A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense

Svedin, Emma; Utorova, Renata; Hühn, Michael; Larsson, Pär; Stone, Virginia M.; Garimella, Manasa G.; Lind, Katharina; Hägglöf, Thomas; Pincikova, T.; Laitinen, Olli H.; McInerney, Gerald M.; Scholte, Bob J.; Hjelte, Lena; Karlsson, Mikael C. I.; Flodström‐Tullberg, Malin

doi:10.1093/infdis/jix474

Cited by 10 publications

(8 citation statements)

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“…We hypothesized that VLPs should be able to induce robust immune responses, since the VLP structures present a repetitive arrangement of antigens [ 52 ], making them immunogenic without the need for immunomodulatory substances. CVB infections induce rapid and strong neutralizing antibody responses in mice [ 33 , 53 ] and humans [ 54 ] and the protective efficacy of vaccines correlates well with the magnitude of the antibody response [ 8 , 13 , 27 , 33 , 55 ]. In our previous studies with inactivated CVB1 whole-virus vaccines [ 55 ] and with CVB1-VLP vaccine [ 19 ] high total IgG and neutralizing antibody responses were induced in C57BL/6J male mice with non-adjuvanted vaccines and the responses were primarily Th2-type (IgG1) oriented.…”

Section: Discussionmentioning

confidence: 99%

Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine

et al. 2020

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Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer important advantages in the manufacturing and epitope engineering. We have previously produced VLPs for CVB3 and CVB1 in insect cells. Here, we describe the production of CVB3-VLPs with enhanced production yield and purity using an improved purification method consisting of tangential flow filtration and ion exchange chromatography, which is compatible with industrial scale production. We also resolved the CVB3-VLP structure by Cryo-Electron Microscopy imaging and single particle reconstruction. The VLP diameter is 30.9 nm on average, and it is similar to Coxsackievirus A VLPs and the expanded enterovirus cell-entry intermediate (the 135s particle), which is ~2 nm larger than the mature virion. High neutralizing and total IgG antibody levels, the latter being a predominantly Th2 type (IgG1) phenotype, were detected in C57BL/6J mice immunized with non-adjuvanted CVB3-VLP vaccine. The structural and immunogenic data presented here indicate the potential of this improved methodology to produce highly immunogenic enterovirus VLP-vaccines in the future.

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Section: Discussionmentioning

confidence: 99%

Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine

et al. 2020

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“…Viral respiratory infections contribute to chronic bacterial colonization of CF lungs. Following infection with the Coxsackie virus B3, CF mice compared to WT mice had increased morbidity and mortality because of an impaired viral clearance [42]. Such an antiviral effect of HspB5 on CF would be worth testing in the future.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR

Degrugillier

Aissat

Escabasse

et al. 2020

IJMS

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Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that is detected by the quality control machinery within the endoplasmic reticulum and targeted for destruction by the proteasome. Modulating quality control proteins as molecular chaperones is a promising strategy for attenuating the degradation and stabilizing the mutant CFTR at the plasma membrane. Among the molecular chaperones, the small heat shock protein HspB1 and HspB4 were shown to promote degradation of F508del-CFTR. Here, we investigated the impact of HspB5 expression and phosphorylation on transport to the plasma membrane, function and stability of F508del-CFTR. We show that a phosphomimetic form of HspB5 increases the transport to the plasma membrane, function and stability of F508del-CFTR. These activities are further enhanced in presence of therapeutic drugs currently used for the treatment of cystic fibrosis (VX-770/Ivacaftor, VX-770+VX-809/Orkambi). Overall, this study highlights the beneficial effects of a phosphorylated form of HspB5 on F508del-CFTR rescue and its therapeutic potential in cystic fibrosis.

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“…Although bacterial infections are usually associated with CF, viral infections can also capitalize on defective mucus clearance and host immunity [ 266 ]. Mice expressing ΔF508 showed increased lethality when infected with an enterovirus (coxsackievirus B3 Nancy) despite viremia levels similar to controls [ 267 ]. Yet ΔF508 mice had increased viral titers in lymphoid tissues, decreased IFNα production, and decreased virus-specific IgM and IgG titers.…”

Section: S1p Metabolismmentioning

confidence: 99%

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Blaho

2020

Druggable Lipid Signaling Pathways

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Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

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A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense

Cited by 10 publications

References 50 publications

Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine

Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine

Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

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