Causes and Consequences of Spatial Within-Host Viral Spread.

Molly Gallagher,Ruian Ke,Katia Koelle,Christopher Brooke

doi:10.3390/v10110627

Abstract

The spread of viral pathogens both between and within hosts is inherently a spatial process. While the spatial aspects of viral spread at the epidemiological level have been increasingly well characterized, the spatial aspects of viral spread within infected hosts are still understudied. Here, with a focus on influenza A viruses (IAVs), we first review experimental studies that have shed light on the mechanisms and spatial dynamics of viral spread within hosts. These studies provide strong empirical evidence for highly localized IAV spread within hosts. Since mathematical and computational within-host models have been increasingly used to gain a quantitative understanding of observed viral dynamic patterns, we then review the (relatively few) computational modeling studies that have shed light on possible factors that structure the dynamics of spatial within-host IAV spread. These factors include the dispersal distance of virions, the localization of the immune response, and heterogeneity in host cell phenotypes across the respiratory tract. While informative, we find in these studies a striking absence of theoretical expectations of how spatial dynamics may impact the dynamics of viral populations. To mitigate this, we turn to the extensive ecological and evolutionary literature on range expansions to provide informed theoretical expectations. We find that factors such as the type of density dependence, the frequency of long-distance dispersal, specific life history characteristics, and the extent of spatial heterogeneity are critical factors affecting the speed of population spread and the genetic composition of spatially expanding populations. For each factor that we identified in the theoretical literature, we draw parallels to its analog in viral populations. We end by discussing current knowledge gaps related to the spatial component of within-host IAV spread and the potential for within-host spatial considerations to inform the development of disease control strategies.

Highlights

More often than not, viral populations are spatially structured
A study by Reperant et al provides an example of this type of approach, in which viral dynamics are considered across three tissue compartments: the trachea/bronchi, the bronchioles, and the alveoli [73]
We have reviewed the current understanding and open questions regarding patterns and mechanisms of within-host viral spread from both empirical and computational perspectives

Summary

Introduction

Viral populations are spatially structured. At the between-host level, this spatial structure is evident for endemic pathogens from observed patterns of genetic differences across space, such as those observed for measles virus at large geographic scales [1] and dengue virus even at intracity scales [2]. Hosts with pre-existing anti-influenza immunity may clear cell-free virions more rapidly than naïve hosts, resulting in a more dominant role for intercellular viral spread in these individuals Both of these processes are subject to stochastic effects, which contribute to variation in the spatial distribution of IAV between infected individuals. Because the respiratory tract is not a highly immune-privileged site, and numerous soluble components of the anti-viral immune response, such as antibodies and interferon, are thought to act at the tissue-wide or systemic level, we expect the spatial dynamics of influenza virus spread to be regulated more strongly by the bottom-up process of local target cell availability than by the top-down process of immune-mediated viral clearance.

Computational Models of Spatial Within-Host Influenza Virus Spread

Ecological Factors Driving Patterns of Spatial Spread

The Consequences of Spatial Spread on Population Evolution

Findings

Discussion