TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection

Santos, Leonardo Duarte; Antunes, Krist Helen; Muraro, Stéfanie Primon; Souza, Gabriela Fabiano de; Silva, Amanda Gonzalez da; Felipe, Jaqueline de Souza; Zanetti, Larissa C; Czepielewski, Rafael S.; Magnus, K. E.; Scottá, Marcelo Comerlato; Mattiello, Rita; Maito, Fábio Luiz Dal Moro; Souza, Ana Paula Duarte de; Weinlich, Ricardo; Vinolo, Marco Aurélio Ramirez; Porto, Bárbara Nery

doi:10.1183/13993003.03764-2020

Cited by 58 publications

(51 citation statements)

References 64 publications

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“…Depleting AMs significantly reduces the survival rate and increases lung injury severity. However, some other pathogens, such as Pseudomonas aeruginosa and respiratory syncytial virus (RSV), can induce AM pyroptosis or necroptosis, thereby causing severe inflammation and increasing lung injury severity (68,69). Some intracellular bacteria, such as Mycobacterium tuberculosis, can infect TR-AMs and, thus, mediate the spread of M. tuberculosis from the alveoli to the lungs (70).…”

Section: Infections and Lung Injurymentioning

confidence: 99%

Diversity of Macrophages in Lung Homeostasis and Diseases

et al. 2021

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Lung macrophages play important roles in the maintenance of homeostasis, pathogen clearance and immune regulation. The different types of pulmonary macrophages and their roles in lung diseases have attracted attention in recent years. Alveolar macrophages (AMs), including tissue-resident alveolar macrophages (TR-AMs) and monocyte-derived alveolar macrophages (Mo-AMs), as well as interstitial macrophages (IMs) are the major macrophage populations in the lung and have unique characteristics in both steady-state conditions and disease states. The different characteristics of these three types of macrophages determine the different roles they play in the development of disease. Therefore, it is important to fully understand the similarities and differences among these three types of macrophages for the study of lung diseases. In this review, we will discuss the physiological characteristics and unique functions of these three types of macrophages in acute and chronic lung diseases. We will also discuss possible methods to target macrophages in lung diseases.

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Section: Infections and Lung Injurymentioning

confidence: 99%

Diversity of Macrophages in Lung Homeostasis and Diseases

et al. 2021

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“…Interestingly, hUCB-MSCs were robustly infected after 72 h when compared to ALMs (Figure 1C). We then investigated whether RSV would trigger ALM death as we have previously described for primary AMs [19] by measuring lactate dehydrogenase (LDH) release. ALMs were resistant to RSV-induced lytic cell death over the course of 24 h (Figure 1D).…”

Section: Alms Are Not Productively Infected By Rsv and Are Resistant To Rsv-induced Cell Deathmentioning

confidence: 99%

Alveolar-like Macrophages Attenuate Respiratory Syncytial Virus Infection

Porto

Litvack

Cen

et al. 2021

Viruses

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Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory infections in young children and infection has been linked to the development of persistent lung disease in the form of wheezing and asthma. Despite substantial research efforts, there are no RSV vaccines currently available and an effective monoclonal antibody targeting the RSV fusion protein (palivizumab) is of limited general use given the associated expense. Therefore, the development of novel approaches to prevent RSV infection is highly desirable to improve pediatric health globally. We have developed a method to generate alveolar-like macrophages (ALMs) from pluripotent stem cells. These ALMs have shown potential to promote airway innate immunity and tissue repair and so we hypothesized that ALMs could be used as a strategy to prevent RSV infection. Here, we demonstrate that ALMs are not productively infected by RSV and prevent the infection of epithelial cells. Prevention of epithelial infection was mediated by two different mechanisms: phagocytosis of RSV particles and release of an antiviral soluble factor different from type I interferon. Furthermore, intratracheal administration of ALMs protected mice from subsequent virus-induced weight loss and decreased lung viral titres and inflammation, indicating that ALMs can impair the pathogenesis of RSV infection. Our results support a prophylactic role for ALMs in the setting of RSV infection and warrant further studies on stem cell-derived ALMs as a novel cell-based therapy for pulmonary viral infections.

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“…Most of the target genes were enriched in the virus-related signaling pathways, TNF signaling pathway, and IL-17 signaling pathway. Several studies [31][32][33] have demonstrated that the TNF signaling pathway and IL-17 signaling pathway were related to RSV infection. The TNF signaling pathway plays a significant role in immune regulation and inflammation [34].…”

Section: Biomed Research Internationalmentioning

confidence: 99%

Molecular Mechanism of Jinchan Oral Liquid in the Treatment of Children with Respiratory Syncytial Virus Pneumonia Based on Network Pharmacology and Molecular Docking Technology

Shen

Jiang

et al. 2021

BioMed Research International

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Objective. Exploration of the underlying molecular mechanism of Jinchan Oral Liquid (JOL) in treating children with the respiratory syncytial virus (RSV) pneumonia to provide new evidence for the clinical application. Methods. The active components and target genes of JOL were screened by the TCMSP database. The targets of RSV pneumonia were obtained from the GeneCards, OMIM, DrugBank, and PharmGKB database. Then, we constructed the active component-target network and screened the core genes. The overlaps were screened for PPI network analysis, GO analysis, and KEGG analysis. Finally, result validation was performed by molecular docking. Results. According to the screening criteria of the ADME, 74 active compounds of JOL were obtained; after removing redundant targets, we selected 180 potential targets. By screening the online database, 893 RSV pneumonia-related targets were obtained. A total of 82 overlapping genes were chosen by looking for the intersection. The STRING online database was used to acquire PPI relationships, and 16 core genes were obtained. GO and KEGG analyses showed that the main pathways of JOL in treating RSV pneumonia include TNF signaling pathway and IL17 signaling pathway. The molecular docking results showed that the active compounds of JOL had a good affinity with the core genes. Conclusion. In this study, we preliminarily discussed the main active ingredients, related targets, and pathways of JOL and predicted the pharmacodynamic basis and the potential therapeutic mechanisms of RSV pneumonia. In summary, the network pharmacology strategy may be helpful for the discovery of multitarget drugs against complex diseases.

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TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection

Cited by 58 publications

References 64 publications

Diversity of Macrophages in Lung Homeostasis and Diseases

Diversity of Macrophages in Lung Homeostasis and Diseases

Alveolar-like Macrophages Attenuate Respiratory Syncytial Virus Infection

Molecular Mechanism of Jinchan Oral Liquid in the Treatment of Children with Respiratory Syncytial Virus Pneumonia Based on Network Pharmacology and Molecular Docking Technology

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