scholarly journals BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

2019 ◽  
pp. 201902310 ◽  
Author(s):  
Bibo Zhu ◽  
Ruixuan Zhang ◽  
Chaofan Li ◽  
Li Jiang ◽  
Min Xiang ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Pulmonary Inflammation ◽  
Influenza Virus Infection ◽  
Neutrophil Apoptosis ◽  
Viral Loads ◽  
Specific Regulation ◽  
Acute Respiratory Viral Infection ◽  
And Function ◽  
Neutrophil Survival

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.

scholarly journals Lung development and the host response to influenza A virus are altered by different doses of neonatal oxygen in mice

2012 ◽  
Vol 302 (10) ◽  
pp. L1078-L1087 ◽  
Author(s):  
Bradley W. Buczynski ◽  
Min Yee ◽  
B. Paige Lawrence ◽  
Michael A. O'Reilly
Keyword(s):  
Viral Infection ◽  
Lung Development ◽  
Host Response ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Body Weight Loss ◽  
Respiratory Viral Infection ◽  
Adult Mice ◽  
Increased Risk ◽  
Different Doses

Oxygen exposure in preterm infants has been associated with altered lung development and increased risk for respiratory viral infections later in life. Although the dose of oxygen sufficient to exert these changes in humans remains unknown, adult mice exposed to 100% oxygen between postnatal days 1– 4 exhibit alveolar simplification and increased sensitivity to influenza virus infection. Additionally, two nonlinear thresholds of neonatal oxygen exposures were previously identified that promote modest (between 40% and 60% oxygen) and severe (between 80% and 100% oxygen) changes in lung development. Here, we investigate whether these two thresholds correlate with the severity of lung disease following respiratory viral infection. Adult mice exposed to 100% oxygen at birth, and to a lesser extent 80% oxygen, demonstrated enhanced body weight loss, persistent inflammation, and fibrosis following infection compared with infected siblings exposed to room air at birth. In contrast, the host response to infection was indistinguishable between mice exposed to room air and 40% or 60% oxygen. Interestingly, levels of monocyte chemoattractant protein (MCP)-1 were equivalently elevated in infected mice that had been exposed to 80% or 100% oxygen as neonates. However, reducing levels of MCP-1 using heterozygous Mcp-1 mice did not affect oxygen-dependent changes in the response to infection. Thus lung development and the host response to respiratory viral infection are disrupted by different doses of oxygen. Our findings suggest that measuring lung function alone may not be sufficient to identify individuals born prematurely who have increased risk for respiratory viral infection.

scholarly journals Pregnancy preserves pulmonary function following influenza virus infection in C57BL/6 mice

2018 ◽  
Vol 315 (4) ◽  
pp. L517-L525 ◽  
Author(s):  
Meghan S. Vermillion ◽  
Andrew Nelson ◽  
Landon vom Steeg ◽  
Jeffery Loube ◽  
Wayne Mitzner ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Influenza A ◽  
Minute Ventilation ◽  
Pulmonary Inflammation ◽  
Influenza Virus Infection ◽  
Lung Compliance ◽  
Functional Changes ◽  
Pregnant Females ◽  
Pulmonary Physiology ◽  
Adverse Pregnancy

Pregnancy is associated with significant anatomic and functional changes to the cardiopulmonary system. Using pregnant C57BL/6 mice, we characterized changes in pulmonary structure and function during pregnancy in healthy animals and following infection with influenza A virus (IAV). We hypothesized that pregnancy-associated alterations in pulmonary physiology would contribute to the more severe outcome of IAV infection. Nonpregnant and pregnant females (at embryonic day 10.5) were either mock-infected or infected with 2009 H1N1 IAV for assessment of pulmonary function, structure, and inflammation at 8 days postinoculation. There were baseline differences in pulmonary function, with pregnant females having greater lung compliance, total lung capacity, and fixed lung volume than nonpregnant females. Following IAV infection, both pregnant and nonpregnant females exhibited reduced circulating progesterone, which in nonpregnant females was associated with increased pulmonary resistance and decreased lung compliance, minute ventilation, and oxygen diffusing capacity compared with uninfected nonpregnant females. In pregnant females, reduced concentrations of progesterone were associated with adverse pregnancy outcomes, but measures of pulmonary function were preserved following IAV infection and were not significantly different from uninfected pregnant mice. Following IAV infection, infectious virus titers and total numbers of pulmonary leukocytes were similar between pregnant and nonpregnant females, but the histological density of pulmonary inflammation was reduced in pregnant animals. These data suggest that pregnancy in mice is associated with significant alterations in pulmonary physiology but that these changes served to preserve lung function during IAV infection. Pregnancy-associated alterations in pulmonary physiology may serve to protect females during severe influenza.

scholarly journals Elucidation of the antiviral mechanism of cystine and theanine through transcriptome analysis of mice and comparison with COVID-19 gene set data

2020 ◽  
Author(s):  
Akira Mitsui ◽  
Ryosei Sakai ◽  
Kiyoshi Miwa ◽  
Susumu Shibahara ◽  
Shigekazu Kurihara ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Transcriptome Profiling ◽  
Cytokine Storm ◽  
Gene Signatures ◽  
Gene Set ◽  
Unique Gene ◽  
Infected Cells ◽  
Intracellular Redox

ABSTRACTWe previously showed that oral administration of cystine and theanine (CT) to mice confers resistance to influenza virus infection. In human studies, CT prevented colds in healthy subjects and enhanced antibody production after influenza vaccination in elderly individuals with a poor nutritional status. The mechanism of action of CT is thought to be glutathione (GSH)-mediated regulation of intracellular redox, which might affect innate immune systems such as macrophages to exert physiological effects. The effect of CT on influenza is independent of viral type, and this treatment has a broad range of antiviral activities. To explore the mechanisms of CT in viral infection, we performed transcriptome profiling of spleen tissues isolated from influenza A virus (IAV)-infected mice. We identified unique gene signatures in response to CT in the IAV-infected mice. Genes upregulated by CT included redox-regulated genes such as GCLC/GCLM (subunits of glutamate cysteine ligase, a rate-limiting enzyme of GSH biosynthesis), TXN1, TXN2, TXNRD2, and SOD1, suggesting that the intracellular redox environment is substantially altered by CT. However, genes downregulated in response to CT included chemokine/chemokine receptor genes (CCL5, CCL19, CXCL9, CXCL12, CXCR3, CXCR4, and ACKR3), some of which are related to cytokine storm. A comparison with public COVID-19-related gene set data showed that the upregulated gene signature was highly similar to the downregulated gene sets of SARS-CoV/SARS-CoV-2-infected cells and the upregulated gene set of attenuated SARS-CoV-infected cells. In conclusion, the unique gene signatures observed in response to orally administered CT in IAV-infected mouse spleen tissues suggested that CT may attenuate viral infection, replication and associated symptoms such as cytokine storm.

Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice

2004 ◽  
Vol 286 (2) ◽  
pp. L388-L398 ◽  
Author(s):  
Rommel S. Lan ◽  
Geoffrey A. Stewart ◽  
Roy G. Goldie ◽  
Peter J. Henry
Keyword(s):  
Lung Function ◽  
Viral Infection ◽  
Influenza A ◽  
Airway Disease ◽  
Protease Activated Receptors ◽  
Altered Expression ◽  
Agonist Peptide ◽  
Tracheal Epithelial Cells ◽  
And Function

Protease-activated receptors (PARs) are widely distributed in human airways, and recent evidence indicates a role for PARs in the pathophysiology of inflammatory airway disease. To further investigate the role of PARs in airway disease, we determined the expression and function of PARs in a murine model of respiratory tract viral infection. PAR-1, PAR-2, PAR-3, and PAR-4 mRNA and protein were expressed in murine airways, and confocal microscopy revealed colocalization of PAR-2 and cyclooxygenase (COX)-2 immunostaining in basal tracheal epithelial cells. Elevated levels of PAR immunostaining, which was particularly striking for PAR-1 and PAR-2, were observed in the airways of influenza A/PR-8/34 virus-infected mice compared with sham-infected mice. Furthermore, increased PAR-1 and PAR-2 expression was associated with significant changes in in vivo lung function responses. PAR-1 agonist peptide potentiated methacholine-induced increases in airway resistance in anesthetized sham-infected mice (and in indomethacin-treated, virus-infected mice), but no such potentiation was observed in virus-infected mice. PAR-2 agonist peptide transiently inhibited methacholine-induced bronchoconstriction in sham-infected mice, and this effect was prolonged in virus-infected mice. These findings suggest that during viral infection, the upregulation of PARs in the airways is coupled to increased activation of COX and enhanced generation of bronchodilatory prostanoids.

scholarly journals Regulation of Neutrophil Survival/Apoptosis by Mcl-1

2011 ◽  
Vol 11 ◽  
pp. 1948-1962 ◽  
Author(s):  
Eric Milot ◽  
János G. Filep
Keyword(s):  
Tissue Injury ◽  
Myeloid Cell ◽  
Neutrophil Granulocytes ◽  
Neutrophil Apoptosis ◽  
Critical Control Points ◽  
Family Protein ◽  
Multiple Levels ◽  
Local Injury ◽  
And Function ◽  
Neutrophil Survival

Neutrophil granulocytes have the shortest lifespan among leukocytes in the circulation and die via apoptosis. At sites of infection or tissue injury, prolongation of neutrophil lifespan is critical for effective host defense. Apoptosis of inflammatory neutrophils and their clearance are critical control points for termination of the inflammatory response. Evasion of neutrophil apoptosis aggravates local injury and leads to persistent tissue damage. The short-lived prosurvival Bcl-2 family protein, Mcl-1 (myeloid cell leukemia-1), is instrumental in controlling apoptosis and consequently neutrophil lifespan in response to rapidly changing environmental cues during inflammation. This paper will focus on multiple levels of control of Mcl-1 expression and function and will discuss targeting Mcl-1 as a potential therapeutic strategy to enhance the resolution of inflammation through accelerating neutrophil apoptosis.

scholarly journals Acetylcholine regulates pulmonary inflammation and facilitates the transition from active immunity to tissue repair during respiratory viral infection

2020 ◽  
Author(s):  
Alexander P. Horkowitz ◽  
Ashley V. Schwartz ◽  
Carlos A. Alvarez ◽  
Edgar B. Herrera ◽  
Marilyn L. Thoman ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
Influenza A ◽  
Early Stage ◽  
Pulmonary Inflammation ◽  
Recovery Phase ◽  
Physical Contact ◽  
Respiratory Viral Infection ◽  
Active Immunity

ABSTRACTInflammatory control is critical to recovery from respiratory viral infection. Acetylcholine (ACh) secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation. This study was designed to explore the role of ACh in acute viral infection and recovery. Using the murine model of influenza A, cholinergic status in the lungs and airway was examined over the course of infection and recovery. The results showed that airway ACh remained constant through the early stage of infection and increased during the peak of the acquired immune response. As the concentration of ACh increased, cholinergic lymphocytes appeared in the airway and lungs. Cholinergic capacity was found primarily in CD4 T cells, but also in B cells and CD8 T cells. The cholinergic CD4+ T cells bound to influenza-specific tetramers at the same frequency as their conventional (i.e., non-cholinergic) counterparts. In addition, they were retained in the lungs throughout the recovery phase and could still be detected in the resident memory regions of the lung up to two months after infection. Histologically, cholinergic lymphocytes were found in direct physical contact with activated macrophages throughout the lung. When ACh production was inhibited, mice exhibited increased tissue inflammation, altered lung architecture, and delayed recovery. Together, these findings point to a previously unrecognized role for ACh in the transition from active immunity to recovery and pulmonary repair following respiratory viral infection.

scholarly journals Antiviral therapy of acute respiratory viral infection and influenza in children in a hospital

2018 ◽  
Vol 10 (4) ◽  
pp. 82-88 ◽  
Author(s):  
E. V. Sharipova ◽  
I. V. Babachenko ◽  
A. S. Levina ◽  
S. G. Grigoriev
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Influenza B ◽  
General Group ◽  
Respiratory Viral Infection ◽  
The Third ◽  
Number Of Patients ◽  
Acute Respiratory Viral Infection

Objective: to study the efficacy and safety of antiviraltherapy for influenza and acute respiratory viral infection with Kagocel in children in a hospital. Materials and methods: in the observational study included 80 children aged 3 to 11 years, hospitalized with symptoms of influenza and acute respiratory viral infection. The etiological confirmation of the diagnosis was carried out by the PCR method based onthe study of nasal swabs.The drug Kagocel was administered according to the instructions for use during the first 24 hours of hospitalization.The analysis of the virus release after the course of therapy with Kagocel (at 5–6 days from the beginning of treatment) was carried out only in patients with verified influenza and acute respiratory viral infection. Results: the dominant influence of viruses in the development of acute respiratory infections in children aged 3 to 11 years in the period of rising morbidity in St. Petersburg from September 2015 to May 2016. At the same time, 25% of the total number of patients were sick with influenza A and/or B. There was a significant decrease in fever to the third day (p <0,001) and normalization of body temperature from the fourth day after the beginning of therapy with Kagocel in the general group and in patients with confirmed influenza diagnosis. The intoxication syndrome, most pronounced with the flu, was mostly stopped by the fourth day(р<0,001). Catarrhalsyndrome, prevalent in the general group of acute respiratory viral infection, had longer periods of clinical manifestation and against the background of the therapy completely eliminated to the third or seventh day of therapy.Negative PCR results after the course of Kagocel therapy were established in 57,1% of the total group of patients. Among all detected viruses, the most typical is the absence of repeated isolation of influenza B and A viruses, PC virus (86% and 53,8%, 71,4%, respectively), the elimination of rhinoviruses was less frequent (33,3%). Conclusion: according to the results of the study, the effectiveness of therapy with the inclusion of the drug Kagocel in relieving fever by 3–4 days of treatment, as well as intoxication syndrome by 5–6 days in patients with acute respiratory viral infections, including patients with influenza, has been established. Negative results of PCR at the time of completion of therapy occurred mainly in patients with influenza A and B, PC infection. No adverse events were noted.

scholarly journals A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity Upon Viral Infection and Advanced Age

2021 ◽  
Author(s):  
Basma H. Joma ◽  
Nalat Siwapornchai ◽  
Vijay K. Vanguri ◽  
Anishma Shrestha ◽  
Sara E. Roggensack ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Viral Infection ◽  
Murine Model ◽  
Influenza A ◽  
Ex Vivo ◽  
Severe Disease ◽  
Pulmonary Inflammation ◽  
Neutrophil Function ◽  
Pneumococcal Infections ◽  
Bacterial Killing

Streptococcus pneumoniae (pneumococcus) resides asymptomatically in the nasopharynx but can progress from benign colonizer to lethal pulmonary or systemic pathogen. Both viral infection and aging are risk factors for serious pneumococcal infections. Previous work established a murine model that featured the movement of pneumococcus from the nasopharynx to the lung upon nasopharyngeal inoculation with influenza A virus (IAV) but did not fully recapitulate the severe disease associated with human co-infection. We built upon this model by first establishing pneumococcal nasopharyngeal colonization, then inoculating both the nasopharynx and lungs with IAV. In young (2 months) mice, co-infection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, disease and mortality in a fraction of mice. In old mice (20-22 months), co-infection resulted in earlier and more severe disease. Aging was not associated with greater bacterial burdens but rather with more rapid pulmonary inflammation and damage. Both aging and IAV infection led to inefficient bacterial killing by neutrophils ex vivo. Conversely, aging and pneumococcal colonization also blunted IFN-α production and increased pulmonary IAV burden. Thus, in this multistep model, IAV promotes pneumococcal pathogenicity by modifying bacterial behavior in the nasopharynx, diminishing neutrophil function, and enhancing bacterial growth in the lung, while pneumococci increase IAV burden likely by compromising a key antiviral response. Thus, this model provides a means to elucidate factors, such as age and co-infection, that promote the evolution of S. pneumoniae from asymptomatic colonizer to invasive pathogen, as well as to investigate consequences of this transition on antiviral defense.

Impact of influenza virus during pregnancy: from disease severity to vaccine efficacy

2020 ◽  
Vol 15 (7) ◽  
pp. 441-453
Author(s):  
Ana Vazquez-Pagan ◽  
Rebekah Honce ◽  
Stacey Schultz-Cherry
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Immune Responses ◽  
Pregnant Women ◽  
Disease Severity ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Influenza Virus Infection ◽  
Severe Influenza ◽  
The Impact

Pregnant women are among the individuals at the highest risk for severe influenza virus infection. Infection of the mother during pregnancy increases the probability of adverse fetal outcomes such as small for gestational age, preterm birth and fetal death. Animal models of syngeneic and allogeneic mating can recapitulate the increased disease severity observed in pregnant women and are used to define the mechanism(s) of that increased severity. This review focuses on influenza A virus pathogenesis, the unique immunological landscape during pregnancy, the impact of maternal influenza virus infection on the fetus and the immune responses at the maternal–fetal interface. Finally, we summarize the importance of immunization and antiviral treatment in this population and highlight issues that warrant further investigation.

Sign in / Sign up

Export Citation Format

Share Document