A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection
Dengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemor...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.00725/full |
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| author | Carolin Zitzmann Carolin Zitzmann Bianca Schmid Alessia Ruggieri Alan S. Perelson Marco Binder Ralf Bartenschlager Lars Kaderali |
| author_facet | Carolin Zitzmann Carolin Zitzmann Bianca Schmid Alessia Ruggieri Alan S. Perelson Marco Binder Ralf Bartenschlager Lars Kaderali |
| author_sort | Carolin Zitzmann |
| collection | DOAJ |
| description | Dengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the latter because of severe plasma leakage. Given that the outcome of infection is likely determined by the kinetics of viral replication and the antiviral host cell immune response (HIR) it is of importance to understand the interaction between these two parameters. In this study, we use mathematical modeling to characterize and understand the complex interplay between intracellular DV replication and the host cells' defense mechanisms. We first measured viral RNA, viral protein, and virus particle production in Huh7 cells, which exhibit a notoriously weak intrinsic antiviral response. Based on these measurements, we developed a detailed intracellular DV replication model. We then measured replication in IFN competent A549 cells and used this data to couple the replication model with a model describing IFN activation and production of IFN stimulated genes (ISGs), as well as their interplay with DV replication. By comparing the cell line specific DV replication, we found that host factors involved in replication complex formation and virus particle production are crucial for replication efficiency. Regarding possible modes of action of the HIR, our model fits suggest that the HIR mainly affects DV RNA translation initiation, cytosolic DV RNA degradation, and naïve cell infection. We further analyzed the potential of direct acting antiviral drugs targeting different processes of the DV lifecycle in silico and found that targeting RNA synthesis and virus assembly and release are the most promising anti-DV drug targets. |
| first_indexed | 2024-12-21T00:10:53Z |
| format | Article |
| id | doaj.art-941a60b06fbe457c85c262d64d24f21f |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-21T00:10:53Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-941a60b06fbe457c85c262d64d24f21f2022-12-21T19:22:21ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-04-011110.3389/fmicb.2020.00725486357A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to InfectionCarolin Zitzmann0Carolin Zitzmann1Bianca Schmid2Alessia Ruggieri3Alan S. Perelson4Marco Binder5Ralf Bartenschlager6Lars Kaderali7Center for Functional Genomics of Microbes, Institute of Bioinformatics, University Medicine Greifswald, Greifswald, GermanyTheoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, United StatesDepartment of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, GermanyDepartment of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, GermanyTheoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, United StatesResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, GermanyCenter for Functional Genomics of Microbes, Institute of Bioinformatics, University Medicine Greifswald, Greifswald, GermanyDengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the latter because of severe plasma leakage. Given that the outcome of infection is likely determined by the kinetics of viral replication and the antiviral host cell immune response (HIR) it is of importance to understand the interaction between these two parameters. In this study, we use mathematical modeling to characterize and understand the complex interplay between intracellular DV replication and the host cells' defense mechanisms. We first measured viral RNA, viral protein, and virus particle production in Huh7 cells, which exhibit a notoriously weak intrinsic antiviral response. Based on these measurements, we developed a detailed intracellular DV replication model. We then measured replication in IFN competent A549 cells and used this data to couple the replication model with a model describing IFN activation and production of IFN stimulated genes (ISGs), as well as their interplay with DV replication. By comparing the cell line specific DV replication, we found that host factors involved in replication complex formation and virus particle production are crucial for replication efficiency. Regarding possible modes of action of the HIR, our model fits suggest that the HIR mainly affects DV RNA translation initiation, cytosolic DV RNA degradation, and naïve cell infection. We further analyzed the potential of direct acting antiviral drugs targeting different processes of the DV lifecycle in silico and found that targeting RNA synthesis and virus assembly and release are the most promising anti-DV drug targets.https://www.frontiersin.org/article/10.3389/fmicb.2020.00725/fulldengue virusmathematical modelinnate immune responsevirus replicationcomputational simulation |
| spellingShingle | Carolin Zitzmann Carolin Zitzmann Bianca Schmid Alessia Ruggieri Alan S. Perelson Marco Binder Ralf Bartenschlager Lars Kaderali A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection Frontiers in Microbiology dengue virus mathematical model innate immune response virus replication computational simulation |
| title | A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection |
| title_full | A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection |
| title_fullStr | A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection |
| title_full_unstemmed | A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection |
| title_short | A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection |
| title_sort | coupled mathematical model of the intracellular replication of dengue virus and the host cell immune response to infection |
| topic | dengue virus mathematical model innate immune response virus replication computational simulation |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.00725/full |
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