scholarly journals TREM-2 promotes macrophage survival and lung disease after respiratory viral infection

2015 ◽  
Vol 212 (5) ◽  
pp. 681-697 ◽  
Author(s):  
Kangyun Wu ◽  
Derek E. Byers ◽  
Xiaohua Jin ◽  
Eugene Agapov ◽  
Jennifer Alexander-Brett ◽  
...  
Keyword(s):  
Lung Disease ◽  
Viral Infections ◽  
Sendai Virus ◽  
Acute Infection ◽  
Chronic Respiratory Disease ◽  
Chronic Inflammatory Disease ◽  
Soluble Form ◽  
Lung Macrophages ◽  
Lung Macrophage ◽  
Macrophage Apoptosis

Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13–dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5–12 d after inoculation). However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infection (49 d after inoculation). At this time, IL-13 and the adapter protein DAP12 promote TREM-2 cleavage to sTREM-2 that is unexpectedly active in preventing macrophage apoptosis. The results thereby define an unprecedented mechanism for a feed-forward expansion of lung macrophages (with IL-13 production and consequent M2 differentiation) that further explains how acute infection leads to chronic inflammatory disease.

scholarly journals Aerosolized TLR Agonists Suppress Acute Sendai Virus Lung Infection and Chronic Airway Disease in Mice

2019 ◽  
Author(s):  
David L. Goldblatt ◽  
Jose R. Flores ◽  
Gabriella Valverde Ha ◽  
Ana M. Jaramillo ◽  
Sofya Tkachman ◽  
...  
Keyword(s):  
Viral Infections ◽  
Sendai Virus ◽  
Acute Infection ◽  
Airway Disease ◽  
Chronic Asthma ◽  
Asthma Phenotype ◽  
Tlr Agonists ◽  
Chronic Airway Disease ◽  
Respiratory Viral Infections

AbstractRespiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll-like receptor (TLR) agonists could attenuate the severity of chronic asthma-like lung disease. Treatment with 1 µM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4 µM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge, resulted in a ∼75% reduction in lung Sendai virus burden five days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion, and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL-33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by downregulating Type 2 (allergic) inflammation. These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce progression of asthma.One Sentence SummaryRespiratory viral infections can induce chronic airway disease, and we find that stimulating innate immunity within the lungs of mice reduces the severity of acute infection and development of a chronic asthma phenotype.

scholarly journals Chronic respiratory disease and survival outcomes after extracorporeal membrane oxygenation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tak Kyu Oh ◽  
Hyoung-Won Cho ◽  
Hun-Taek Lee ◽  
In-Ae Song
Keyword(s):  
Respiratory Failure ◽  
Extracorporeal Membrane Oxygenation ◽  
Lung Disease ◽  
Respiratory Disease ◽  
Chronic Respiratory Disease ◽  
Newly Diagnosed ◽  
Membrane Oxygenation ◽  
Obstructive Sleep ◽  
All Cause Mortality ◽  
Ecmo Therapy

Abstract Background Quality of life following extracorporeal membrane oxygenation (ECMO) therapy is an important health issue. We aimed to describe the characteristics of patients who developed chronic respiratory disease (CRD) following ECMO therapy, and investigate the association between newly diagnosed post-ECMO CRDs and 5-year all-cause mortality among ECMO survivors. Methods We analyzed data from the National Health Insurance Service in South Korea. All adult patients who underwent ECMO therapy in the intensive care unit between 2006 and 2014 were included. ECMO survivors were defined as those who survived for 365 days after ECMO therapy. Chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease, lung cancer, lung disease due to external agents, obstructive sleep apnea, and lung tuberculosis were considered as CRDs. Results A total of 3055 ECMO survivors were included, and 345 (11.3%) were newly diagnosed with CRDs 365 days after ECMO therapy. The prevalence of asthma was the highest at 6.1% (185). In the multivariate logistic regression, ECMO survivors who underwent ECMO therapy for acute respiratory distress syndrome (ARDS) or respiratory failure had a 2.00-fold increase in post-ECMO CRD (95% confidence interval [CI]: 1.39 to 2.89; P < 0.001). In the multivariate Cox regression, newly diagnosed post-ECMO CRD was associated with a 1.47-fold (95% CI: 1.17 to 1.86; P = 0.001) higher 5-year all-cause mortality. Conclusions At 12 months after ECMO therapy, 11.3% of ECMO survivors were newly diagnosed with CRDs. Patients who underwent ECMO therapy for ARDS or respiratory failure were associated with a higher incidence of newly diagnosed post-ECMO CRD compared to those who underwent ECMO for other causes. Additionally, post-ECMO CRDs were associated with a higher 5-year all-cause mortality. Our results suggest that ECMO survivors with newly diagnosed post-ECMO CRD might be a high-risk group requiring dedicated interventions.

scholarly journals sFasL—The Key to a Riddle: Immune Responses in Aging Lung and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2177
Author(s):  
Shulamit B. Wallach-Dayan ◽  
Dmytro Petukhov ◽  
Ronit Ahdut-HaCohen ◽  
Mark Richter-Dayan ◽  
Raphael Breuer
Keyword(s):  
Cell Death ◽  
Lung Disease ◽  
Fas Ligand ◽  
Death Receptor ◽  
Mesenchymal Cells ◽  
Soluble Form ◽  
Cell Accumulation ◽  
Key Factor ◽  
Aged Subjects

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

scholarly journals Distinct cellular immune signatures in acute Zika virus infection are associated with high or low persisting neutralizing antibody titers

2021 ◽  
Author(s):  
Elizabeth E. McCarthy ◽  
Pamela M. Odorizzi ◽  
Emma Lutz ◽  
Carolyn P. Smullin ◽  
Iliana Tenvooren ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Immune Cell ◽  
Acute Infection ◽  
Neutralizing Antibody ◽  
Natural Immunity ◽  
Zikv Infection ◽  
Antibody Titers ◽  
Cellular Immune

Although the formation of a durable neutralizing antibody response after an acute viral infection is a key component of protective immunity, little is known about why some individuals generate high versus low neutralizing antibody titers to infection or vaccination. Infection with Zika virus (ZIKV) during pregnancy can cause devastating fetal outcomes, and efforts to understand natural immunity to this infection are essential for optimizing vaccine design. In this study, we leveraged the high-dimensional single-cell profiling capacity of mass cytometry (CyTOF) to deeply characterize the cellular immune response to acute and convalescent ZIKV infection in a cohort of blood donors in Puerto Rico incidentally found to be viremic during the 2015-2016 epidemic in the Americas. During acute ZIKV infection, we identified widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated innate immune subsets, as well as activated follicular helper CD4+ T cells and proliferating CD27-IgD- B cells, during acute infection were associated with high titers of ZIKV neutralizing antibodies at 6 months post-infection. On the other hand, low titers of ZIKV neutralizing antibodies were associated with immune features that suggested a cytotoxic-skewed immune "set-point." Our study offers insight into the cellular coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials for ZIKV and other acute viral infections aimed at inducing high titers of neutralizing antibodies.

VIRAL INFECTION POTENTIATES THE INCREASE IN AIRWAY BLOOD FLOW PRODUCED BY SUBSTANCE P

PEDIATRICS ◽  
1996 ◽  
Vol 98 (2) ◽  
pp. 336-337
Author(s):  
Roger H. Kobayaski ◽  
Brett Kettlehut
Keyword(s):  
Blood Flow ◽  
Substance P ◽  
Viral Infection ◽  
Airway Obstruction ◽  
Viral Infections ◽  
Sendai Virus ◽  
Neutral Endopeptidase ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Growth Media

Purpose of the Study. Substance P is a tachykinin found in the airways of many animals, including humans. Tachykinins may induce inflammation, increase blood flow, increase mucus secretion, and induce bronchoconstriction. The purpose of this study was to determine whether viral infections might enhance blood flow produced by substance P. Methods. Male F344 rats were intranasally inoculated with Sendai virus or sterile viral growth media. Airway blood flow was measured by an ingenious microsphere method. Substance P or histamine was injected to determine effects on baseline airway blood flow; subsequently inhibition of neutral endopeptidase: phosphoramidon (NEP, 2.5 mg/kg) and angiotensin-converting enzyme: captopril (ACE, 2.5 mg/dL) were injected to determine whether they (inhibitors) modulate substance P increases in pulmonary vasculature blood flow. Results. Viral infection magnified the increase in airway blood flow evoked by substance P, but histamine did not. Both NEP inhibitor and ACE inhibitor potentiated the increase in substance P-induced airway blood flow. Therefore, this may be a possible mechanism for exaggerated substance P-induced airway blood flow. Reviewers' Comments. This is an elegant, well-thoughtout series of experiments which help shed additional light on the mechanisms of viral-induced airway obstruction. Viral infections may potentiate tachykinin-mediated airway obstruction by disturbing the intricate interplay among mediators; in this case, the downregulation of NEP and ACE. Previous studies have shown that other agents such as tobacco smoke (J Appl Physiol. 1993;74:2537-2542) may cause tachykinin-mediated inflammation. These studies help us understand the mechanisms of airway inflammation and may help us develop effective therapeutic interventions.

scholarly journals HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 204 ◽  
Author(s):  
Marina Jerebtsova ◽  
Asrar Ahmad ◽  
Xiaomei Niu ◽  
Ornela Rutagarama ◽  
Sergei Nekhai
Keyword(s):  
Lung Disease ◽  
Neutrophil Infiltration ◽  
Lung Macrophage ◽  
Transcription Inhibitor ◽  
Endothelial Migration ◽  
Fast Resolution ◽  
Bleeding Score ◽  
Hiv 1

Human immunodeficiency virus (HIV)-infected individuals treated with anti-retroviral therapy often develop chronic non-infectious lung disease. To determine the mechanism of HIV-1-associated lung disease we evaluated the dynamics of lung leukocytes in HIV-1 transgenic (Tg) mice with integrated HIV-1 provirus. In HIV-Tg mice, lipopolysacharide (LPS) induced significantly higher levels of neutrophil infiltration in the lungs compared to wild-type (WT) mice. In WT mice, the initial neutrophil infiltration was followed by macrophage infiltration and fast resolution of leukocytes infiltration. In HIV-Tg mice, resolution of lung infiltration by both neutrophils and macrophages was significantly delayed, with macrophages accumulating in the lumen of lung capillaries resulting in a 45% higher rate of mortality. Trans-endothelial migration of HIV-Tg macrophages was significantly reduced in vitro and this reduction correlated with lower HIV-1 gene expression. HIV-1 transcription inhibitor, 1E7-03, enhanced trans-endothelial migration of HIV-Tg macrophages in vitro, decreased lung neutrophil infiltration in vivo, and increased lung macrophage levels in HIV-Tg mice. Moreover, 1E7-03 reduced levels of inflammatory IL-6 cytokine, improved bleeding score and decreased lung injury. Together this indicates that inhibitors of HIV-1 transcription can correct abnormal dynamics of leukocyte infiltration in HIV-Tg, pointing to the utility of transcription inhibition in the treatment of HIV-1 associated chronic lung disease.

scholarly journals Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach

2020 ◽  
Vol 9 (8) ◽  
pp. 2623
Author(s):  
Yosuke Fukuda ◽  
Kaho Akimoto ◽  
Tetsuya Homma ◽  
Jonathan R Baker ◽  
Kazuhiro Ito ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Hospital Admissions ◽  
Viral Infections ◽  
Clinical Problem ◽  
Chronic Respiratory Disease ◽  
Upper Respiratory Tract ◽  
Asthma Exacerbations

The prevalence of asthma has increased worldwide. Asthma exacerbations triggered by upper respiratory tract viral infections remain a major clinical problem and account for hospital admissions and time lost from work. Virus-induced asthma exacerbations cause airway inflammation, resulting in worsening asthma and deterioration in the patients’ quality of life, which may require systemic corticosteroid therapy. Despite recent advances in understanding the cellular and molecular mechanisms underlying asthma exacerbations, current therapeutic modalities are inadequate for complete prevention and treatment of these episodes. The pathological role of cellular senescence, especially that involving the silent information regulator 2 homolog sirtuin (SIRT) protein family, has recently been demonstrated in stable and exacerbated chronic respiratory disease states. This review discusses the role of SIRT1 in the pathogenesis of bronchial asthma. It also discusses the role of SIRT1 in inflammatory cells that play an important role in virus-induced asthma exacerbations. Recent studies have hypothesized that SIRT1 is one of major contributors to cellular senescence. SIRT1 levels decrease in Th2 and non-Th2-related airway inflammation, indicating the role of SIRT1 in several endotypes and phenotypes of asthma. Moreover, several models have demonstrated relationships between viral infection and SIRT1. Therefore, targeting SIRT1 is a novel strategy that may be effective for treating virus-induced asthma exacerbations in the future.

scholarly journals Expansion ofCD8+CD57+T Cells in an Immunocompetent Patient with Acute Toxoplasmosis

2009 ◽  
Vol 2009 ◽  
pp. 1-3 ◽  
Author(s):  
R. García-Muñoz ◽  
P. Rodríguez-Otero ◽  
A. Galar ◽  
J. Merino ◽  
J. J. Beunza ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Viral Infections ◽  
Acute Infection ◽  
Chronic Phase ◽  
Immune Dysfunction ◽  
Immunocompetent Patient ◽  
Acute Toxoplasmosis ◽  
Clinical Conditions ◽  
First Time

CD57+T cells increase in several viral infections like cytomegalovirus, herpesvirus, parvovirus, HIV and hepatitis C virus and are associated with several clinical conditions related to immune dysfunction and ageing. We report for the first time an expansion of CD8+CD57+T cells in a young patient with an acute infection with Toxoplasma gondii. Our report supports the concept that CD8+CD57+T cells could be important in the control of chronic phase of intracellular microorganisms and that the high numbers of these cells may reflect the continuing survey of the immune system, searching for parasite proliferation in the tissues.

scholarly journals Virus-Induced Abrogation of Transplantation Tolerance Induced by Donor-Specific Transfusion and Anti-CD154 Antibody

2000 ◽  
Vol 74 (5) ◽  
pp. 2210-2218 ◽  
Author(s):  
Raymond M. Welsh ◽  
Thomas G. Markees ◽  
Bruce A. Woda ◽  
Keith A. Daniels ◽  
Michael A. Brehm ◽  
...  
Keyword(s):  
Allograft Rejection ◽  
Viral Infections ◽  
Acute Infection ◽  
Tolerance Induction ◽  
Lymphocytic Choriomeningitis ◽  
Murine Cytomegalovirus ◽  
Transplantation Tolerance ◽  
High Dose ◽  
Pichinde Virus ◽  
Skin Allografts

ABSTRACT Treatment with a 2-week course of anti-CD154 antibody and a single transfusion of donor leukocytes (a donor-specific transfusion or DST) permits skin allografts to survive for >100 days in thymectomized mice. As clinical trials of this methodology in humans are contemplated, concern has been expressed that viral infection of graft recipients may disrupt tolerance to the allograft. We report that acute infection with lymphocytic choriomeningitis virus (LCMV) induced allograft rejection in mice treated with DST and anti-CD154 antibody if inoculated shortly after transplantation. Isografts resisted LCMV-induced rejection, and the interferon-inducing agent polyinosinic:polycytidylic acid did not induce allograft rejection, suggesting that the effect of LCMV is not simply a consequence of nonspecific inflammation. Administration of anti-CD8 antibody to engrafted mice delayed LCMV-induced allograft rejection. Pichinde virus also induced acute allograft rejection, but murine cytomegalovirus and vaccinia virus (VV) did not. Injection of LCMV ∼50 days after tolerance induction and transplantation had minimal effect on subsequent allograft survival. Treatment with DST and anti-CD154 antibody did not interfere with clearance of LCMV, but a normally nonlethal high dose of VV during tolerance induction and transplantation killed graft recipients. We conclude that DST and anti-CD154 antibody induce a tolerant state that can be broken shortly after transplantation by certain viral infections. Clinical application of transplantation tolerance protocols may require patient isolation to facilitate the procedure and to protect recipients.

scholarly journals Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

2016 ◽  
Vol 84 (4) ◽  
pp. 1123-1136 ◽  
Author(s):  
Ester Roffê ◽  
Ana Paula M. P. Marino ◽  
Joseph Weaver ◽  
Wuzhou Wan ◽  
Fernanda F. de Araújo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Trypanosoma Cruzi ◽  
Acute Infection ◽  
Chronic Inflammatory Disease ◽  
Interleukin 17 ◽  
Type I ◽  
Necrotizing Vasculitis ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Inflammatory Monocytes

Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain ofTrypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80+macrophages, andT. cruzitetramer-specific CD8+T lymphocytes capable of producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) but not interleukin-17 (IL-17).T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus,T. cruziinfection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses.

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