Yoneto T, Yoshimoto T, Wang C R, Takahama Y, Tsuji M, Waki S, Nariuchi H
Department of Allergology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Infect Immun. 1999 May;67(5):2349-56. doi: 10.1128/IAI.67.5.2349-2356.1999.
We have examined the roles of gamma interferon (IFN-gamma), nitric oxide (NO), and natural killer (NK) cells in the host resistance to infection with the blood-stage malarial parasite Plasmodium berghei XAT, an irradiation-induced attenuated variant of the lethal strain P. berghei NK65. Although the infection with P. berghei XAT enhanced NK cell lytic activity of splenocytes, depletion of NK1.1(+) cells caused by the treatment of mice with anti-NK1.1 antibody affected neither parasitemia nor IFN-gamma production by their splenocytes. The P. berghei XAT infection induced a large amount of NO production by splenocytes during the first peak of parasitemia, while P. berghei NK65 infection induced a small amount. Unexpectedly, however, mice deficient in inducible nitric oxide synthase (iNOS-/-) cleared P. berghei XAT after two peaks of parasitemia were observed, as occurred for wild-type control mice. Although the infected iNOS-/- mouse splenocytes did not produce a detectable level of NO, they produced an amount of IFN-gamma comparable to that produced by wild-type control mouse splenocytes, and treatment of these mice with neutralizing anti-IFN-gamma antibody led to the progression of parasitemia and fatal outcome. CD4(-/-) mice infected with P. berghei XAT could not clear the parasite, and all these mice died with apparently reduced IFN-gamma production. Furthermore, treatment with carrageenan increased the susceptibility of mice to P. berghei XAT infection. These results suggest that neither NO production nor NK cell activation is critical for the resistance to P. berghei XAT infection and that IFN-gamma plays an important role in the elimination of malarial parasites, possibly by the enhancement of phagocytic activity of macrophages.
我们研究了γ干扰素（IFN-γ）、一氧化氮（NO）和自然杀伤（NK）细胞在宿主抵抗血液期疟原虫伯氏疟原虫XAT感染中的作用，XAT是致死性伯氏疟原虫NK65株经辐射诱导的减毒株。尽管感染伯氏疟原虫XAT可增强脾细胞的NK细胞裂解活性，但用抗NK1.1抗体处理小鼠导致NK1.1(+)细胞耗竭，这对其脾细胞的寄生虫血症和IFN-γ产生均无影响。伯氏疟原虫XAT感染在寄生虫血症的第一个高峰期间诱导脾细胞产生大量NO，而伯氏疟原虫NK65感染诱导产生的量较少。然而，出乎意料的是，在观察到寄生虫血症出现两个高峰后，缺乏诱导型一氧化氮合酶的小鼠（iNOS-/-）清除了伯氏疟原虫XAT，野生型对照小鼠也是如此。尽管受感染的iNOS-/-小鼠脾细胞未产生可检测水平的NO，但它们产生的IFN-γ量与野生型对照小鼠脾细胞产生的量相当，用中和抗IFN-γ抗体处理这些小鼠会导致寄生虫血症进展并导致致命结局。感染伯氏疟原虫XAT的CD4(-/-)小鼠无法清除寄生虫，所有这些小鼠均死亡，且IFN-γ产生明显减少。此外，用角叉菜胶处理会增加小鼠对伯氏疟原虫XAT感染的易感性。这些结果表明，NO产生和NK细胞激活对抵抗伯氏疟原虫XAT感染均不关键，且IFN-γ在消除疟原虫中起重要作用，可能是通过增强巨噬细胞的吞噬活性来实现的。
