Mechanisms of NK cell-macrophage Bacillus anthracis crosstalk: a balance between stimulation by spores and differential disruption by toxins.
Mechanisms of NK cell-macrophage Bacillus anthracis crosstalk: a balance between stimulation by spores and differential disruption by toxins.
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DOI：
10.1371/journal.ppat.1002481
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发表时间：
2012-01
期刊：
影响因子：
6.7
通讯作者：
Goossens PL
中科院分区：
文献类型：
--
作者：
Klezovich-Bénard M;Corre JP;Jusforgues-Saklani H;Fiole D;Burjek N;Tournier JN;Goossens PL
NK细胞通过天然的细胞毒作用和细胞因子的分泌，是防止微生物入侵和扩散的重要免疫效应细胞。炭疽芽胞杆菌芽胞能有效促进NK细胞产生干扰素-γ。本研究提供了炭疽杆菌激活NK细胞过程中的细胞因子和细胞信号的机制，以及细菌颠覆和逃避这一反应的策略。感染非产毒炭疽杆菌可诱导NK细胞和巨噬细胞重新聚集到小鼠引流淋巴结。感染期间产生的水肿性(ET)或致死性(LT)毒素损害了这种细胞募集。NK细胞耗尽导致全身性细菌传播加速。自然杀伤细胞对炭疽芽胞的干扰素-γ的产生是：(1)通过RAE-1-NKG2D与巨噬细胞的相互作用而依赖接触；(2)依赖IL-12、IL-18和IL-15，其中IL-12起关键作用并调节NK细胞和巨噬细胞的激活；以及(Iii)仅在最初的短时间窗内需要IL-18。炭疽杆菌毒素颠覆了两种NK细胞的基本功能。ET和LT通过不同的机制干扰干扰素-γ的产生。其作用于巨噬细胞和NK细胞，而ET主要作用于巨噬细胞，不改变NK细胞分泌γ的能力。相反，无论在体内还是体外，ET和LT都能抑制NK细胞的天然细胞毒作用。因此，ET的颠覆作用导致NK细胞功能的解离，并在不影响干扰素-γ分泌的情况下阻断了自然的细胞毒作用。这一过程的高效率强调了这种毒素在炭疽发病机制中可能发挥的影响，并突出了在免疫病理疾病中控制过度细胞毒性反应的潜在用途。因此，我们的发现例证了细菌刺激和逃避策略之间的微妙平衡。这突出了寄主固有防御和炭疽杆菌之间的串扰在最初的炭疽控制机制中的潜在含义。NK细胞是重要的免疫效应器，执行监视任务，并对转化、应激和病毒感染的细胞做出反应。它们代表着对抗癌症和病原体入侵的第一线防御。不同的病原体会触发不同的NK细胞激活途径。炭疽芽孢杆菌孢子是一种高度抵抗的形式，进入宿主并引发炭疽病。这种微生物通过急性细菌感染和毁灭性的毒血症相结合而致死。在目前的研究中，我们描述了NK细胞和孢子之间的串扰，以及炭疽杆菌用来逃避最初的控制机制和影响炭疽病发病的策略。我们的发现例证了孢子有效地驱动NK细胞产生高水平干扰素-γ的特性，以及用于激活的复杂途径，这需要细胞因子和细胞信号。炭疽杆菌通过其毒素瘫痪基本的NK细胞功能来颠覆这种反应。此外，炭疽杆菌的水肿性毒素可在不影响干扰素-γ分泌的情况下阻断天然的细胞毒作用。百日咳杆菌苏胞毒素具有相同的酶活性和相似的作用。这些毒素在体内阻断细胞毒作用的高效率意味着可能利用它们的颠覆活性来调节免疫病理疾病中的过度细胞毒反应。
NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-γ production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non-toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-γ production by NK cells in response to B. anthracis spores was: i) contact-dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-γ production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-γ secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-γ secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms. NK cells are important immune effectors that perform a surveillance task and react to transformed, stressed, and virally infected cells. They represent a first-line defence against cancer and pathogen invasion. Different pathogens trigger distinct NK-cell activation pathways. The Bacillus anthracis spore is the highly resistant form that enters the host and provokes anthrax. This microbe kills through a combination of acute bacterial infection and devastating toxemia. In the present study, we characterise the crosstalk between NK cells and spores, as well as the strategies used by B. anthracis to evade initial control mechanisms and impact anthrax pathogenesis. Our findings exemplify the spores' property to efficiently drive a high production of IFN-γ by NK cells, as well as the complex pathways used for activation which require both cytokine and cellular signaling. B. anthracis subverts this response through its toxins by paralysing essential NK cell functions. Furthermore, edema toxin from B. anthracis blocks natural cytotoxicity without affecting IFN-γ secretion. The CyaA toxin of Bordetella pertussis possesses the same enzymatic activity and has a similar effect. The high efficiency of these toxins in blocking cytotoxicity in vivo implies possible exploitation of their subverting activity to modulate excessive cytotoxic responses in immunopathological diseases.
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影响因子：
6.4
作者：
CROMARTIE, WJ;BLOOM, WL;WATSON, DW
通讯作者：
WATSON, DW
影响因子：
20.3
作者：
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影响因子：
3.1
作者：
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通讯作者：
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20.3
作者：
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Zitvogel, L