Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
J Virol. 2020 Feb 14;94(5). doi: 10.1128/JVI.01831-19.
Chronic viral infections. like those of humans with cytomegalovirus, human immunodeficiency virus (even when under antiretroviral therapy), and hepatitis C virus or those of mice with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13), result in immune dysfunction that predisposes the host to severe infections with unrelated pathogens. It is known that C57BL/6 (B6) mice are resistant to mousepox, a lethal disease caused by the orthopoxvirus ectromelia virus (ECTV), and that this resistance requires natural killer (NK) cells and other immune cells. We show that most B6 mice chronically infected with CL13 succumb to mousepox but that most of those that recovered from acute infection with the LCMV Armstrong (Arm) strain survive. We also show that B6 mice chronically infected with CL13 and those that recovered from Arm infection have a reduced frequency and a reduced number of NK cells. However, at steady state, NK cells in mice that have recovered from Arm infection mature normally and, in response to ECTV, get activated, become more mature, proliferate, and increase their cytotoxicity Conversely, in mice chronically infected with CL13, NK cells are immature and residually activated, and following ECTV infection, they do not mature, proliferate, or increase their cytotoxicity. Given the well-established importance of NK cells in resistance to mousepox, these data suggest that the NK cell dysfunction caused by CL13 persistence may contribute to the susceptibility of CL13-infected mice to mousepox. Whether chronic infections similarly affect NK cells in humans should be explored. Infection of adult mice with the clone 13 (CL13) strain of lymphocytic choriomeningitis virus (LCMV) is extensively used as a model of chronic infection. In this paper, we show that mice chronically infected with CL13 succumb to challenge with ectromelia virus (ECTV; the agent of mousepox) and that natural killer (NK) cells in CL13-infected mice are reduced in numbers and have an immature and partially activated phenotype but do respond to ECTV. These data may provide additional clues why humans chronically infected with certain pathogens are less resistant to viral diseases.
慢性病毒感染，如巨细胞病毒、人类免疫缺陷病毒（即便接受抗逆转录病毒治疗）和丙型肝炎病毒感染者，或淋巴细胞性脉络丛脑膜炎病毒（LCMV）CL13 株感染的小鼠，会导致免疫功能障碍，使宿主易发生无关病原体的严重感染。众所周知，C57BL/6（B6）小鼠对由正粘病毒属的细疹病毒（ECTV）引起的致死性鼠痘具有抗性，这种抗性需要自然杀伤（NK）细胞和其他免疫细胞。我们发现，大多数慢性感染 CL13 的 B6 小鼠会死于鼠痘，但大多数从 LCMV Armstrong（Arm）株急性感染中恢复的小鼠都存活了下来。我们还发现，慢性感染 CL13 的 B6 小鼠和从 Arm 感染中恢复的小鼠的 NK 细胞频率和数量都减少了。然而，在稳定状态下，从 Arm 感染中恢复的小鼠的 NK 细胞正常成熟，并且对 ECTV 作出反应时会被激活，变得更加成熟、增殖，并增加其细胞毒性。相反，在慢性感染 CL13 的小鼠中，NK 细胞不成熟且持续被激活，并且在 ECTV 感染后，它们不会成熟、增殖或增加其细胞毒性。鉴于 NK 细胞在抵抗鼠痘中的重要性已得到充分证实，这些数据表明 CL13 持续存在引起的 NK 细胞功能障碍可能导致 CL13 感染小鼠易感染鼠痘。慢性感染是否以类似方式影响人类的 NK 细胞，这一点值得进一步研究。感染成年小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV）CL13 株是慢性感染的广泛应用模型。在本文中，我们发现慢性感染 CL13 的小鼠会死于细疹病毒（ECTV；即鼠痘的病原体）的攻击，并且 CL13 感染小鼠的 NK 细胞数量减少，且具有不成熟和部分激活的表型，但对 ECTV 有反应。这些数据可能为解释为什么某些病原体慢性感染的人类对病毒性疾病的抵抗力较低提供了更多线索。
