Increased Viral Loads and Exacerbated Innate Host Responses in Aged Macaques Infected with the 2009 Pandemic H1N1 Influenza A Virus
Increased Viral Loads and Exacerbated Innate Host Responses in Aged Macaques Infected with the 2009 Pandemic H1N1 Influenza A Virus
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DOI：
10.1128/jvi.01571-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Messaoudi, Ilhem
中科院分区：
文献类型：
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作者：
Josset, Laurence;Engelmann, Flora;Messaoudi, Ilhem
季节性流感病毒感染通常会导致老年人发病率和死亡率很高，而2009年H1N1病毒则会导致年轻人严重感染。这种现象是由于老年人在以前接触H1N1病毒时获得的交叉保护抗体的存在。然而，这一假设无法通过实证检验。为了解决这个问题，我们比较了病毒复制和免疫反应的发展，在幼稚的年轻成年和老年女性恒河猴感染A/加州/04/2009 H1N1（CA 04）病毒。我们发现老年动物的支气管肺泡灌洗液（BAL）以及鼻拭子和眼拭子中的病毒载量较高，表明下呼吸道和上呼吸道中的病毒复制增加。T细胞增殖较高的BAL液，但延迟和减少在外周血中老年动物。这种增殖延迟与老年动物中效应CD 4 T细胞频率降低相关。老年动物也动员炎性细胞因子在BAL液中达到更高水平。最后，我们比较了基因表达的变化，使用微阵列分析的BAL液样本。我们的分析显示，在感染后第4天检测到老年和年轻成年动物之间宿主反应的最大差异，老年动物中与炎症和先天免疫反应相关的基因的诱导显著更高。总体而言，我们的数据表明，在不存在预先存在的抗体的情况下，老年猕猴中的CA 04感染与先天性和适应性免疫应答的变化相关，这些变化显示出与其他呼吸道疾病模型中疾病严重程度增加相关。
In contrast to seasonal influenza virus infections, which typically cause significant morbidity and mortality in the elderly, the 2009 H1N1 virus caused severe infection in young adults. This phenomenon was attributed to the presence of cross-protective antibodies acquired by older individuals during previous exposures to H1N1 viruses. However, this hypothesis could not be empirically tested. To address this question, we compared viral replication and the development of the immune response in naive young adult and aged female rhesus macaques infected with A/California/04/2009 H1N1 (CA04) virus. We show higher viral loads in the bronchoalveolar lavage (BAL) fluid and nasal and ocular swabs in aged animals, suggesting increased viral replication in both the lower and upper respiratory tracts. T cell proliferation was higher in the BAL fluid but delayed and reduced in peripheral blood in aged animals. This delay in proliferation correlated with a reduced frequency of effector CD4 T cells in old animals. Aged animals also mobilized inflammatory cytokines to higher levels in the BAL fluid. Finally, we compared changes in gene expression using microarray analysis of BAL fluid samples. Our analyses revealed that the largest difference in host response between aged and young adult animals was detected at day 4 postinfection, with a significantly higher induction of genes associated with inflammation and the innate immune response in aged animals. Overall, our data suggest that, in the absence of preexisting antibodies, CA04 infection in aged macaques is associated with changes in innate and adaptive immune responses that were shown to correlate with increased disease severity in other respiratory disease models.