Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although extremely limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which can stabilize the effector cells, and is becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allow a great improvement in the management of asthma.

Download Full-text

Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

10.20944/preprints202103.0597.v2 ◽

2021 ◽

Author(s):

Francesco Menzella ◽

Giulia Ghidoni ◽

Carla Galeone ◽

Silvia Capobelli ◽

Chiara Scelfo ◽

...

Keyword(s):

Innate Immunity ◽

Severe Asthma ◽

Viral Infections ◽

Respiratory Infections ◽

Antiviral Effect ◽

Point Of View ◽

Type I ◽

Effector Cells ◽

Viral Spread ◽

Increased Risk

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although very limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which is able to stabilize the effector cells becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allows a great improvement in the management of asthma.

Download Full-text

Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

10.20944/preprints202103.0597.v1 ◽

2021 ◽

Author(s):

Francesco Menzella ◽

Giulia Ghidoni ◽

Carla Galeone ◽

Silvia Capobelli ◽

Chiara Scelfo ◽

...

Keyword(s):

Innate Immunity ◽

Severe Asthma ◽

Viral Infections ◽

Respiratory Infections ◽

Antiviral Effect ◽

Point Of View ◽

Type I ◽

Effector Cells ◽

Viral Spread ◽

Increased Risk

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although very limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which is able to stabilize the effector cells becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allows a great improvement in the management of asthma.

Download Full-text

Innate Immunity in Children and the Role of ACE2 Expression in SARS-CoV-2 Infection

Pediatric Reports ◽

10.3390/pediatric13030045 ◽

2021 ◽

Vol 13 (3) ◽

pp. 363-382

Author(s):

Mario Dioguardi ◽

Angela Pia Cazzolla ◽

Claudia Arena ◽

Diego Sovereto ◽

Giorgia Apollonia Caloro ◽

...

Keyword(s):

Innate Immunity ◽

Viral Infections ◽

Respiratory Infections ◽

Viral Disease ◽

Receptor Expression ◽

Virus Infections ◽

Search Terms ◽

Bibliographic Search ◽

Meta Analyses

COVID-19 (Coronavirus Disease 2019) is an emerging viral disease caused by the coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which leads to severe respiratory infections in humans. The first reports came in December 2019 from the city of Wuhan in the province of Hubei in China. It was immediately clear that children developed a milder disease than adults. The reasons for the milder course of the disease were attributed to several factors: innate immunity, difference in ACE2 (angiotensin-converting enzyme II) receptor expression, and previous infections with other common coronaviruses (CovH). This literature review aims to summarize aspects of innate immunity by focusing on the role of ACE2 expression and viral infections in children in modulating the antibody response to SARS-CoV-2 infection. This review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles deemed potentially eligible were considered, including those dealing with COVID-19 in children and providing more up-to-date and significant data in terms of epidemiology, prognosis, course, and symptoms, focusing on the etiopathogenesis of SARS-CoV-2 disease in children. The bibliographic search was conducted using the search engines PubMed and Scopus. The following search terms were entered in PubMed and Scopus: COVID-19 AND ACE2 AND Children; COVID-19 AND Immunity innate AND children. The search identified 857 records, and 18 studies were applicable based on inclusion and exclusion criteria that addressed the issues of COVID-19 concerning the role of ACE2 expression in children. The scientific literature agrees that children develop milder COVID-19 disease than adults. Milder symptomatology could be attributed to innate immunity or previous CovH virus infections, while it is not yet fully understood how the differential expression of ACE2 in children could contribute to milder disease.

Download Full-text

The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses

Journal of Virology ◽

10.1128/jvi.00655-16 ◽

2016 ◽

Vol 90 (19) ◽

pp. 8780-8794 ◽

Cited By ~ 46

Author(s):

Subhajit Poddar ◽

Jennifer L. Hyde ◽

Matthew J. Gorman ◽

Michael Farzan ◽

Michael S. Diamond

Keyword(s):

Viral Infections ◽

Transmembrane Protein ◽

Flow Cytometric Analysis ◽

Antiviral Effect ◽

Host Cells ◽

Type I ◽

Targeted Gene Deletion ◽

Multiple Organs ◽

Viral Burden ◽

Alphavirus Infection

ABSTRACTHost cells respond to viral infections by producing type I interferon (IFN), which induces the expression of hundreds of interferon-stimulated genes (ISGs). Although ISGs mediate a protective state against many pathogens, the antiviral functions of the majority of these genes have not been identified. IFITM3 is a small transmembrane ISG that restricts a broad range of viruses, including orthomyxoviruses, flaviviruses, filoviruses, and coronaviruses. Here, we show that alphavirus infection is increased inIfitm3−/−andIfitmlocus deletion (Ifitm-del) fibroblasts and, reciprocally, reduced in fibroblasts transcomplemented with Ifitm3. Mechanistic studies showed that Ifitm3 did not affect viral binding or entry but inhibited pH-dependent fusion. In a murine model of chikungunya virus arthritis,Ifitm3−/−mice sustained greater joint swelling in the ipsilateral ankle at days 3 and 7 postinfection, and this correlated with higher levels of proinflammatory cytokines and viral burden. Flow cytometric analysis suggested thatIfitm3−/−macrophages from the spleen were infected at greater levels than observed in wild-type (WT) mice, results that were supported by experiments withIfitm3−/−bone marrow-derived macrophages.Ifitm3−/−mice also were more susceptible than WT mice to lethal alphavirus infection with Venezuelan equine encephalitis virus, and this was associated with greater viral burden in multiple organs. Collectively, our data define an antiviral role for Ifitm3 in restricting infection of multiple alphaviruses.IMPORTANCEThe interferon-induced transmembrane protein 3 (IFITM3) inhibits infection of multiple families of viruses in cell culture. Compared to other viruses, much less is known about the antiviral effect of IFITM3 on alphaviruses. In this study, we characterized the antiviral activity of mouse Ifitm3 against arthritogenic and encephalitic alphaviruses using cells and animals with a targeted gene deletion ofIfitm3as well as deficient cells transcomplemented with Ifitm3. Based on extensive virological analysis, we demonstrate greater levels of alphavirus infection and disease pathogenesis when Ifitm3 expression is absent. Our data establish an inhibitory role for Ifitm3 in controlling infection of alphaviruses.

Download Full-text

COVID-19 Mortality is Associated with Impaired Innate Immunity in Pre-existing Health Conditions

10.1101/2021.05.31.446476 ◽

2021 ◽

Author(s):

Matthew E Lee ◽

Yung Chang ◽

Navid Ahmadinejad ◽

Crista E Johnson-Agbakwu ◽

Celeste Bailey ◽

...

Keyword(s):

Risk Factors ◽

Innate Immunity ◽

Viral Infections ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Therapeutic Interventions ◽

Health Conditions ◽

Molecular Abnormalities ◽

Hazard Ratios ◽

Increased Risk

Background: COVID-19 poses a life-threatening endangerment to individuals with chronic diseases. However, not all comorbidities affect COVID-19 prognosis equally. Some increase the risk of COVID-19 related death by more than six folds while others show little to no impact. To prevent severe outcomes, it is critical that we comprehend pre-existing molecular abnormalities in common health conditions that predispose patients to poor prognoses. In this study, we aim to discover some of these molecular risk factors by associating gene expression dysregulations in common health conditions with COVID-19 mortality rates in different cohorts. Methods: We focused on fourteen pre-existing health conditions, for which age-and-sex-adjusted hazard ratios of COVID-19 mortality have been documented. For each health condition, we analyzed existing transcriptomics data to identify differentially expressed genes (DEGs) between affected individuals and unaffected individuals. We then tested if fold changes of any DEG in these pre-existing conditions were correlated with hazard ratios of COVID-19 mortality to discover molecular risk factors. We performed gene set enrichment analysis to identify functional groups overrepresented in these risk factor genes and examined their relationships with the COVID-19 disease pathway. Results: We found that upregulated expression of 70 genes and downregulated expression of 181 genes in pre-existing health conditions were correlated with increased risk of COVID-19 related death. These genes were significantly enriched with endoplasmic reticulum (ER) function, proinflammatory reaction, and interferon production that participate in viral transcription and immune responses to viral infections. Conclusions: Impaired innate immunity in pre-existing health conditions are associated with increased hazard of COVID-19 mortality. The discovered molecular risk factors are potential prognostic biomarkers and targets for therapeutic interventions.

Download Full-text

Nasopharyngeal Type-I Interferon for Immediately Available Prophylaxis Against Emerging Respiratory Viral Infections

Frontiers in Immunology ◽

10.3389/fimmu.2021.660298 ◽

2021 ◽

Vol 12 ◽

Author(s):

Amos C. Lee ◽

Yunjin Jeong ◽

Sumin Lee ◽

Haewook Jang ◽

Allen Zheng ◽

...

Keyword(s):

Interferon Beta ◽

Viral Infections ◽

Respiratory Infections ◽

Type I ◽

Emerging Viruses ◽

Respiratory Viral Infection ◽

Respiratory Viral Infections ◽

Viral Respiratory Infections ◽

Viral Respiratory

In addition to SARS-CoV-2 and its variants, emerging viruses that cause respiratory viral infections will continue to arise. Increasing evidence suggests a delayed, possibly suppressed, type 1 interferon (IFN-I) response occurs early during COVID-19 and other viral respiratory infections such as SARS and MERS. These observations prompt considering IFN-β as a prophylactic or early intervention for respiratory viral infections. A rationale for developing and testing intranasal interferon beta (IFN-β) as an immediately available intervention for new respiratory viral infections that will arise unexpectedly in the future is presented and supported by basic and clinical trial observations. IFN-β prophylaxis could limit the spread and consequences of an emerging respiratory viral infection in at-risk individuals while specific vaccines are being developed.

Download Full-text

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Journal of Virology ◽

10.1128/jvi.00352-16 ◽

2016 ◽

Vol 90 (15) ◽

pp. 6832-6845 ◽

Cited By ~ 18

Author(s):

Binbin Xue ◽

Darong Yang ◽

Jingjing Wang ◽

Yan Xu ◽

Xiaohong Wang ◽

...

Keyword(s):

Innate Immunity ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Viral Infection ◽

Viral Protein ◽

E3 Ligase ◽

Antiviral Effect ◽

Degradation Pathway ◽

Viral Spread ◽

Ubiquitin E3 Ligase

ABSTRACTInterferons (IFNs) restrict various kinds of viral infection via induction of hundreds of IFN-stimulated genes (ISGs), while the functions of the majority of ISGs are broadly unclear. Here, we show that a high-IFN-inducible gene, ISG12a (also known as IFI27), exhibits a nonapoptotic antiviral effect on hepatitis C virus (HCV) infection. Viral NS5A protein is targeted specifically by ISG12a, which mediates NS5A degradation via a ubiquitination-dependent proteasomal pathway. K374R mutation in NS5A domain III abrogates ISG12a-induced ubiquitination and degradation of NS5A. S-phase kinase-associated protein 2 (SKP2) is identified as an ubiquitin E3 ligase for NS5A. ISG12a functions as a crucial adaptor that promotes SKP2 to interact with and degrade viral protein. Moreover, the antiviral effect of ISG12a is dependent on the E3 ligase activity of SKP2. These findings uncover an intriguing mechanism by which ISG12a restricts viral infection and provide clues for understanding the actions of innate immunity.IMPORTANCEUpon virus invasion, IFNs induce numerous ISGs to control viral spread, while the functions of the majority of ISGs are broadly unclear. The present study shows a novel antiviral mechanism of ISGs and elucidated that ISG12a recruits an E3 ligase, SKP2, for ubiquitination and degradation of viral protein and restricts viral infection. These findings provide important insights into exploring the working principles of innate immunity.

Download Full-text

Osteopontin ImpactsWest Nile virusPathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points

Mediators of Inflammation ◽

10.1155/2017/7582437 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Nikki Bortell ◽

Claudia Flynn ◽

Bruno Conti ◽

Howard S. Fox ◽

Maria Cecilia G. Marcondes

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Viral Infections ◽

Early Time ◽

Cns Infection ◽

Critical Threshold ◽

Type I ◽

Time Points ◽

Viral Spread ◽

The Impact

Osteopontin (OPN) is a molecule that is common in central nervous system (CNS) pathologies, which participates in the activation, migration, and survival of inflammatory cells. However, the mechanisms by which OPN modulates inflammatory pathways are not clear. To understand the role of OPN in CNS viral infections, we used a lethal mouse model ofWest Nile virus(WNV), characterized by the injection of high doses of the Eg101 strain of WNV, causing the increase of OPN levels in the brain since early time points. To measure the impact of OPN in neuropathogenesis and resistance, we compared C57BI/6 WT with mice lacking the OPN gene (OPN KO). OPN KO presented a significantly higher mortality compared to WT mice, detectable since day 5 pi. Our data suggests that OPN expression at early time points may provide protection against viral spread in the CNS by negatively controlling the type I IFN-sensitive, caspase 1-dependent inflammasome, while promoting an alternative caspase 8-associated pathway, to control the apoptosis of infected cells during WNV infection in the CNS. Overall, we conclude that the expression of OPN maintains a critical threshold in the innate immune response that controls apoptosis and lethal viral spread in early CNS infection.

Download Full-text

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Blood ◽

10.1182/blood-2008-01-130500 ◽

2008 ◽

Vol 112 (5) ◽

pp. 1750-1758 ◽

Cited By ~ 117

Author(s):

James L. Wynn ◽

Philip O. Scumpia ◽

Robert D. Winfield ◽

Matthew J. Delano ◽

Kindra Kelly-Scumpia ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Adaptive Immune System ◽

Neutrophil Recruitment ◽

Polymicrobial Sepsis ◽

Type I ◽

Sepsis Mortality ◽

Tlr Agonists ◽

Adaptive Immune ◽

Increased Risk

Abstract Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell–directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b+ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

Download Full-text

ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Viruses ◽

10.3390/v13020315 ◽

2021 ◽

Vol 13 (2) ◽

pp. 315

Author(s):

Barkha Ramnani ◽

Praveen Manivannan ◽

Sarah Jaggernauth ◽

Krishnamurthy Malathi

Keyword(s):

Cellular Proliferation ◽

Viral Infections ◽

Antiviral Effect ◽

Host Protein ◽

Type I ◽

Rnase L ◽

Oligoadenylate Synthetase ◽

Interferon Stimulated Genes ◽

Antiviral Effects ◽

Increased Activity

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects.

Download Full-text