title: Potential for evolution of complex defense strategies in a multi-scale model of virus-host coevolution.
abstract: Host resistance and viral pathogenicity are determined by molecular interactions that are part of the evolutionary arms race between viruses and their hosts. Viruses are obligate intracellular parasites and entry to the host cell is the first step of any virus infection. Commonly, viruses enter host cells by binding cell surface receptors. We adopt a computational modeling approach to study the evolution of the first infection step, where we consider two possible levels of resistance mechanism: at the level of the binding interaction between the host receptor and a virus binding protein, and at the level of receptor protein expression where we use a standard gene regulatory network model. At the population level we adopted the Susceptible-Infected-Susceptible (SIS) model. We used our multi-scale model to understand what conditions might determine the balance between use of resistance mechanisms at the two different levels.
  
  
  
  We explored a range of different conditions (model parameters) that affect host evolutionary dynamics and, in particular, the balance between the use of different resistance mechanisms. These conditions include the complexity of the receptor binding protein-protein interaction, selection pressure on the host population (pathogenicity), and the number of expressed cell-surface receptors. In particular, we found that as the receptor binding complexity (understood as the number of amino acids involved in the interaction between the virus entry protein and the host receptor) increases, viruses tend to become specialists and target one specific receptor. At the same time, on the host side, the potential for resistance shifts from the changes at the level of receptor binding (protein-protein) interaction towards changes at the level of gene regulation, suggesting a mechanism for increased biological complexity.
  
  
  
  Host resistance and viral pathogenicity depend on quite different evolutionary conditions. Viruses may evolve cell entry strategies that use small receptor binding regions, represented by low complexity binding in our model. Our modeling results suggest that if the virus adopts a strategy based on binding to low complexity sites on the host receptor, the host will select a defense strategy at the protein (receptor) level, rather than at the level of the regulatory network - a virus-host strategy that appears to have been selected most often in nature.
authors: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.
authors: Jeewoen
authors: J
authors: Shin
authors: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA. thomas.maccarthy@stonybrook.edu.|Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA. thomas.maccarthy@stonybrook.edu.
authors: Thomas
authors: 0000-0003-0025-9285
authors: T
authors: MacCarthy
mesh_terms: D060467:Disease Resistance / Q000235:genetics* / Q000276:immunology; D019143:Evolution, Molecular; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D054884:Host-Pathogen Interactions / Q000235:genetics*; D008962:Models, Theoretical; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D011991:Receptors, Virus / Q000737:chemistry / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D014764:Viral Proteins
keywords: Gene regulatory network; Host cell surface receptor; Virus entry