Lethal Monkeypox Virus Infection of CAST/EiJ Mice Is Associated with a Deficient Gamma Interferon Response
Lethal Monkeypox Virus Infection of CAST/EiJ Mice Is Associated with a Deficient Gamma Interferon Response
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DOI：
10.1128/jvi.00162-12
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发表时间：
2012-09-01
影响因子：
5.4
通讯作者：
Moss, Bernard
中科院分区：
文献类型：
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作者：
Earl, Patricia L.;Americo, Jeffrey L.;Moss, Bernard
猴痘病毒(MPXV)在非洲流行，在那里它会在人类身上引起类似天花的疾病。最近将感染MPXV的动物输入美国，增加了全球传播的可能性。啮齿动物是MPXV的主要宿主，各种这样的动物，即使是那些原产于北美的动物，也很容易受到影响。相比之下，常见的近交系小鼠，包括BALB/c和C57BL/6，对MPXV具有很强的抵抗力。然而，包括CAST/EIJ在内的几个来源于野生小鼠的近交系小鼠在相对较低的MPXV接种量下表现出发病率和死亡率。阐明CAST/EIJ小鼠易感性的基础有助于理解MPXV的致病性和宿主防御机制，并提高该小鼠品系作为评价治疗和疫苗的模型系统的价值。在这里，我们比较了病毒在CAST/EIJ小鼠和耐药株BALB/c小鼠中的传播和诱导的细胞因子产生。鼻腔感染后，病毒在两个菌株的肺部都发生了强劲的复制，尽管BALB/c需要相对较高的接种量。然而，尽管在CAST/EIJ小鼠中传播到其他内脏是快速和有效的，但在BALB/c小鼠中病毒主要局限于肺部。病毒复制时，BALB/c小鼠肺部可产生干扰素和CCL5，而CAST/EIJ小鼠则无。通过将小鼠细胞因子滴鼻给CAST/EIJ小鼠和由此产生的对MPXV的保护作用，证明了干扰素-γ在预防MPXV病中的重要性。此外，干扰素-γ基因或干扰素-γ受体基因失活的C57BL/6小鼠对MPXV的敏感性增强。
Monkeypox virus (MPXV) is endemic in Africa, where it causes disease in humans resembling smallpox. A recent importation of MPXV-infected animals into the United States raises the possibility of global spread. Rodents comprise the major reservoir of MPXV, and a variety of such animals, even those native to North America, are susceptible. In contrast, common inbred strains of mice, including BALB/c and C57BL/6, are greatly resistant to MPXV. However, several inbred strains of mice derived from wild mice, including CAST/EiJ, exhibit morbidity and mortality at relatively low inoculums of MPXV. Elucidating the basis for the susceptibility of CAST/EiJ mice could contribute to an understanding of MPXV pathogenicity and host defense mechanisms and enhance the value of this mouse strain as a model system for evaluation of therapeutics and vaccines. Here we compared virus dissemination and induced cytokine production in CAST/EiJ mice to those in the resistant BALB/c strain. Following intranasal infection, robust virus replication occurred in the lungs of both strains, although a relatively higher inoculum was required for BALB/c. However, while spread to other internal organs was rapid and efficient in CAST/EiJ mice, the virus was largely restricted to the lungs in BALB/c mice. Gamma interferon (IFN-gamma) and CCL5 were induced in lungs of BALB/c mice concomitant with virus replication but not in CAST/EiJ mice. The importance of IFN-gamma in protection against MPXV disease was demonstrated by the intranasal administration of the mouse cytokine to CAST/EiJ mice and the resulting protection against MPXV. Furthermore, C57BL/6 mice with inactivation of the IFN-gamma gene or the IFN-gamma receptor gene exhibited enhanced sensitivity to MPXV.