Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands.
PLoS One. 2012;7(8):e43115. doi: 10.1371/journal.pone.0043115. Epub 2012 Aug 28.
Influenza virus tissue tropism defines the host cells and tissues that support viral replication and contributes to determining which regions of the respiratory tract are infected in humans. The location of influenza virus infection along the respiratory tract is a key determinant of virus pathogenicity and transmissibility, which are at the basis of influenza burdens in the human population. As the pathogenicity and transmissibility of influenza virus ultimately determine its reproductive fitness at the population level, strong selective pressures will shape influenza virus tissue tropisms that maximize fitness. At present, the relationships between influenza virus tissue tropism within hosts and reproductive fitness at the population level are poorly understood. The selective pressures and constraints that shape tissue tropism and thereby influence the location of influenza virus infection along the respiratory tract are not well characterized. We use mathematical models that link within-host infection dynamics in a spatially-structured human respiratory tract to between-host transmission dynamics, with the aim of characterizing the possible selective pressures on influenza virus tissue tropism. The results indicate that spatial heterogeneities in virus clearance, virus pathogenicity or both, resulting from the unique structure of the respiratory tract, may drive optimal receptor binding affinity--that maximizes influenza virus reproductive fitness at the population level--towards sialic acids with α2,6 linkage to galactose. The expanding cell pool deeper down the respiratory tract, in association with lower clearance rates, may result in optimal infectivity rates--that likewise maximize influenza virus reproductive fitness at the population level--to exhibit a decreasing trend towards deeper regions of the respiratory tract. Lastly, pre-existing immunity may drive influenza virus tissue tropism towards upper regions of the respiratory tract. The proposed framework provides a new template for the cross-scale study of influenza virus evolutionary and epidemiological dynamics in humans.
流感病毒组织嗜性决定了支持病毒复制的宿主细胞和组织，并有助于确定人类呼吸道的哪些区域受到感染。流感病毒感染在呼吸道的位置是病毒致病性和传染性的关键决定因素，而这些因素是流感在人群中负担的基础。由于流感病毒的致病性和传染性最终决定了其在人群水平上的繁殖适应性，强烈的选择压力将塑造最大限度提高适应性的流感病毒组织嗜性。目前，宿主内流感病毒组织嗜性与人群水平生殖适应性之间的关系尚不清楚。塑造组织嗜性并因此影响流感病毒感染在呼吸道位置的选择压力和限制因素尚未得到很好的描述。我们使用将宿主内感染动力学与宿主间传播动力学联系起来的数学模型，目的是描述流感病毒组织嗜性可能受到的选择压力。结果表明，呼吸道独特结构导致的病毒清除、病毒致病性或两者的空间异质性，可能导致最佳受体结合亲和力——最大程度地提高人群水平的流感病毒生殖适应性——偏向于与半乳糖连接的α2,6 键唾液酸。与清除率降低相关的呼吸道更深部位的细胞池扩大，可能导致最佳感染率——同样最大程度地提高人群水平的流感病毒生殖适应性——向呼吸道的更深区域呈下降趋势。最后，预先存在的免疫可能会导致流感病毒组织嗜性向呼吸道的上部区域发展。所提出的框架为在人类中跨尺度研究流感病毒进化和流行病学动力学提供了一个新的模板。
