Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines
Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines
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DOI：
10.4049/jimmunol.167.8.4574
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发表时间：
2001-10-15
影响因子：
4.4
通讯作者：
Sibley, LD
中科院分区：
文献类型：
--
作者：
Mordue, DG;Monroy, F;Sibley, LD
弓形虫的毒力受寄生虫的基因影响很大。无论宿主基因型或挑战剂量如何，I型菌株都会导致小鼠迅速死亡。相比之下，感染II型菌株的结果高度依赖于攻击剂量和宿主的基因。为了了解弓形虫病急性毒力的基础，我们在杂交小鼠中比较了弓形虫RH株(I型)和ME49/PTG株(II型)的低剂量和高剂量。毒力的差异反映在体内的生长速度只有轻微的不同，而且两种菌株都广泛传播到不同的组织。RH毒株的关键区别是在低剂量攻击后迅速达到高组织负荷的能力。由I型(RH)或II型(PTG)毒株感染引起的致死性感染伴随着血清中Th1细胞因子水平的极高水平，包括干扰素-γ、肿瘤坏死因子-α、白介素12和白介素18。在致死性感染期间，伴随着细胞因子水平升高的是广泛的肝脏损伤和淋巴变性。致死性感染RH株后存活时间的延长是通过中和IL-18提供的，而不是通过中和肿瘤坏死因子-α或干扰素-γ。低剂量的II型PTG株寄生虫非致死性感染的特点是适度诱导Th1细胞因子，导致感染得到控制，对宿主组织的损害最小。我们的发现证实，过度刺激免疫反应是急性弓形虫病的一个重要特征，而免疫反应通常是保护所必需的。
Virulence in Toxoplasma gondii is strongly influenced by the genotype of the parasite. Type I strains uniformly cause rapid death in mice regardless of the host genotype or the challenge dose. In contrast, the outcome of infections with type II strains is highly dependent on the challenge dose and the genotype of the host. To understand the basis of acute virulence in toxoplasmosis, we compared low and high doses of the RH strain (type I) and the ME49/PTG strain (type II) of T. gondii in outbred mice. Differences in virulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference in the virulent RH strain was the ability to reach high tissue burdens rapidly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated levels of Th1 cytokines in the serum, including IFN-gamma, TNF-alpha, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied the elevated levels of cytokines produced during lethal infection. Increased time of survival following lethal infection with the RH strain was provided by neutralization of IL-18, but not TNF-alpha or IFN-gamma. Nonlethal infections with a low dose of type II PTG strain parasites were characterized by a modest induction of Th1 cytokines that led to control of infection and minimal damage to host tissues. Our findings establish that overstimulation of immune responses that are normally necessary for protection is an important feature of acute toxoplasmosis.