Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
mBio. 2011 Sep 6;2(5). doi: 10.1128/mBio.00171-11. Print 2011.
The genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host's immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host's susceptibility to a given H5N1 virus.
Highly pathogenic H5N1 influenza virus has circulated in Southeast Asia since 2003 but has been confirmed in relatively few individuals. It has been postulated that host genetic polymorphisms increase the susceptibility to infection and severe disease. The mechanisms and host proteins affected during severe disease are unknown. Inbred mouse strains vary considerably in their ability to resist H5N1 virus and were used to identify the primary mechanism determining disease severity. After inoculation with H5N1, resistant mouse strains had reduced amounts of virus in their lungs, which subsequently resulted in lower production of proinflammatory mediators and less pathology. We therefore conclude that the host genetic component controlling disease severity is primarily influencing viral replication. This is an important concept, as it emphasizes the need to limit virus replication through antiviral therapies and it shows that the hyperinflammatory environment is simply a reflection of more viral genetic material inducing a response.
宿主的基因型是引发传染病的多种因素之一，可能是高致病性 H5N1 流感病毒在人类中感染的流行病学的关键参数。基因多态性可能影响病毒的复制率或改变宿主对病毒的免疫反应。在人类中，尚不清楚哪种因素决定 H5N1 病毒病的严重程度。为了确定在遗传多样性人群中对 H5N1 病毒感染的不同反应的机制，我们评估了 21 种近交系小鼠在鼻腔接种 A/Hong Kong/213/03（H5N1）后的宿主反应和肺部病毒载量。抗性小鼠株在接种大剂量时存活，而易感株在接种 1000 至 10000 倍低剂量时就会死亡。接种中间剂量后对病毒载量的定量分析发现，早在接种后 2 天，与致死性相关的显著关联早于任何其他疾病指标。在高度易感的菌株中，病毒滴度的增加介导了一个过度充气的环境，这表现在第 3 天明显的表达谱和炎症介质产生增加。支持病毒载量而非对病毒的不适当反应是决定严重程度的关键因素的假说，我们进行了定量实时 PCR 测量细胞因子/病毒 RNA 比值。在易感和抗性小鼠株之间未检测到显著差异，这证实了控制病毒载量的宿主遗传成分，因此复制动力学，主要负责宿主对特定 H5N1 病毒的易感性。
高致病性 H5N1 流感病毒自 2003 年以来一直在东南亚传播，但在相对较少的个体中得到证实。据推测，宿主遗传多态性增加了感染和严重疾病的易感性。在严重疾病期间受影响的机制和宿主蛋白尚不清楚。近交系小鼠在抵抗 H5N1 病毒的能力上差异很大，被用来确定决定疾病严重程度的主要机制。接种 H5N1 后，抗性小鼠株肺部的病毒量减少，随后导致促炎介质的产生减少和病理学减少。因此，我们得出结论，控制疾病严重程度的宿主遗传成分主要影响病毒复制。这是一个重要的概念，因为它强调了通过抗病毒疗法限制病毒复制的必要性，并且表明过度充气的环境只是更多病毒遗传物质诱导反应的反映。
