Easterbrook Judith D, Zink M Christine, Klein Sabra L
The W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15502-7. doi: 10.1073/pnas.0707453104. Epub 2007 Sep 18.
Hantaviruses are zoonotic pathogens that maintain a persistent infection in their reservoir hosts, yet the mechanisms mediating persistence remain unknown. Regulatory T cell responses cause persistent infection by suppressing proinflammatory and effector T cell activity; hantaviruses may exploit these responses to cause persistence. To test this hypothesis, male Norway rats were inoculated with Seoul virus and regulatory T cells were monitored during infection. Increased numbers of CD4(+)CD25(+)Forkhead box P3(+) T cells and expression of Forkhead box P3 and TGF-beta were observed in the lungs of male rats during persistent Seoul virus infection. To determine whether regulatory T cells modulate Seoul virus persistence, regulatory T cells were inactivated in male rats by using an anti-rat CD25 monoclonal antibody (NDS-63). Inactivation of regulatory T cells reduced the amount of Seoul virus RNA present in the lungs and the proportion of animals shedding viral RNA in saliva. Because regulatory T cells suppress proinflammatory-induced pathogenesis, pathologic observations in the lungs were evaluated during infection. Subclinical acute multifocal areas of hemorrhage and edema were noted in the lungs during infection; inactivation of regulatory T cells reduced the amount of pathologic foci. Expression of TNF was suppressed during the persistent phase of infection; inactivation of regulatory T cells eliminated the suppression of TNF. Taken together, these data suggest that regulatory T cells mediate Seoul virus persistence, possibly through elevated transcription and synthesis of TGF-beta and suppression of TNF. These data provide evidence of regulatory T cell involvement in the persistence of a zoonotic pathogen in its natural reservoir host.
汉坦病毒是一种人畜共患病原体，可在其储存宿主中维持持续感染，但其介导持续性感染的机制尚不清楚。调节性T细胞反应通过抑制促炎和效应T细胞活性导致持续感染；汉坦病毒可能利用这些反应来引发持续性感染。为了验证这一假设，将雄性挪威大鼠接种汉城病毒，并在感染期间监测调节性T细胞。在汉城病毒持续感染期间，雄性大鼠的肺中观察到CD4(+)CD25(+)叉头框P3(+) T细胞数量增加以及叉头框P3和转化生长因子-β的表达。为了确定调节性T细胞是否调节汉城病毒的持续性，通过使用抗大鼠CD25单克隆抗体（NDS-63）使雄性大鼠体内的调节性T细胞失活。调节性T细胞失活减少了肺中存在的汉城病毒RNA的量以及唾液中排出病毒RNA的动物比例。由于调节性T细胞抑制促炎诱导的发病机制，因此在感染期间评估了肺中的病理观察结果。感染期间肺中出现亚临床急性多灶性出血和水肿；调节性T细胞失活减少了病理病灶的数量。在感染的持续阶段，肿瘤坏死因子的表达受到抑制；调节性T细胞失活消除了对肿瘤坏死因子的抑制。综上所述，这些数据表明调节性T细胞可能通过提高转化生长因子-β的转录和合成以及抑制肿瘤坏死因子来介导汉城病毒的持续性。这些数据提供了调节性T细胞参与人畜共患病原体在其自然储存宿主中持续性感染的证据。
