SARS-CoV-2、COVID-19、インターフェロン、インターロイキン、マクロファージ

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◆Expression of the readthrough transcript CiDRE in alveolar macrophages boosts SARS-CoV-2 susceptibility and promotes COVID-19 severity【Cell Immunity　2023年7月12日】

Summary

Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and led to the COVID-19 pandemic, which has globally disrupted society. The excess mortality rate of COVID-19 was reported to be 120.3 deaths per 100,000 persons. The main cause of death is respiratory failure related to severe pneumonia, also termed acute respiratory distress syndrome. Although there are asymptomatic cases of SARS-CoV-2 infection, some patients progress rapidly into a severe and fatal illness. In a recent retrospective study, several indexes, including sex, age, and body mass index, were reported to be risk factors for the exacerbation of COVID-19. From a genetics perspective, several polymorphisms involved in immune responses were reported to be associated with COVID-19 susceptibility and severity in genome-wide association studies (GWASs). However, the detailed molecular mechanism of severe pneumonia in COVID-19 remains unknown.

The marked amplification of inflammatory responses triggered by SARS-CoV-2 infection, termed a “cytokine storm,” is considered to be a key process in the course of COVID-19 progression and leads to multiple organ dysfunction. Various cytokines (including interleukin [IL]-6) and chemokines produced by virus-infected cells in the lungs are thought to be important for the establishment of cytokine storms. In addition, the accumulation of several types of immune cells, including monocytes, dendritic cells, and CD4 and CD8 T-cells, by chemotaxis facilitates this process. In the first step of this mechanism, SARS-CoV-2 invades host cells via the spike (S) glycoprotein that normally binds to the host cell-surface receptor, angiotensin-I-converting enzyme 2 (ACE2), which is expressed abundantly in proximal airway cells of the human respiratory system and partially in the distal epithelium, including on alveolar epithelial cells. Because the focus of cytokine storms is the alveolar space, it is unclear how proximal airway-dominant infections of SARS-CoV-2 lead to widespread inflammation in the distal alveolar area.

In alveoli, alveolar macrophages, which are mainly involved in the maintenance of the immune system, have been considered to not be susceptible to infection by SARS-CoV-2 because of their low ACE2 expression. However, some recent research has suggested that alveolar macrophages are susceptible to SARS-CoV-2 infection and are involved in the virus-induced cytokine storm, although it is still unclear how these low-ACE2-expressing cells are hijacked by SARS-CoV-2. In this study, we focused on alveolar macrophages and investigated their functional involvement in COVID-19 severity using multiple molecular biology and genetic techniques. Consequently, we found that the modulation of alveolar macrophages by IL-10 was an important determinant of COVID-19 severity. We also found that IL-10 response of human alveolar macrophages varied among individuals and was affected by the IFNAR2-IL-10RB hybrid receptor, COVID-19 infectivity-enhancing dual receptor (CiDRE), which is regulated by genetic polymorphisms involved in COVID-19 severity.