scholarly journals A morphological transformation in respiratory syncytial virus leads to enhanced complement deposition

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jessica P Kuppan ◽  
Margaret D Mitrovich ◽  
Michael D Vahey
Keyword(s):  
Respiratory Syncytial Virus ◽  
Complement Activation ◽  
Protective Role ◽  
Respiratory Pathogen ◽  
Classical Pathway ◽  
Morphological Transformation ◽  
Virus Particles ◽  
Syncytial Virus ◽  
The Complement System ◽  
Complement Deposition

The complement system is a critical host defense against infection, playing a protective role that can also enhance disease if dysregulated. Although many consequences of complement activation during viral infection are well established, mechanisms that determine the extent to which viruses activate complement remain elusive. Here, we investigate complement activation by human respiratory syncytial virus (RSV), a filamentous respiratory pathogen that causes significant morbidity and mortality. By engineering a strain of RSV harboring tags on the surface glycoproteins F and G, we are able to monitor opsonization of single RSV particles using fluorescence microscopy. These experiments reveal an antigenic hierarchy, where antibodies that bind toward the apex of F in either the pre- or postfusion conformation activate the classical pathway whereas other antibodies do not. Additionally, we identify an important role for virus morphology in complement activation: as viral filaments age, they undergo a morphological transformation which lowers the threshold for complement deposition through changes in surface curvature. Collectively, these results identify antigenic and biophysical characteristics of virus particles that contribute to the formation of viral immune complexes, and suggest models for how these factors may shape disease severity and adaptive immune responses to RSV.

scholarly journals A morphological transformation in respiratory syncytial virus leads to enhanced complement activation

2021 ◽  
Author(s):  
Jessica P. Kuppan ◽  
Margaret D. Mitrovich ◽  
Michael D. Vahey
Keyword(s):  
Respiratory Syncytial Virus ◽  
Complement Activation ◽  
Severe Disease ◽  
The Elderly ◽  
Protective Role ◽  
Respiratory Pathogen ◽  
Morphological Transformation ◽  
Complement Components ◽  
Syncytial Virus ◽  
Human Viruses

The complement system is a critical host defense against infection, playing a protective role that can also enhance disease if misregulated. Although many consequences of complement activation during viral infection are well-established, specific mechanisms that contribute to activation by different human viruses remain elusive. Here, we investigate complement activation by human respiratory syncytial virus (RSV), a respiratory pathogen that causes severe disease in infants, the immunocompromised, and the elderly. Using a strain of RSV harboring tags on the surface glycoproteins F and G, we were able to monitor opsonization of single RSV particles with monoclonal antibodies and complement components using fluorescence microscopy. These experiments revealed an antigenic hierarchy in complement activation, where antibodies that bind towards the apex of F in either the pre- or postfusion conformation are able to activate complement whereas other antibodies are not. Additionally, among antibodies that were able to activate complement, we observed preferential targeting of a subset of particles with globular morphology, in contrast to the more prevalent viral filaments. We found that enhanced complement activation on these particles arises from changes in surface curvature that occur when the viral matrix detaches from the surrounding membrane. This transformation occurs naturally over time under mild conditions, and correlates with the accumulation of postfusion F on the viral surface. Collectively, these results identify antigenic and biophysical characteristics of virus particles that contribute to the formation of immune complexes, and suggest models for how these factors may shape disease severity and adaptive immune responses to RSV.

scholarly journals Protective role of Indoleamine 2,3 dioxygenase in Respiratory Syncytial Virus associated immune response in airway epithelial cells

Virology ◽  
2017 ◽  
Vol 512 ◽  
pp. 144-150 ◽  
Author(s):  
Devi Rajan ◽  
Raghavan Chinnadurai ◽  
Evan L. O'Keefe ◽  
Seyhan Boyoglu-Barnum ◽  
Sean O. Todd ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Protective Role ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Indoleamine 2,3 Dioxygenase ◽  
Syncytial Virus

scholarly journals MTOR Kinase is a Therapeutic Target for Respiratory Syncytial Virus and Coronaviruses

2021 ◽  
Author(s):  
HoangDinh Huynh ◽  
Ruth Levitz ◽  
Jeffrey Kahn
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Protein Production ◽  
Viral Infections ◽  
Antiviral Treatment ◽  
Effective Means ◽  
Therapeutic Interventions ◽  
Respiratory Pathogen ◽  
Upper Respiratory Tract ◽  
Syncytial Virus

Abstract Therapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as targeting host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, limits RSV protein production and viral replication. Further, we show that this approach is generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, protein production and replication. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particular in the absence of antiviral drugs.

scholarly journals mTOR kinase is a therapeutic target for respiratory syncytial virus and coronaviruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
HoangDinh Huynh ◽  
Ruth Levitz ◽  
Rong Huang ◽  
Jeffrey S. Kahn
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Protein Production ◽  
Viral Infections ◽  
Antiviral Treatment ◽  
Effective Means ◽  
Respiratory Pathogen ◽  
Progeny Virus ◽  
Upper Respiratory Tract ◽  
Syncytial Virus

AbstractTherapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops, making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as the targeting of host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, reduces RSV protein production and generation of infectious progeny virus. Further, we show that this approach can be generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, mRNA transcription and protein production. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particularly in the absence of antiviral drugs.

Ribavirin Use Questioned

PEDIATRICS ◽  
1988 ◽  
Vol 82 (2) ◽  
pp. 283-283
Author(s):  
BARRY DASHEFSKY ◽  
ELLEN R. WALD ◽  
MICHAEL GREEN
Keyword(s):  
Respiratory Syncytial Virus ◽  
Virus Infection ◽  
Respiratory Syncytial Virus Infection ◽  
Laboratory Tests ◽  
Respiratory Pathogen ◽  
Duration Of Hospitalization ◽  
Syncytial Virus

To the Editor.— The report by McMillan and colleagues1 of the nonpredictiveness of certain clinical and laboratory tests in determining the duration of hospitalization of patients with respiratory syncytial virus adds to our understanding of this important respiratory pathogen. However, we disagree with the authors' implied assumption that ribavirin therapy might be expected to shorten hospitalization and with their concluding recommendation "to institute aerosolized ribavirin therapy for essentially all infants with documented respiratory syncytial virus infection who require hospitalization."1(p26)

scholarly journals TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection

Thorax ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 64-72
Author(s):  
Hayley Pearson ◽  
Eleanor J A A Todd ◽  
Mareike Ahrends ◽  
Samantha E Hover ◽  
Adrian Whitehouse ◽  
...  
Keyword(s):  
Life Cycle ◽  
Respiratory Syncytial Virus ◽  
Human Lung ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
Human Respiratory Syncytial Virus ◽  
Respiratory Pathogen ◽  
Human Lung Epithelial Cell ◽  
Syncytial Virus ◽  
Tract Infections

IntroductionHuman respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally and is one of the most fatal infectious diseases for infants in developing countries. Of those infected, 25%–40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. Evidence also suggests that HRSV infection early in life is a major cause of adult asthma. There is no HRSV vaccine, and the only clinically approved treatment is immunoprophylaxis that is expensive and only moderately effective. New anti-HRSV therapeutic strategies are therefore urgently required.MethodsIt is now established that viruses require cellular ion channel functionality to infect cells. Here, we infected human lung epithelial cell lines and ex vivo human lung slices with HRSV in the presence of a defined panel of chloride (Cl−) channel modulators to investigate their role during the HRSV life-cycle.ResultsWe demonstrate the requirement for TMEM16A, a calcium-activated Cl− channel, for HRSV infection. Time-of-addition assays revealed that the TMEM16A blockers inhibit HRSV at a postentry stage of the virus life-cycle, showing activity as a postexposure prophylaxis. Another important negative-sense RNA respiratory pathogen influenza virus was also inhibited by the TMEM16A-specific inhibitor T16Ainh-A01.DiscussionThese findings reveal TMEM16A as an exciting target for future host-directed antiviral therapeutics.

scholarly journals TUNABLE COMPLEMENT ACTIVATION BY PARTICLES WITH VARIABLE SIZE AND Fc DENSITY

Nano LIFE ◽  
2013 ◽  
Vol 03 (02) ◽  
pp. 1341001 ◽  
Author(s):  
PATRICIA M. PACHECO ◽  
BENJAMIN LE ◽  
DAVID WHITE ◽  
TODD SULCHEK
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
High Surface ◽  
Treatment Strategies ◽  
Surface Concentration ◽  
Engineered Nanoparticles ◽  
Classical Pathway ◽  
Highly Sensitive ◽  
And Control ◽  
The Complement System

The complement system is an integral innate immune component that is made up of a cascade of enzymatic proteins that, once activated, results in lysis of invading pathogens, opsonization or recruitment of other innate and/or acquired immune responders, or some combination of the three. Due to the importance of the signal amplification and control points present in the cascade, complement is highly sensitive to subtle variations in initiation conditions, including nanoscale changes to molecular spacing. Using Fc-functionalized microparticles and nanoparticles, we find that activation requires a minimum threshold surface concentration of Fc of at least 20% surface coverage. This result indicates that a high surface density Fc is necessary for micro/nanoparticle complement activation through the classical pathway. In addition, the magnitude of the response was dependent on the size of the particle, with larger particles causing decreased activation. We hypothesize that a high density of Fc is needed to efficiently bind and closely appose molecular initiators of the complement cascade, from initiation to terminal complement complex formation. These fundamental studies of the interaction of microparticles and nanoparticles with the immune system suggest design rules for particle size and molecular density that impact immunostimulation through the complement system. Providing a therapeutic agent to modulate the complement response could aid a variety of treatment strategies. Engineered nanoparticles with controlled gaps between molecular activators could lead to new types of immunomodulatory agents.

scholarly journals Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis

2001 ◽  
Vol 69 (12) ◽  
pp. 7304-7309 ◽  
Author(s):  
Ilhan Celik ◽  
Cordula Stover ◽  
Marina Botto ◽  
Steffen Thiel ◽  
Sotiria Tzima ◽  
...  
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Immune Defense ◽  
Classical Pathway ◽  
Complement Factor ◽  
Wild Type ◽  
Factor B ◽  
The Complement System ◽  
Deficient Mice

ABSTRACT The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.

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