Publicover Jean, Ramsburg Elizabeth, Robek Michael, Rose John K
Section of Microbial Pathogenesis, Yale University School of Medicine, 310 Cedar St., New Haven, CT 06510, USA.
J Virol. 2006 Jul;80(14):7028-36. doi: 10.1128/JVI.00478-06.
Vesicular stomatitis virus (VSV) matrix (M) protein blocks host mRNA export from the nucleus and thereby inhibits interferon induction in infected cells. M mutants with mutations of methionine 51 (M51) lack this shutoff function. We examined pathogenesis of a VSV M mutant with a deletion of M51 (VSVDeltaM51) after intranasal infection of BALB/c mice and found an unexpected phenotype. Mice that received VSVDeltaM51 experienced a more rapid but overall less severe weight loss than mice that received the recombinant wild-type VSV (rwtVSV). Rapid weight loss was not explained by faster initial replication because VSVDeltaM51 replication was controlled faster than rwtVSV replication in the lungs and did not spread systemically like rwtVSV. This faster control of VSVDeltaM51 correlated with a more rapid induction of interferon in the lung. Because tumor necrosis factor alpha (TNF-alpha) is associated with weight loss, we examined TNF-alpha induction in mice infected with rwtVSV or VSVDeltaM51. We found more-rapid induction of TNF-alpha by the mutant at early times after infection, while rwtVSV induced more TNF-alpha later in infection. This result suggested that TNF-alpha induction might explain both the rapid weight loss caused by the mutant and the overall greater weight loss caused by the rwtVSV. Using TNF-alpha knockout mice (C57BL/6 background), we showed that weight loss following rwtVSV infection was greatly reduced in the absence of TNF-alpha. Although the rapid weight loss caused by VSVDeltaM51 was less pronounced in C57BL/6 mice, it was eliminated in the absence of TNF-alpha. These results indicate a role for TNF-alpha in the pathogenesis of VSV.
水泡性口炎病毒（VSV）的基质（M）蛋白可阻断宿主mRNA从细胞核输出，从而抑制受感染细胞中的干扰素诱导。甲硫氨酸51（M51）发生突变的M突变体缺乏这种阻断功能。我们在对BALB/c小鼠进行鼻内感染后，研究了缺失M51的VSV M突变体（VSVDeltaM51）的发病机制，发现了一个意外的表型。与接受重组野生型VSV（rwtVSV）的小鼠相比，接受VSVDeltaM51的小鼠体重减轻更快，但总体上严重程度较低。体重快速减轻并非由更快的初始复制所解释，因为VSVDeltaM51在肺部的复制比rwtVSV的复制更快受到控制，并且不像rwtVSV那样全身扩散。对VSVDeltaM51的这种更快控制与肺中干扰素的更快诱导相关。由于肿瘤坏死因子α（TNF-α）与体重减轻有关，我们研究了感染rwtVSV或VSVDeltaM51的小鼠中TNF-α的诱导情况。我们发现突变体在感染后的早期能更快地诱导TNF-α，而rwtVSV在感染后期诱导更多的TNF-α。这一结果表明，TNF-α的诱导可能解释了突变体导致的快速体重减轻以及rwtVSV导致的总体更大体重减轻。使用TNF-α基因敲除小鼠（C57BL/6背景），我们发现，在没有TNF-α的情况下，rwtVSV感染后的体重减轻大大减少。尽管VSVDeltaM51在C57BL/6小鼠中引起的快速体重减轻不太明显，但在没有TNF-α的情况下这种情况被消除了。这些结果表明TNF-α在VSV发病机制中发挥作用。
