Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice
Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice
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DOI：
10.1128/jvi.01857-08
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Varga, Steven M.
中科院分区：
文献类型：
--
作者：
Khanolkar, Aaruni;Hartwig, Stacey M.;Varga, Steven M.
严重急性呼吸综合征(SARS)以严重的急性肺部炎症为特征，病死率高。尽管SARS冠状病毒(SARS-CoV)已被确认为SARS的病原体，但由于缺乏合适的动物模型来概括人类疾病，深入了解SARS的潜在疾病发病机制一直受到阻碍。鼻腔(I.N.)冠状病毒1型小鼠肝炎病毒株(MHV-1)感染A/J小鼠可引起一种高致死率的急性呼吸道疾病，在病理上与人类SARS-CoV感染有许多相似之处。在本研究中，我们检测了MHV-1感染小鼠(A/J、C3H/HeJ和BALB/c)和耐药株(C57BL/6)的病毒复制和肺部炎症的特点。病毒复制和分布与A/J、BALB/c、C3H/HeJ和C57BL/6小鼠的相对易感性无关。为了进一步明确宿主遗传背景在影响MHV-1诱导的疾病易感性中的作用，我们检测了14个不同的近交系小鼠。巴尔布。B和BALB/c小鼠表现出MHV-1诱导的体重减轻，而所有其他品系的H-2(B)和H-2(D)小鼠在MHV-1感染后没有表现出任何疾病迹象。H-2(K)小鼠表现出中等易感性，其中C3H/HeJ小鼠表现出最严重的疾病。C3H/HeJ小鼠编码Toll样受体4(TLR4)的基因存在自然突变，这种突变会扰乱TLR4信号。C3H/HeJ小鼠在I.N后表现出更高的发病率和死亡率。MHV-1感染与野生型C3H/HEN小鼠的比较。我们的结果表明TLR4在呼吸道冠状病毒的致病中起重要作用。
Severe acute respiratory syndrome (SARS) is characterized by substantial acute pulmonary inflammation with a high mortality rate. Despite the identification of SARS coronavirus (SARS-CoV) as the etiologic agent of SARS, a thorough understanding of the underlying disease pathogenesis has been hampered by the lack of a suitable animal model that recapitulates the human disease. Intranasal (i.n.) infection of A/J mice with the CoV mouse hepatitis virus strain 1 (MHV-1) induces an acute respiratory disease with a high lethality rate that shares several pathological similarities with SARS-CoV infection in humans. In this study, we examined virus replication and the character of pulmonary inflammation induced by MHV-1 infection in susceptible (A/J, C3H/HeJ, and BALB/c) and resistant (C57BL/6) strains of mice. Virus replication and distribution did not correlate with the relative susceptibilities of A/J, BALB/ c, C3H/HeJ, and C57BL/6 mice. In order to further define the role of the host genetic background in influencing susceptibility to MHV-1-induced disease, we examined 14 different inbred mouse strains. BALB. B and BALB/ c mice exhibited MHV-1-induced weight loss, whereas all other strains of H-2(b) and H-2(d) mice did not show any signs of disease following MHV-1 infection. H-2(k) mice demonstrated moderate susceptibility, with C3H/HeJ mice exhibiting the most severe disease. C3H/HeJ mice harbor a natural mutation in the gene that encodes Toll-like receptor 4 (TLR4) that disrupts TLR4 signaling. C3H/HeJ mice exhibit enhanced morbidity and mortality following i.n. MHV-1 infection compared to wild-type C3H/HeN mice. Our results indicate that TLR4 plays an important role in respiratory CoV pathogenesis.