Ivinson Karen, Deliyannis Georgia, McNabb Leanne, Grollo Lara, Gilbertson Brad, Jackson David, Brown Lorena E
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
J Virol. 2017 Jun 26;91(14). doi: 10.1128/JVI.00624-17. Print 2017 Jul 15.
It is possible to model the progression of influenza virus from the upper respiratory tract to the lower respiratory tract in the mouse using viral inoculum delivered in a restricted manner to the nose. In this model, infection with the A/Udorn/307/72 (Udorn) strain of virus results ultimately in high viral titers in both the trachea and lungs. In contrast, the A/Puerto Rico/8/34 (PR8) strain causes an infection that is almost entirely limited to the nasal passages. The factors that govern the progression of virus down the respiratory tract are not well understood. Here, we show that, while PR8 virus grows to high titers in the nose, an inhibitor present in the saliva blocks further progression of infection to the trachea and lungs and renders an otherwise lethal dose of virus completely asymptomatic. , the salivary inhibitor was capable of potent neutralization of PR8 virus and an additional 20 strains of type A virus and two type B strains that were tested. The exceptions were Udorn virus and the closely related H3N2 strains A/Port Chalmers/1/73 and A/Victoria/3/75. Characterization of the salivary inhibitor showed it to be independent of sialic acid and other carbohydrates for its function. This and other biochemical properties, together with its virus strain specificity and function, indicate that the mouse salivary inhibitor is a previously undescribed innate inhibitory molecule that may have evolved to provide pulmonary protection of the species from fatal influenza virus infection. Influenza A virus occasionally jumps from aquatic birds, its natural host, into mammals to cause outbreaks of varying severity, including pandemics in humans. Despite the laboratory mouse being used as a model to study influenza virus pathogenesis, natural outbreaks of influenza have not been reported in the species. Here, we shed light on one mechanism that might allow mice to be protected from influenza in the wild. We show that virus deposited in the mouse upper respiratory tract will not progress to the lower respiratory tract due to the presence of a potent inhibitor of the virus in saliva. Containing inhibitor-sensitive virus to the upper respiratory tract renders an otherwise lethal infection subclinical. This knowledge sheds light on how natural inhibitors may have evolved to improve survival in this species.
利用以受限方式经鼻腔接种病毒悬液的方法，在小鼠体内模拟流感病毒从上呼吸道向下呼吸道的进展过程是可行的。在这个模型中，用A/Udorn/307/72（乌东）病毒株感染最终会导致气管和肺部出现高病毒滴度。相比之下，A/波多黎各/8/34（PR8）病毒株引起的感染几乎完全局限于鼻腔。目前对于控制病毒在呼吸道中进展的因素还了解甚少。在此，我们表明，虽然PR8病毒在鼻腔中能生长到高滴度，但唾液中存在的一种抑制剂会阻止感染进一步发展到气管和肺部，并使原本致死剂量的病毒完全无症状。唾液抑制剂能够有效中和PR8病毒以及另外20种经测试的甲型病毒株和两种乙型病毒株。例外的是乌东病毒以及密切相关的H3N2病毒株A/查尔姆斯港/1/73和A/维多利亚/3/75。对唾液抑制剂的特性分析表明，其功能独立于唾液酸和其他碳水化合物。这种以及其他生化特性，连同其病毒株特异性和功能，表明小鼠唾液抑制剂是一种此前未被描述的天然抑制分子，可能已经进化以保护该物种的肺部免受致命流感病毒感染。甲型流感病毒偶尔会从其天然宿主水鸟传播到哺乳动物中，引发不同严重程度的疫情，包括人类大流行。尽管实验室小鼠被用作研究流感病毒发病机制的模型，但该物种尚未有自然爆发流感的报道。在此，我们揭示了一种可能使小鼠在野外免受流感感染的机制。我们表明，由于唾液中存在一种强效病毒抑制剂，沉积在小鼠上呼吸道的病毒不会进展到下呼吸道。将对抑制剂敏感的病毒限制在上呼吸道会使原本致死的感染成为亚临床感染。这一知识揭示了天然抑制剂可能是如何进化以提高该物种的生存能力的。
