Interferon responses in viral pneumonias

doi:10.1126/science.abd2208

GSTDTAP > 气候变化

DOI	10.1126/science.abd2208
	Interferon responses in viral pneumonias
	Gary E. Grajales-Reyes; Marco Colonna
	2020-08-07
发表期刊	Science
出版年	2020
英文摘要	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak quickly developed into a pandemic in March 2020. To date, no vaccines or antiviral medications are available, and given the urgency, many clinical trials have started screening existing antiviral drugs for efficacy against SARS-CoV-2 infection. Among a variety of therapeutic approaches, the use of different types of interferon (IFN) as antiviral agents is under investigation owing to promising outcomes in other coronavirus-induced pathologies ([ 1 ][1]). Through different mechanisms and effector proteins, IFNs play an important role in the inhibition of viral replication ([ 2 ][2]). On pages 712 and 706 of this issue, Major et al. ([ 3 ][3]) and Broggi et al. ([ 4 ][4]), respectively, describe the mechanisms by which IFN-λ responses contribute to pathogenesis in viral pneumonias. Conversely, on page ZZZ, Hadjadj et al. ([ 5 ][5]) studied peripheral blood responses from a cohort of 50 patients with coronavirus disease 2019 (COVID-19), demonstrating that critically ill patients have reduced IFN responses paired with a proinflammatory response. IFNs are important cytokines of the innate and adaptive immune system and are classified into three main types: I (α or β), II (γ), and III (λ). During viral infections, pattern-recognition receptors detect viral nucleic acids, inducing the production of IFNs. The expression of type I, II, and III IFNs is not redundant among all the IFN-producing cells. In particular, expression of IFN-λ is tissue specific and is mainly produced by dendritic cells, epithelial cells, and hepatocytes. In humans, IFN-λ includes four members (IFNL1 to -4), all of which bind and induce signaling through the heterodimeric IFN-λ receptor (IFNLR) ([ 6 ][6]), which is mostly restricted to epithelial cells, dendritic cells, and neutrophils ([ 7 ][7], [ 8 ][8]). Signaling through the IFNLR triggers an intracellular signaling pathway, which in turn induces expression of a group of IFN-stimulated genes (ISGs) ([ 9 ][9]). IFNLR signaling also induces expression of the tumor suppressor p53, which limits viral replication by enhancing IFN signaling and causing cell cycle arrest of infected cells ([ 10 ][10], [ 11 ][11]). Although IFN-λ has antiviral effects, it has been shown that in mice, IFN-λ produced in response to influenza virus infection increased susceptibility to pneumonia caused by subsequent infection with methicillin-resistant Staphylococcus aureus (called superinfection) ([ 12 ][12]). IFN-λ caused expansion and restructuring of the nasal microbiota, as well as impaired epithelial barrier function, which allow bacteria to invade and colonize the tissue. Consistent with this observation, Broggi et al. showed that amounts of IFN-λ messenger RNA (mRNA) from bronchoalveolar lavage fluid and naso-oropharyngeal samples correlated with disease morbidity in SARS-CoV-2–positive patients. They found that the association between morbidity and IFN-λ observed in humans was reproduced in mice treated with intratracheal polyinosinic:polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA that mimics viral RNA and induces innate immune responses. Intratracheal poly(I:C) administration was also associated with impaired lung epithelial barrier function. SARS-CoV and influenza virus infect lung alveolar epithelial cells. As viral replication proceeds, lung epithelial cells die because of cytopathic effects as well as immune-mediated damage. Recovery is then achieved through epithelial cell proliferation and differentiation. Both Major et al. and Broggi et al. show that after influenza virus infection or intratracheal poly(I:C) challenge, respectively, IFN-λ impairs lung epithelial cell proliferation during recovery. Major et al. further found that IFN-λ impairs differentiation of alveolar epithelial progenitor cells into secretory and multiciliated cell subtypes. In accordance, both groups identified that the impaired epithelial proliferation is dependent on expression of IFNLR. Mice in which the Ifnlr1 gene is deleted ( Ifnlr1 −/−) had improved epithelial proliferation after an influenza virus or poly(I:C) challenge. This phenotype was mediated by lung stromal cells because chimeric mice with wild-type bone marrow and Ifnlr1 −/− lung stroma display the same enhancement in epithelial proliferation as that of Ifnlr1 −/− mice. As a consequence of enhanced epithelial recovery, Ifnlr1 −/− mice had better survival in models of S. aureus and Streptococcus pneumoniae superinfections. Mechanistically, gene expression analyses by Major et al. and Broggi et al. demonstrated that IFN-λ signaling in lung epithelial cells induces expression of ISGs and the p53 pathway (see the figure). Given the intrinsic antiviral effects of IFN-λ and expression of IFNLR in the airway epithelium, IFN-λ is being investigated as a therapeutic agent for COVID-19. However, data from both Major et al. and Broggi et al. caution against the unintended consequences of appropriate antiviral responses in pneumonias, as caused by SARS-CoV-2. In other tissues, inhibition of cell division and death of the infected cells would be the appropriate response to prevent spreading of the virus to live cells. By contrast, in the context of viral pneumonias and alveolar epithelial cells, failure to proliferate results in destruction of the gas exchange barrier and susceptibility to bacterial superinfections. ![Figure][13] Responses to lung viral infections Lung alveolar epithelial cells and dendritic cells release type I interferons (IFN-α/β) and type III IFN-λ in response to viral infection. IFNs limit viral replication; however, IFN-λ signaling can cause cell death through apoptosis and impaired epithelial proliferation, which prevents tissue recovery. GRAPHIC: V. ALTOUNIAN/ SCIENCE These findings will certainly impose a challenge on the ongoing clinical trials and future treatment regimen design. These trials are investigating the effects of subcutaneous pegylated IFNL1a in different cohorts of patients with COVID-19. Despite its physiological role in epithelial antiviral immunity, clinical trials have mainly evaluated the effects of IFN-λ in viral hepatitis rather than viral pneumonia. It is unclear whether short pulses rather than sustained administration of IFN-λ can have the desired antiviral effects without affecting lung epithelial proliferation. A potential alternative approach considering these data is IFNLR blockade. As Major et al. and Broggi et al. showed in mice, it is possible that the enhanced proliferative response observed after blocking IFN-λ signaling would outweigh the benefit of a deficient epithelial IFN-λ response in the lungs for SARS-CoV-2 infection. The study by Hadjadj et al. focused on type I IFN responses in human SARS-CoV-2 infection. Like IFN-λ, type I IFNs induce expression of ISGs and p53. However, their antiviral action is broader because the type I IFN receptor is ubiquitously expressed. Hadjadj et al. discovered a profound suppression of type I IFN signatures in peripheral blood from critically ill COVID-19 patients. Plasma concentrations of IFN-α in these patients were lower than in mild to moderate patients, suggesting that systemic type I IFN responses may be beneficial. Multiplex gene analysis revealed that critically ill patients had down-regulation of ISG expression. Irrespective of disease severity, SARS-CoV-2–positive patients had reduced numbers of plasmacytoid dendritic cells, which are an important cellular source of type I IFNs. Severe and critically ill patients had increased plasma viral load when compared with that of mild to moderate patients. These patients also displayed a proinflammatory response driven by the transcription factor nuclear factor κB (NF-κB), which was characterized by increased interleukin-6 (IL-6) and tumor necrosis factor–α (TNF-α). In seeming contrast with the peripheral blood data by Hadjadj et al. , Broggi et al. showed that SARS-CoV-2–positive patients had increased amounts of type I IFN mRNA in naso-oropharyngeal and bronchoalveolar lavage fluid. Major et al. also tested whether type I IFNs damage airway epithelium in a mouse influenza model. Blockade of endogenous type I IFN signaling did not augment epithelial cell proliferation, suggesting that type I IFNs may not be as detrimental to lung epithelia as IFN-λ. Given the complexity of IFN responses in SARS-CoV-2 infection, further insight into their impact on the disease is of the utmost importance for continued development of drugs targeting the IFN pathways. Research is needed to establish whether IFN-λ and type I IFNs have similar effects or whether one is more beneficial or detrimental than the other. It should be conclusively established whether type I IFN responses are augmented in lungs of COVID-19 patients in contrast to the suppressed type I IFN responses observed in the blood. Further research will be necessary to determine whether suppression of blood type I IFN in critically ill COVID-19 patients is due to the ability of SARS-CoV-2 proteins to interfere with IFN signaling. This possibility is supported by the observation of Hadjadj et al. that down-regulated expression of type I IFNs and ISG signatures in peripheral blood are paired with up-regulated expression of genes promoting type I IFN signaling, suggesting a compensatory response to blockade of IFN signaling. Alternatively, low type I IFN may be the consequence rather than the cause of a generalized immunosuppression induced by high viral titers. Although mouse influenza virus infection is a prototypic model of viral pneumonia, it may not precisely recapitulate the cytopathic and proinflammatory effects of SARS-CoV-2. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/287995
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Gary E. Grajales-Reyes,Marco Colonna. Interferon responses in viral pneumonias[J]. Science,2020.
APA	Gary E. Grajales-Reyes,&Marco Colonna.(2020).Interferon responses in viral pneumonias.Science.
MLA	Gary E. Grajales-Reyes,et al."Interferon responses in viral pneumonias".Science (2020).