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Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus

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Abstract
Background: Macrophages are essential to innate immunity against many pathogens, but some pathogens also target macrophages as routes to infection. The Porcine Reproductive and Respiratory Syndrome virus (PRRSV) is an RNA virus that infects porcine alveolar macrophages (PAMs) causing devastating impact on global pig production. Identifying the cellular mechanisms that mediate PAM susceptibility to the virus is crucial for developing effective interventions. Previous evidence suggests that the scavenger receptor CD163 is essential for productive infection of PAMs with PRRSV. Here we use an integrative in-vitro-in-silico modelling approach to determine whether and how PAM susceptibility to PRRSV changes over time, to assess the role of CD163 expression on such changes, and to infer other potential causative mechanisms altering cell susceptibility. Results: Our in-vitro experiment showed that PAM susceptibility to PRRSV changed considerably over incubation time. Moreover, an increasing proportion of PAMs apparently lacking CD163 were found susceptible to PRRSV at the later incubation stages, thus conflicting with current understanding that CD163 is essential for productive infection of PAMs with PRRSV. We developed process based dynamic mathematical models and fitted these to the data to assess alternative hypotheses regarding potential underlying mechanisms for the observed susceptibility and biomarker trends. The models informed by our data support the hypothesis that although CD163 may have enhanced cell susceptibility, it was not essential for productive infection in our study. Instead the models promote the existence of a reversible cellular state, such as macrophage polarization, mediated in a density dependent manner by autocrine factors, to be responsible for the observed kinetics in cell susceptibility. Conclusions: Our dynamic model-inference approach provides strong support that PAM susceptibility to the PRRS virus is transient, reversible and can be mediated by compounds produced by the target cells themselves, and that these can render PAMs lacking the CD163 receptor susceptible to PRRSV. The results have implications for the development of therapeutics aiming to boost target cell resistance and prompt future investigation of dynamic changes in macrophage susceptibility to PRRSV and other viruses.
Keywords
PRRSV, CD163, Alveolar macrophages, Host cell susceptibility, Mathematical model, Infection dynamics, Statistical inference, Host-pathogen interaction, Pigs, RESPIRATORY SYNDROME VIRUS, PORCINE ALVEOLAR MACROPHAGES, PRACTICAL IDENTIFIABILITY ANALYSIS, TOLL-LIKE RECEPTORS, ALTERNATIVE ACTIVATION, IMMUNE-RESPONSES, INFECTION, REPLICATION, STRAINS, PIGS

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MLA
Doeschl-Wilson, Andrea et al. “Combining Laboratory and Mathematical Models to Infer Mechanisms Underlying Kinetic Changes in Macrophage Susceptibility to an RNA Virus.” BMC SYSTEMS BIOLOGY 10.1 (2016): n. pag. Print.
APA
Doeschl-Wilson, A., Wilson, A., Nielsen, J., Nauwynck, H., Archibald, A., & Ait-Ali, T. (2016). Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus. BMC SYSTEMS BIOLOGY, 10(1).
Chicago author-date
Doeschl-Wilson, Andrea, Alison Wilson, Jens Nielsen, Hans Nauwynck, Alan Archibald, and Tahar Ait-Ali. 2016. “Combining Laboratory and Mathematical Models to Infer Mechanisms Underlying Kinetic Changes in Macrophage Susceptibility to an RNA Virus.” Bmc Systems Biology 10 (1).
Chicago author-date (all authors)
Doeschl-Wilson, Andrea, Alison Wilson, Jens Nielsen, Hans Nauwynck, Alan Archibald, and Tahar Ait-Ali. 2016. “Combining Laboratory and Mathematical Models to Infer Mechanisms Underlying Kinetic Changes in Macrophage Susceptibility to an RNA Virus.” Bmc Systems Biology 10 (1).
Vancouver
1.
Doeschl-Wilson A, Wilson A, Nielsen J, Nauwynck H, Archibald A, Ait-Ali T. Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus. BMC SYSTEMS BIOLOGY. 2016;10(1).
IEEE
[1]
A. Doeschl-Wilson, A. Wilson, J. Nielsen, H. Nauwynck, A. Archibald, and T. Ait-Ali, “Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus,” BMC SYSTEMS BIOLOGY, vol. 10, no. 1, 2016.
@article{8504569,
  abstract     = {Background: Macrophages are essential to innate immunity against many pathogens, but some pathogens also target macrophages as routes to infection. The Porcine Reproductive and Respiratory Syndrome virus (PRRSV) is an RNA virus that infects porcine alveolar macrophages (PAMs) causing devastating impact on global pig production. Identifying the cellular mechanisms that mediate PAM susceptibility to the virus is crucial for developing effective interventions. Previous evidence suggests that the scavenger receptor CD163 is essential for productive infection of PAMs with PRRSV. Here we use an integrative in-vitro-in-silico modelling approach to determine whether and how PAM susceptibility to PRRSV changes over time, to assess the role of CD163 expression on such changes, and to infer other potential causative mechanisms altering cell susceptibility. 
Results: Our in-vitro experiment showed that PAM susceptibility to PRRSV changed considerably over incubation time. Moreover, an increasing proportion of PAMs apparently lacking CD163 were found susceptible to PRRSV at the later incubation stages, thus conflicting with current understanding that CD163 is essential for productive infection of PAMs with PRRSV. We developed process based dynamic mathematical models and fitted these to the data to assess alternative hypotheses regarding potential underlying mechanisms for the observed susceptibility and biomarker trends. The models informed by our data support the hypothesis that although CD163 may have enhanced cell susceptibility, it was not essential for productive infection in our study. Instead the models promote the existence of a reversible cellular state, such as macrophage polarization, mediated in a density dependent manner by autocrine factors, to be responsible for the observed kinetics in cell susceptibility. 
Conclusions: Our dynamic model-inference approach provides strong support that PAM susceptibility to the PRRS virus is transient, reversible and can be mediated by compounds produced by the target cells themselves, and that these can render PAMs lacking the CD163 receptor susceptible to PRRSV. The results have implications for the development of therapeutics aiming to boost target cell resistance and prompt future investigation of dynamic changes in macrophage susceptibility to PRRSV and other viruses.},
  articleno    = {101},
  author       = {Doeschl-Wilson, Andrea and Wilson, Alison and Nielsen, Jens and Nauwynck, Hans and Archibald, Alan and Ait-Ali, Tahar},
  issn         = {1752-0509},
  journal      = {BMC SYSTEMS BIOLOGY},
  keywords     = {PRRSV,CD163,Alveolar macrophages,Host cell susceptibility,Mathematical model,Infection dynamics,Statistical inference,Host-pathogen interaction,Pigs,RESPIRATORY SYNDROME VIRUS,PORCINE ALVEOLAR MACROPHAGES,PRACTICAL IDENTIFIABILITY ANALYSIS,TOLL-LIKE RECEPTORS,ALTERNATIVE ACTIVATION,IMMUNE-RESPONSES,INFECTION,REPLICATION,STRAINS,PIGS},
  language     = {eng},
  number       = {1},
  pages        = {17},
  title        = {Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus},
  url          = {http://dx.doi.org/10.1186/s12918-016-0345-5},
  volume       = {10},
  year         = {2016},
}

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