A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection

Zitzmann, Carolin; Schmid, Bianca; Ruggieri, Alessia; Perelson, Alan S.; Binder, Marco; Bartenschlager, Ralf; Kaderali, Lars

doi:10.3389/fmicb.2020.00725

A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection

Journal Article · Wed Apr 29 00:00:00 EDT 2020 · Frontiers in Microbiology

DOI:https://doi.org/10.3389/fmicb.2020.00725· OSTI ID:1819137

Zitzmann, Carolin ^[1]; Schmid, Bianca ^[2]; Ruggieri, Alessia ^[2]; Perelson, Alan S. ^[3]; Binder, Marco ^[4]; Bartenschlager, Ralf ^[2]; Kaderali, Lars ^[5]

Univ. Medicine Greifswald (Germany). Inst. of Bioinformatics, Center for Functional Genomics of Microbes; Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Heidelberg Univ. (Germany)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
German Cancer Research Center (DKFZ), Heidelberg (Germany)
Univ. Medicine Greifswald (Germany). Inst. of Bioinformatics, Center for Functional Genomics of Microbes

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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; BMBF; National Institutes of Health (NIH)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1819137

Report Number(s):: LA-UR--19-26241

Journal Information:: Frontiers in Microbiology, Journal Name: Frontiers in Microbiology Vol. 11; ISSN 1664-302X

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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