Department of Biological Sciences and Center for Modeling Complex Interactions, University of Idaho, Moscow, Idaho, USA.
Idaho WWAMI Medical Education Program, University of Idaho, Moscow, Idaho, USA.
J Virol. 2018 Nov 12;92(23). doi: 10.1128/JVI.00881-18. Print 2018 Dec 1.
Influenza viruses and rhinoviruses are responsible for a large number of acute respiratory viral infections in human populations and are detected as copathogens within hosts. Clinical and epidemiological studies suggest that coinfection by rhinovirus and influenza virus may reduce disease severity and that they may also interfere with each other's spread within a host population. To determine how coinfection by these two unrelated respiratory viruses affects pathogenesis, we established a mouse model using a minor serogroup rhinovirus (rhinovirus strain 1B [RV1B]) and mouse-adapted influenza A virus (A/Puerto Rico/8/1934 [PR8]). Infection of mice with RV1B 2 days before PR8 reduced the severity of infection by a low or medium, but not high, dose of PR8. Disease attenuation was associated with an early inflammatory response in the lungs and enhanced clearance of PR8. However, coinfection by RV1B did not reduce PR8 viral loads early in infection or inhibit replication of PR8 within respiratory epithelia or Inflammation in coinfected mice remained focal compared to diffuse inflammation and damage in the lungs of mice infected by PR8. The timing of RV1B coinfection was a critical determinant of protection, suggesting that sufficient time is needed to induce this response. Finally, disease attenuation was not unique to RV1B: dose-dependent coinfection by a murine coronavirus (mouse hepatitis virus strain 1 [MHV-1]) also reduced the severity of PR8 infection. Unlike RV1B, coinfection with MHV-1 reduced early PR8 replication, which was associated with upregulation of beta interferon (IFN-β) expression. This model is critical for understanding the mechanisms responsible for influenza disease attenuation during coinfection by unrelated respiratory viruses. Viral infections in the respiratory tract can cause severe disease and are responsible for a majority of pediatric hospitalizations. Molecular diagnostics have revealed that approximately 20% of these patients are infected by more than one unrelated viral pathogen. To understand how viral coinfection affects disease severity, we inoculated mice with a mild viral pathogen (rhinovirus or murine coronavirus), followed 2 days later by a virulent viral pathogen (influenza A virus). This model demonstrated that rhinovirus can reduce the severity of influenza A virus, which corresponded with an early but controlled inflammatory response in the lungs and early clearance of influenza A virus. We further determined the dose and timing parameters that were important for effective disease attenuation and showed that influenza disease is also reduced by coinfection with a murine coronavirus. These findings demonstrate that coinfecting viruses can alter immune responses and pathogenesis in the respiratory tract.
流感病毒和鼻病毒是导致人群中大量急性呼吸道病毒感染的原因，并在宿主中被检测为共病原体。临床和流行病学研究表明，鼻病毒和流感病毒的合并感染可能会降低疾病的严重程度，并且它们也可能相互干扰在宿主人群中的传播。为了确定这两种无关的呼吸道病毒的合并感染如何影响发病机制，我们使用一种次要血清群鼻病毒（鼻病毒 1B 株[RV1B]）和适应小鼠的流感 A 病毒（A/波多黎各/8/1934[PR8]）建立了小鼠模型。在感染 PR8 之前 2 天感染 RV1B 可降低低或中剂量 PR8 感染的严重程度，但不能降低高剂量 PR8 感染的严重程度。疾病减轻与肺部早期炎症反应和 PR8 的清除增强有关。然而，RV1B 的合并感染并没有降低感染早期 PR8 的病毒载量，也没有抑制 PR8 在呼吸道上皮细胞内的复制或减轻感染小鼠肺部的炎症。与感染 PR8 的小鼠肺部弥漫性炎症和损伤相比，合并感染小鼠的炎症仍为局灶性。合并感染 RV1B 的时间是保护的关键决定因素，这表明需要足够的时间来诱导这种反应。最后，疾病减轻并非 RV1B 所特有：与小鼠冠状病毒（鼠肝炎病毒 1 株[MHV-1]）的剂量依赖性合并感染也降低了 PR8 感染的严重程度。与 RV1B 不同，MHV-1 的合并感染降低了 PR8 的早期复制，这与β干扰素（IFN-β）表达的上调有关。该模型对于理解在无关的呼吸道病毒合并感染期间导致流感疾病减轻的机制至关重要。呼吸道病毒感染可导致严重疾病，并且是大多数儿科住院治疗的原因。分子诊断显示，大约 20%的这些患者感染了两种以上无关的病毒病原体。为了了解病毒合并感染如何影响疾病严重程度，我们用一种轻度病毒病原体（鼻病毒或小鼠冠状病毒）感染小鼠，2 天后再用一种毒力较强的病毒病原体（流感 A 病毒）感染。该模型表明，鼻病毒可降低流感 A 病毒的严重程度，这与肺部的早期但受控制的炎症反应和流感 A 病毒的早期清除相对应。我们进一步确定了有效疾病减轻所必需的剂量和时间参数，并表明流感疾病也可通过与小鼠冠状病毒的合并感染来减轻。这些发现表明，合并感染的病毒可以改变呼吸道的免疫反应和发病机制。
