Title: Within-host infectious disease models accommodating cellular coinfection, with an application to influenza

Abstract

Within-host models are useful tools for understanding the processes regulating viral load dynamics. While existing models have considered a wide range of within-host processes, at their core these models have shown remarkable structural similarity. Specifically, the structure of these models generally consider target cells to be either uninfected or infected, with the possibility of accommodating further resolution (e.g. cells that are in an eclipse phase). Recent findings, however, indicate that cellular coinfection is the norm rather than the exception for many viral infectious diseases, and that cells with high multiplicity of infection are present over at least some duration of an infection. The reality of these cellular coinfection dynamics is not accommodated in current within-host models although it may be critical for understanding within-host dynamics. This is particularly the case if multiplicity of infection impacts infected cell phenotypes such as their death rate and their viral production rates. Here, we present a new class of within-host disease models that allow for cellular coinfection in a scalable manner by retaining the low-dimensionality that is a desirable feature of many current within-host models. The models we propose adopt the general structure of epidemiological ‘macroparasite’ models that allow hosts to be variably infectedmore » by parasites such as nematodes and host phenotypes to flexibly depend on parasite burden. Specifically, our within-host models consider target cells as ‘hosts’ and viral particles as ‘macroparasites’, and allow viral output and infected cell lifespans, among other phenotypes, to depend on a cell’s multiplicity of infection. We show with an application to influenza that these models can be statistically fit to viral load and other within-host data, and demonstrate using model selection approaches that they have the ability to outperform traditional within-host viral dynamic models. Important in vivo quantities such as the mean multiplicity of cellular infection and time-evolving reassortant frequencies can also be quantified in a straightforward manner once these macroparasite models have been parameterized. The within-host model structure we develop here provides a mathematical way forward to address questions related to the roles of cellular coinfection, collective viral interactions, and viral complementation in within-host viral dynamics and evolution.« less

Authors:

Koelle, Katia ^[1]; Farrell, Alex ^[2]; Brooke, Christopher ^[3]; Ke, Ruian  ^[4]

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+ Show Author Affiliations

1. Emory Univ., Atlanta, GA (United States). Dept. of Biology
2. North Carolina State Univ., Raleigh, NC (United States). Dept. of Mathematics; Univ. of Arizona, Tucson, AZ (United States). Dept. of Mathematics
3. Univ. of Illinois at Urbana-Champaign, IL (United States). Dept. of Microbiology; Univ. of Illinois at Urbana-Champaign, IL (United States). Carl R. Woese Institute for Genomic Biology
4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Publication Date:

Mon Jul 01 00:00:00 EDT 2019

Research Org.:

Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Org.:

National Institutes of Health (NIH)

OSTI Identifier:

1781372

Report Number(s):

LA-UR-19-25291
Journal ID: ISSN 2057-1577

Grant/Contract Number:  

89233218CNA000001

Resource Type:

Accepted Manuscript

Journal Name:

Virus Evolution

Additional Journal Information:

Journal Volume: 5; Journal Issue: 2; Journal ID: ISSN 2057-1577

Publisher:

Oxford University Press

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; influenza virus; within-host dynamics; macroparasite model; cellular coinfection; viral complementation