title: Estimating biologically relevant parameters under uncertainty for experimental within-host murine West Nile virus infection.
abstract: West Nile virus (WNV) is an emerging pathogen that has decimated bird populations and caused severe outbreaks of viral encephalitis in humans. Currently, little is known about the within-host viral kinetics of WNV during infection. We developed mathematical models to describe viral replication, spread and host immune response in wild-type and immunocompromised mice. Our approach fits a target cell-limited model to viremia data from immunocompromised knockout mice and an adaptive immune response model to data from wild-type mice. Using this approach, we first estimate parameters governing viral production and viral spread in the host using simple models without immune responses. We then use these parameters in a more complex immune response model to characterize the dynamics of the humoral immune response. Despite substantial uncertainty in input parameters, our analysis generates relatively precise estimates of important viral characteristics that are composed of nonlinear combinations of model parameters: we estimate the mean within-host basic reproductive number,R0, to be 2.3 (95% of values in the range 1.7-2.9); the mean infectious virion burst size to be 2.9 plaque-forming units (95% of values in the range 1.7-4.7); and the average number of cells infected per infectious virion to be between 0.3 and 0.99. Our analysis gives mechanistic insights into the dynamics of WNV infection and produces estimates of viral characteristics that are difficult to measure experimentally. These models are a first step towards a quantitative understanding of the timing and effectiveness of the humoral immune response in reducing host viremia and consequently the epidemic spread of WNV.
authors.affiliation: Department of Computer Science, University of New Mexico, Albuquerque, NM, USA Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA neel.soumya@gmail.com.
authors.forename: Soumya
authors.identifier: http://orcid.org/0000-0001-7748-9885
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Ruy M
authors.identifier: http://orcid.org/0000-0002-3988-8241
authors.initials: RM
authors.lastname: Ribeiro
authors.affiliation: Department of Computer Science, University of New Mexico, Albuquerque, NM, USA Department of Biology, University of New Mexico, Albuquerque, NM, USA External Faculty, Santa Fe Institute, Santa Fe, NM, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Moses
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA External Faculty, Santa Fe Institute, Santa Fe, NM, USA.
authors.forename: Alan S
authors.identifier: http://orcid.org/0000-0002-2455-0002
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D014766:Viremia / Q000235:genetics / Q000378:metabolism; D014901:West Nile Fever / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014902:West Nile virus / Q000502:physiology*
keywords: West Nile virus infection; basic reproductive number; biologically relevant parameters; ordinary differential equation models; parameter estimation; within-host viral dynamics