Pedra Joao H F, Sutterwala Fayyaz S, Sukumaran Bindu, Ogura Yasunori, Qian Feng, Montgomery Ruth R, Flavell Richard A, Fikrig Erol
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
J Immunol. 2007 Oct 1;179(7):4783-91. doi: 10.4049/jimmunol.179.7.4783.
Anaplasma phagocytophilum is an obligate intracellular pathogen that resides within neutrophils and can cause fever, pancytopenia, or death. IFN-gamma plays a critical role in the control of A. phagocytophilum; however, the mechanisms that regulate IFN-gamma production remain unclear. In this study, we demonstrate that apoptotic specklike protein with a caspase-activating recruiting domain (ASC)/PYCARD, a central adaptor molecule in the Nod-like receptor (NLR) pathway, regulates the IL-18/IFN-gamma axis during A. phagocytophilum infection through its effect on caspase-1. Caspase-1- and asc-null mice were more susceptible than control animals to A. phagocytophilum infection due to the absence of IL-18 secretion and reduced IFN-gamma levels in the peripheral blood. Moreover, caspase-1 and ASC deficiency reduced CD4+ T cell-mediated IFN-gamma after in vitro restimulation with A. phagocytophilum. The NLR family member IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN-gamma production in response to A. phagocytophilum. Taken together, our data demonstrate that ASC and caspase-1 are critical for IFN-gamma-mediated control of A. phagocytophilum infection.
嗜吞噬细胞无形体是一种专性胞内病原体，寄生于中性粒细胞内，可引起发热、全血细胞减少或死亡。干扰素-γ在控制嗜吞噬细胞无形体方面发挥着关键作用；然而，调节干扰素-γ产生的机制仍不清楚。在本研究中，我们证明了含半胱天冬酶激活招募结构域的凋亡斑点样蛋白（ASC）/PYCARD，一种核苷酸结合寡聚化结构域样受体（NLR）途径中的核心衔接分子，在嗜吞噬细胞无形体感染期间通过其对半胱天冬酶-1的作用调节白细胞介素-18/干扰素-γ轴。由于缺乏白细胞介素-18分泌以及外周血中干扰素-γ水平降低，半胱天冬酶-1缺陷型和asc基因敲除小鼠比对照动物更易感染嗜吞噬细胞无形体。此外，半胱天冬酶-1和ASC缺陷降低了用嗜吞噬细胞无形体进行体外再刺激后CD4 + T细胞介导的干扰素-γ产生。NLR家族成员IPAF/NLRC4而非NALP3/NLRP3在对嗜吞噬细胞无形体产生干扰素-γ的反应中部分发挥作用。综上所述，我们的数据表明ASC和半胱天冬酶-1对于干扰素-γ介导的嗜吞噬细胞无形体感染控制至关重要。
