title: Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Edinburgh, UK. Andrea.Wilson@roslin.ed.ac.uk.
authors: Andrea
authors: 0000-0002-2658-6973
authors: A
authors: Doeschl-Wilson
authors: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Edinburgh, UK.
authors: Alison
authors: A
authors: Wilson
authors: Department of Mircrobiological Diagnostics and Virology, Statens Serum Institute, Copenhagen, Denmark.
authors: Jens
authors: J
authors: Nielsen
authors: Department of Virology, Parasitology and Immunity, Ghent University, Ghent, Belgium.
authors: Hans
authors: H
authors: Nauwynck
authors: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Edinburgh, UK.
authors: Alan
authors: A
authors: Archibald
authors: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Edinburgh, UK.
authors: Tahar
authors: T
authors: Ait-Ali
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D005786:Gene Expression Regulation; D007700:Kinetics; D007753:Laboratories; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D008954:Models, Biological; D019316:Porcine respiratory and reproductive syndrome virus / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface
keywords: Alveolar macrophages; CD163; Host cell susceptibility; Host-pathogen interaction; Infection dynamics; Mathematical model; PRRSV; Pigs; Statistical inference