scholarly journals Efficacy of oseltamivir treatment in influenza virus infected obese mice

2021 ◽  
Author(s):  
Rebekah Honce ◽  
Jeremy Jones ◽  
Brandi Livingston ◽  
Leonardo D. Estrada ◽  
Lindsey Wang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Treatment ◽  
Severe Disease ◽  
Viral Clearance ◽  
Interferon Response ◽  
Viral Population ◽  
Type I ◽  
Drug Resistant ◽  
Obese Mice ◽  
Deficient Mice

ABSTRACTObesity has been epidemiologically and empirically linked with more severe disease upon influenza infection. To ameliorate severe disease, treatment with antivirals, such as the neuraminidase inhibitor oseltamivir, are suggested to begin within days of infection, especially in hosts at higher risk for poor outcomes. However, this treatment is often poorly effective and can generate resistance variants within the treated host. Here, we hypothesized that oseltamivir treatment would not be effective in genetically obese mice and would generate a more diverse and drug resistant viral population. We demonstrated that oseltamivir treatment does not improve viral clearance in obese mice. While no traditional variants associated with oseltamivir resistance emerged, we did note that drug treatment failed to quench the viral population and did lead to phenotypic drug resistance in vitro. Mechanistically, we demonstrate the blunted interferon response in obese hosts may be contributing to treatment failure, as type I interferon receptor deficient mice also fail to clear influenza virus infection upon oseltamivir administration. Together, these studies suggest that the unique pathogenesis and immune responses in obese mice could have implications for pharmaceutical interventions and the within-host dynamics of the influenza virus population.IMPORTANCEInfluenza virus infections, while typically resolving within days to weeks, can turn critical especially in high-risk populations. Prompt antiviral administration is crucial to mitigating these severe sequalae, yet concerns remain if antiviral treatment is effective in hosts with obesity. Here, we show that oseltamivir does not improve viral clearance in genetically obese or type I IFN receptor-deficient mice and increases the genetic entropy of the within-host viral population. This suggests a blunted immune response may impair oseltamivir efficacy and render a host more susceptible to severe disease. This study furthers our understanding of oseltamivir treatment dynamics both systemically and in the lungs of obese mice, as well as the consequences of oseltamivir treatment for the within-host emergence of drug-resistant variants.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

scholarly journals Canine Influenza Virus is Mildly Restricted by Canine Tetherin Protein

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 565
Author(s):  
Yun Zheng ◽  
Xiangqi Hao ◽  
Qingxu Zheng ◽  
Xi Lin ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cellular Damage ◽  
Interferon Response ◽  
Type I ◽  
Canine Influenza Virus ◽  
Immune Factor ◽  
Canine Influenza ◽  
The Impact

Tetherin (BST2/CD317/HM1.24) has emerged as a key host-cell ·defence molecule that acts by inhibiting the release and spread of diverse enveloped virions from infected cells. We analysed the biological features of canine tetherin and found it to be an unstable hydrophilic type I transmembrane protein with one transmembrane domain, no signal peptide, and multiple glycosylation and phosphorylation sites. Furthermore, the tissue expression profile of canine tetherin revealed that it was particularly abundant in immune organs. The canine tetherin gene contains an interferon response element sequence that can be regulated and expressed by canine IFN-α. A CCK-8 assay showed that canine tetherin was effective in helping mitigate cellular damage caused by canine influenza virus (CIV) infection. Additionally, we found that the overexpression of canine tetherin inhibited replication of the CIV and that interference with the canine tetherin gene enhanced CIV replication in cells. The impact of canine tetherin on CIV replication was mild. However, these results elucidate the role of the innate immune factor, canine tetherin, during CIV infection for the first time.

scholarly journals Knockout of IRF7 Highlights its Modulator Function of Host Response Against Avian Influenza Virus and the Involvement of MAPK and TOR Signaling Pathways in Chicken

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 385
Author(s):  
Tae Hyun Kim ◽  
Colin Kern ◽  
Huaijun Zhou
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Host Response ◽  
Antiviral Response ◽  
Influenza Viruses ◽  
Interferon Response ◽  
Type I

Interferon regulatory factor 7 (IRF7) is known as the master transcription factor of the type I interferon response in mammalian species along with IRF3. Yet birds only have IRF7, while they are missing IRF3, with a smaller repertoire of immune-related genes, which leads to a distinctive immune response in chickens compared to in mammals. In order to understand the functional role of IRF7 in the regulation of the antiviral response against avian influenza virus in chickens, we generated IRF7-/- chicken embryonic fibroblast (DF-1) cell lines and respective controls (IRF7wt) by utilizing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system. IRF7 knockout resulted in increased viral titers of low pathogenic avian influenza viruses. Further RNA-sequencing performed on H6N2-infected IRF7-/- and IRF7wt cell lines revealed that the deletion of IRF7 resulted in the significant down-regulation of antiviral effectors and the differential expression of genes in the MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) signaling pathways. Dynamic gene expression profiling of the host response between the wildtype and IRF7 knockout revealed potential signaling pathways involving AP1 (activator protein 1), NF-κB (nuclear factor kappa B) and inflammatory cytokines that may complement chicken IRF7. Our findings in this study provide novel insights that have not been reported previously, and lay a solid foundation for enhancing our understanding of the host antiviral response against the avian influenza virus in chickens.

scholarly journals Type I Interferons Promote Severe Disease in a Mouse Model of Lethal Ehrlichiosis

2014 ◽  
Vol 82 (4) ◽  
pp. 1698-1709 ◽  
Author(s):  
Yubin Zhang ◽  
Vinh Thai ◽  
Amanda McCabe ◽  
Maura Jones ◽  
Katherine C. MacNamara
Keyword(s):  
Mouse Model ◽  
Severe Disease ◽  
Type I Interferons ◽  
Type I ◽  
Bacterial Burden ◽  
Chimeric Mice ◽  
Content Type ◽  
Type I Ifns ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTHuman monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the orderRickettsiales. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-α] and IFN-β) in severe disease in a mouse model of fatal ehrlichiosis caused byIxodes ovatusEhrlichia(IOE). IFN-α and IFN-β were induced by IOE infection but not in response to a less virulent strain,Ehrlichia muris. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (Ifnardeficient) or neutralization of IFN-α and IFN-β resulted in a reduced bacterial burden.Ifnar-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild-type (WT) mice, that correlated with increased type II IFN (IFN-γ) production. Pathogen-specific antibody responses were also elevated inIfnar-deficient mice, and this required IFN-γ. Remarkably, increased IFN-γ and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containingIfnar-deficient hematopoietic cells succumbed to infection early, whereasIfnar-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-α receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infectionin vivoand promote severe disease.

scholarly journals Interferon type I receptor-deficient mice have altered disease symptoms in response to influenza virus

2007 ◽  
Vol 21 (3) ◽  
pp. 311-322 ◽  
Author(s):  
Tim R. Traynor ◽  
Jeannine A. Majde ◽  
Stewart G. Bohnet ◽  
James M. Krueger
Keyword(s):  
Influenza Virus ◽  
Type I ◽  
Disease Symptoms ◽  
Deficient Mice

scholarly journals A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice

2016 ◽  
Vol 90 (7) ◽  
pp. 3783-3788 ◽  
Author(s):  
V. Martín ◽  
E. Pascual ◽  
M. Avia ◽  
G. Rangel ◽  
A. de Molina ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Recombinant Adenovirus ◽  
Biologically Active ◽  
Interferon Response ◽  
Broad Host Range ◽  
Type I ◽  
Interferon Tau ◽  
Unique Type ◽  
Low Toxicity

Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host rangein vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication.

scholarly journals TF protein of Sindbis virus antagonizes host type I interferon responses in a palmitoylation-dependent manner

2019 ◽  
Author(s):  
Rogers KJ. ◽  
Jones-Burrage S. ◽  
Maury W. ◽  
Mukhopadhyay S.
Keyword(s):  
Sindbis Virus ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Wild Type ◽  
Particle Assembly ◽  
Viral Loads ◽  
Interferon Responses ◽  
Deficient Mice

AbstractSindbis virus (SINV) produces the small membrane protein TF from the 6K gene via a (−1) programmed ribosomal frameshifting. While several groups have shown that TF-deficient virus exhibits reduced virulence, mechanism(s) by which this occurs remain unknown. Here, we demonstrate a role for TF in antagonizing the host interferon response. Using wild-type and type 1 interferon receptor-deficient mice and primary cells derived from these animals, we show that TF controls the induction of the host interferon responses at early times during infection. Loss of TF production leads to elevated interferon and a concurrent reduction in viral loads with a loss of pathogenicity. Palmitoylation of TF has been shown to be important for particle assembly and morphology. We find that palmitoylation of TF also contributes to the ability of TF to antagonize host interferon responses as dysregulated palmitoylation of TF reduces virulence in a manner similar to loss of TF.

scholarly journals Pyridoxal 5'-phosphate to mitigate immune dysregulation and coagulopathy in COVID-19

2020 ◽  
Author(s):  
Julie Desbarats
Keyword(s):  
Severe Disease ◽  
The Elderly ◽  
Immune Dysregulation ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Clotting Factors ◽  
Clotting System ◽  
Viral Spread ◽  
Endothelial Integrity

Although most cases of COVID-19 are paucisymptomatic, severe disease is characterized by immune dysregulation, with a decreased type I interferon response, increased inflammatory indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia, and abnormal blood clotting. Factors determining susceptibility to severe disease are poorly understood, although mortality correlates with increasing age and co-morbidities including diabetes and cardiovascular disease (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection and inflammation. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension. In inflammatory disease, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability.

scholarly journals A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Katina D Hulme ◽  
Anjana C Karawita ◽  
Cassandra Pegg ◽  
Myrna JM Bunte ◽  
Helle Bielefeldt-Ohmann ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Disease Severity ◽  
Type I Interferon ◽  
Polymerase Activity ◽  
Interferon Response ◽  
Type I ◽  
Interferon Production ◽  
Wild Type ◽  
Host Environment ◽  
Severe Influenza

Influenza virus has a high mutation rate, such that within one host different viral variants can emerge. Evidence suggests that influenza virus variants are more prevalent in pregnant and/or obese individuals due to their impaired interferon response. We have recently shown that the non-allergic, paucigranulocytic subtype of asthma is associated with impaired type I interferon production. Here, we seek to address if this is associated with an increased emergence of influenza virus variants. Compared to controls, mice with paucigranulocytic asthma had increased disease severity and an increased emergence of influenza virus variants. Specifically, PB1 mutations exclusively detected in asthmatic mice were associated with increased polymerase activity. Furthermore, asthmatic host-derived virus led to increased disease severity in wild-type mice. Taken together, these data suggest that at least a subset of patients with asthma may be more susceptible to severe influenza and may be a possible source of new influenza virus variants.

scholarly journals Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells

2021 ◽  
Author(s):  
Yanshan Zhu ◽  
Keng Yih Chew ◽  
Anjana C. Karawita ◽  
Ayaho Yamamoto ◽  
Larisa L. Labzin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Plaque Assay ◽  
Receptor Expression ◽  
Interferon Response ◽  
Type I ◽  
Nasal Epithelial Cells ◽  
Significant Difference ◽  
Adult Cells

AbstractRationaleYoung children (typically those <10 years old) are less susceptible to SARS-CoV-2 infection and symptoms compared to adults. However, the mechanisms that underlie these age-dependent differences remain to be determined and could inform future therapeutics for adults.ObjectiveTo contrast the infection dynamics of SARS-CoV-2 in primary nasal epithelial cells from adults and children.MethodsViral replication was quantified by plaque assay. The cellular transcriptome of infected and uninfected cells was assessed by RNA-seq. ACE2 and TMPRSS2 protein expression were quantified by Western Blot.Measurements and Main ResultsWe report significantly higher SARS-CoV-2 replication in adult compared to pediatric nasal epithelial cells. This was restricted to SARS-CoV-2 infection, as the same phenomenon was not observed with influenza virus infection. The differentiational SARS-CoV-2 replication dynamics were associated with an elevated type I and III interferon response, and a more pronounced inflammatory response in pediatric cells. No significant difference between the two age groups was observed in the protein levels of ACE2 and TMPRSS2.ConclusionsOur data suggest that the innate immune response of pediatric nasal epithelial cells, and not differential receptor expression, may contribute to the reported reduced SARS-COV-2 infection and symptoms reported amongst children.At a Glance CommentaryScientific Knowledge on the SubjectThere is now a growing body of evidence that children are less susceptible to SARS-CoV-2 infection compared to adults and if infected, children are more likely to develop an asymptomatic infection. The reasons for this remain unclear. In particular, the role of the pediatric nasal epithelium, the primary point of viral entry into the human host, in this differential susceptibility has yet to be investigated.What This Study Adds to the FieldOur study indicates that pediatric nasal epithelial cells produce a more vigorous anti-viral and pro-inflammatory response to SARS-CoV-2 compared to adult cells. This is associated with reduced SARS-CoV-2, but not influenza virus, replication in pediatric epithelial cells. We also show that on a protein level SARS-CoV-2 receptor expression on nasal epithelial cells is not significantly different between children and adults. These data provide an important insight into pediatric infections with SARS-CoV-2.

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