Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
Division of Basic Biomedical Sciences, University of South Dakota, 414 E Clark St, Vermillion, South Dakota 57069.
Proc Natl Acad Sci U S A. 2022 Feb 22;119(8). doi: 10.1073/pnas.2118535119.
Functional plasticity of innate lymphoid cells (ILCs) and T cells is regulated by host environmental cues, but the influence of pathogen-derived virulence factors has not been described. We now report the interplay between host interferon (IFN)-γ and viral PB1-F2 virulence protein in regulating the functions of ILC2s and T cells that lead to recovery from influenza virus infection of mice. In the absence of IFN-γ, lung ILC2s from mice challenged with the A/California/04/2009 (CA04) H1N1 virus, containing nonfunctional viral PB1-F2, initiated a robust IL-5 response, which also led to improved tissue integrity and increased survival. Conversely, challenge with Puerto Rico/8/1934 (PR8) H1N1 virus expressing fully functional PB1-F2, suppressed IL-5 ILC2 responses, and induced a dominant IL-13 CD8 T cell response, regardless of host IFN-γ expression. IFN-γ-deficient mice had increased survival and improved tissue integrity following challenge with lethal doses of CA04, but not PR8 virus, and increased resistance was dependent on the presence of IFN-γR ILC2s. Reverse-engineered influenza viruses differing in functional PB1-F2 activity induced ILC2 and T cell phenotypes similar to the PB1-F2 donor strains, demonstrating the potent role of viral PB1-F2 in host resistance. These results show the ability of a pathogen virulence factor together with host IFN-γ to regulate protective pulmonary immunity during influenza infection.
先天淋巴细胞（ILC）和 T 细胞的功能可塑性受宿主环境线索的调节，但尚未描述病原体衍生的毒力因子的影响。我们现在报告宿主干扰素（IFN）-γ和病毒 PB1-F2 毒力蛋白之间的相互作用，调节 ILC2 和 T 细胞的功能，从而导致小鼠流感病毒感染的恢复。在缺乏 IFN-γ 的情况下，来自挑战 A/加利福尼亚/04/2009（CA04）H1N1 病毒的小鼠的肺 ILC2 启动了强烈的 IL-5 反应，这也导致组织完整性提高和存活率增加。相反，用表达完全功能 PB1-F2 的波多黎各/8/1934（PR8）H1N1 病毒进行挑战，抑制了 IL-5 ILC2 反应，并诱导了占主导地位的 IL-13 CD8 T 细胞反应，而与宿主 IFN-γ 的表达无关。在接受致死剂量的 CA04 挑战后，IFN-γ 缺陷小鼠的存活率提高，组织完整性改善，但对 PR8 病毒则不然，并且增加的抗性依赖于 IFN-γR ILC2 的存在。在功能 PB1-F2 活性不同的反向工程流感病毒诱导的 ILC2 和 T 细胞表型类似于 PB1-F2 供体株，证明了病毒 PB1-F2 在宿主抗性中的强大作用。这些结果表明，病原体毒力因子与宿主 IFN-γ 一起，能够在流感感染期间调节保护性肺免疫。
