this receptor may be involved in the supposed effect of butyrate on the exacerbation of COPD induced by SARS-CoV-2 infection. In this scenario, we will investigate the effect of butyrate on the pro-inflammatory pulmonary response and dysfunction of the antiviral response in murine and human macrophages exposed to cigarette smoke and infected with SARS-CoV-2. (AU)