Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection
Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors—such as aging, pregnancy, and genetic polymorphisms—influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) ago...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 23; pp. 1 - 10 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
08.06.2021
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors—such as aging, pregnancy, and genetic polymorphisms—influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5- dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure–activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines. |
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| AbstractList | Significance
Effective vaccine strategies are needed to overcome genetic, physiologic, or age-related deficits in immune responses relevant to vulnerable populations. Vaccine adjuvants that overcome these variants and do not compromise safety are highly desirable. We identified a synthetic small-molecule compound 81 [
N
-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] and its derivative 2F52 [
N
-benzyl-
N
-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] as activators of innate immunity via mitochondrial stress pathways, circumventing classic pathogen-recognition receptors. Neither 81 nor 2F52 as adjuvants caused local or systemic toxicity in mice after injection. Moreover, in a mouse influenza challenge study, compound 2F52 demonstrated protective effects when used with inactivated virus. Thus, compound 2F52, acting through an unconventional pathway to stimulate innate immunity, could be a useful synthetic adjuvant to enhance current and future vaccines.
Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors—such as aging, pregnancy, and genetic polymorphisms—influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [
N
-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure–activity relationship studies, 2F52 [
N
-benzyl-
N
-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines. Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure–activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines. Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [ -(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [ -benzyl- -(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines. Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines. Effective vaccine strategies are needed to overcome genetic, physiologic, or age-related deficits in immune responses relevant to vulnerable populations. Vaccine adjuvants that overcome these variants and do not compromise safety are highly desirable. We identified a synthetic small-molecule compound 81 [ N -(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] and its derivative 2F52 [ N -benzyl- N -(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] as activators of innate immunity via mitochondrial stress pathways, circumventing classic pathogen-recognition receptors. Neither 81 nor 2F52 as adjuvants caused local or systemic toxicity in mice after injection. Moreover, in a mouse influenza challenge study, compound 2F52 demonstrated protective effects when used with inactivated virus. Thus, compound 2F52, acting through an unconventional pathway to stimulate innate immunity, could be a useful synthetic adjuvant to enhance current and future vaccines. Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors—such as aging, pregnancy, and genetic polymorphisms—influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [ N -(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure–activity relationship studies, 2F52 [ N -benzyl- N -(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines. |
| Author | Chan, Michael Carson, Dennis A. Pu, Minya Lao, Fitzgerald S. Saito, Tetsuya Cheng, Annette Hayashi, Tomoko Yao, Shiyin Nan, Jason Shukla, Nikunj M. Sato-Kaneko, Fumi Messer, Karen Cottam, Howard B. Corr, Maripat Shpigelman, Jonathan Molina, Anthony J. |
| Author_xml | – sequence: 1 givenname: Fumi surname: Sato-Kaneko fullname: Sato-Kaneko, Fumi – sequence: 2 givenname: Shiyin surname: Yao fullname: Yao, Shiyin – sequence: 3 givenname: Fitzgerald S. surname: Lao fullname: Lao, Fitzgerald S. – sequence: 4 givenname: Jason surname: Nan fullname: Nan, Jason – sequence: 5 givenname: Jonathan surname: Shpigelman fullname: Shpigelman, Jonathan – sequence: 6 givenname: Annette surname: Cheng fullname: Cheng, Annette – sequence: 7 givenname: Tetsuya surname: Saito fullname: Saito, Tetsuya – sequence: 8 givenname: Karen surname: Messer fullname: Messer, Karen – sequence: 9 givenname: Minya surname: Pu fullname: Pu, Minya – sequence: 10 givenname: Nikunj M. surname: Shukla fullname: Shukla, Nikunj M. – sequence: 11 givenname: Howard B. surname: Cottam fullname: Cottam, Howard B. – sequence: 12 givenname: Michael surname: Chan fullname: Chan, Michael – sequence: 13 givenname: Anthony J. surname: Molina fullname: Molina, Anthony J. – sequence: 14 givenname: Maripat surname: Corr fullname: Corr, Maripat – sequence: 15 givenname: Tomoko surname: Hayashi fullname: Hayashi, Tomoko – sequence: 16 givenname: Dennis A. surname: Carson fullname: Carson, Dennis A. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34078669$$D View this record in MEDLINE/PubMed |
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| DOI | 10.1073/pnas.2025718118 |
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| Keywords | influenza virus NF-κB vaccine adjuvant mitochondrial reactive oxygen species mitochondrial stress |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: F.S.-K., M. Corr, T.H., and D.A.C. designed research; F.S.-K., S.Y., F.S.L., J.N., J.S., A.C., T.S., and A.J.M. performed research; N.M.S., H.B.C., and M. Chan contributed new reagents/analytic tools; F.S.-K., K.M., M.P., M. Corr, and T.H. analyzed data; and F.S.-K., M. Corr, T.H., and D.A.C. wrote the paper. Reviewers: D.J.D., Boston Children’s Hospital; and J.A.N., Oregon Health & Science University. Contributed by Dennis A. Carson, April 30, 2021 (sent for review December 14, 2020; reviewed by David J. Dowling and Jay A. Nelson) |
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| Snippet | Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors—such as aging, pregnancy, and... Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and... Significance Effective vaccine strategies are needed to overcome genetic, physiologic, or age-related deficits in immune responses relevant to vulnerable... Effective vaccine strategies are needed to overcome genetic, physiologic, or age-related deficits in immune responses relevant to vulnerable populations.... |
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| SubjectTerms | Adjuvants Adjuvants, Immunologic - pharmacology Aging Animals Antibodies, Viral - immunology Antioxidants Biological Sciences Bone marrow Cytokines Dendritic cells Dendritic Cells - immunology Female Gene Expression Gene polymorphism Humans Immune system Immunity, Innate - drug effects Influenza Influenza Vaccines - immunology Influenza Vaccines - pharmacology Influenza, Human - immunology Innate immunity Interferon Leukocytes (mononuclear) Leukocytes, Mononuclear - immunology Lipopolysaccharides Mice Mice, Inbred BALB C Mitochondria Mitochondria - drug effects Mitochondria - genetics Mitochondria - metabolism NF-κB protein Orthomyxoviridae Infections - immunology Pattern recognition Peripheral blood mononuclear cells Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Receptors Saponins Signaling Stress, Physiological Toll-Like Receptors Toxicity Vaccines Viruses |
| Title | Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection |
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