Regulatory T Cells Are Critical for Clearing Influenza A Virus in Neonatal Mice

OliphantSamantha,; Louise, LinesJ.; HollifieldMelissa, L; GarvyBeth, A

doi:10.1089/vim.2015.0039

Cited by 23 publications

(30 citation statements)

References 48 publications

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“…Excessive inflammation and structural damages to the lungs are consequences of infection by influenza virus (IAV) ( 40 ). Previous studies suggest that Treg cells can play a central role in immune homeostasis during viral infection ( 13 , 16 ). Since we previously reported that administration of MDP to mice infected with IAV reduces lung inflammation ( 32 ), we first wanted to determine if such effects of MDP treatment could lead to the mobilization of Treg cells in lungs of IAV-infected mice.…”

Section: Resultsmentioning

confidence: 99%

“…It was proposed that Tregs can control immune balance during viral infection and to limit the extent of tissue damage that occurs in the course of infection ( 13 – 15 ). For example, Tregs appear essential to clear influenza virus infection in neonatal mice ( 16 ), as their depletion results in enhanced lung inflammatory response to IAV infection. In line with these observations, it was also demonstrated that Tregs contribute to the resolution of lung inflammation after influenza virus infection ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Egarnes

Gosselin

2018

Front. Immunol.

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Influenza A virus (IAV) is recognized to cause severe pulmonary illnesses in humans, particularly in elderly and children. One of the features associated with IAV infection is an excessive lung inflammation due to an uncontrolled immune response. The nucleotide-binding oligomerization domain 2 (NOD2) receptor is known to recognize ssRNA viruses such as IAV, but its role in the inflammatory process during viral infections remains to be clarified. In a previous report, we have shown that activation of NOD2 with muramyl dipeptide (MDP) significantly reduces both viral loads and lung inflammation and also improves pulmonary function during IAV infection. These findings prompted us to further investigate whether NOD2 receptor may contribute to regulate inflammation during viral infection. In the present study, we show that administration of MDP to mice infected with IAV stimulates the migration of regulatory T (Treg) cells to the lungs. Such a presence of Treg cells was also accompanied with a reduction of neutrophils in the lungs during IAV infection, which correlated, with a significant decrease of Th17 cells. In our model, Treg cell recruitment is dependent of CXCL12 and CCL5 chemokines. Moreover, we show that the presence of Ly6Clow patrolling monocytes is required for Treg cells mobilization to the lung of mice treated with MDP. In fact, following monocyte depletion by administration of clodronate liposome, mobilization of Treg cells to the lungs of treated mice was found to occur when circulating Ly6Clow monocytes begin to reemerge. In addition, we also detected an increased production of TGF-β, a cytokine contributing to Treg activity when blood Ly6Clow monocytes are restored. Together, our results demonstrate that MDP treatment can promote an anti-inflammatory environment through the mobilization of Treg cells to the lung, a mechanism that requires the presence of Ly6Clow monocytes during IAV infection. Overall, our results suggest that activation of NOD2 receptor could be an appealing approach to control pulmonary inflammation in patients infected with IAV.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Egarnes

Gosselin

2018

Front. Immunol.

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“…Additionally, MSC-EVs interact with immune cells and cause the production of transforming growth factor (TGF)β and T-regulatory cells (Tregs) [48]. Tregs promote virus clearance and recovery in influenza virus-infected mice [54,55]. In future studies, we will examine whether MSC-EV treatment induces the generation of M2-type macrophages and Tregs in a pig model of influenza virus.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model

2018

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Background: Mesenchymal stem (stromal) cells (MSCs) mediate their immunoregulatory and tissue repair functions by secreting paracrine factors, including extracellular vesicles (EVs). In several animal models of human diseases, MSC-EVs mimic the beneficial effects of MSCs. Influenza viruses cause annual outbreaks of acute respiratory illness resulting in significant mortality and morbidity. Influenza viruses constantly evolve, thus generating drug-resistant strains and rendering current vaccines less effective against the newly generated strains. Therefore, new therapies that can control virus replication and the inflammatory response of the host are needed. The objective of this study was to examine if MSC-EV treatment can attenuate influenza virus-induced acute lung injury in a preclinical model. Methods: We isolated EVs from swine bone marrow-derived MSCs. Morphology of MSC-EVs was determined by electron microscopy and expression of mesenchymal markers was examined by flow cytometry. Next, we examined the anti-influenza activity of MSC-EVs in vitro in lung epithelial cells and anti-viral and immunomodulatory properties in vivo in a pig model of influenza virus.

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“…MSC-EVs are known to decrease production of proinflammatory cytokines and chemokines and increase production of anti-inflammatory IL-10 [4]. MSCs interact with immune cells and promote T-regulatory cells (Tregs) which improves influenza virus clearance [87,88]. MSC-EV inhibition of viral replication has also been demonstrated in hepatitis C virus (HCV) infected fibroblasts [89].…”

Section: Mscs Are Anti-viralmentioning

confidence: 99%

Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients

et al. 2020

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In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.

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Regulatory T Cells Are Critical for Clearing Influenza A Virus in Neonatal Mice

Cited by 23 publications

References 48 publications

Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model

Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients

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