Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Curr Biol. 2018 Jul 23;28(14):2338-2347.e6. doi: 10.1016/j.cub.2018.05.063. Epub 2018 Jul 12.
Skin-penetrating parasitic nematodes infect approximately one billion people worldwide and are a major source of neglected tropical disease [1-6]. Their life cycle includes an infective third-larval (iL3) stage that searches for hosts to infect in a poorly understood process that involves both thermal and olfactory cues. Here, we investigate the temperature-driven behaviors of skin-penetrating iL3s, including the human-parasitic threadworm Strongyloides stercoralis and the human-parasitic hookworm Ancylostoma ceylanicum. We show that human-parasitic iL3s respond robustly to thermal gradients. Like the free-living nematode Caenorhabditis elegans, human-parasitic iL3s show both positive and negative thermotaxis, and the switch between them is regulated by recent cultivation temperature [7]. When engaging in positive thermotaxis, iL3s migrate toward temperatures approximating mammalian body temperature. Exposing iL3s to a new cultivation temperature alters the thermal switch point between positive and negative thermotaxis within hours, similar to the timescale of thermal plasticity in C. elegans [7]. Thermal plasticity in iL3s may enable them to optimize host finding on a diurnal temperature cycle. We show that temperature-driven responses can be dominant in multisensory contexts such that, when thermal drive is strong, iL3s preferentially engage in temperature-driven behaviors despite the presence of an attractive host odorant. Finally, targeted mutagenesis of the S. stercoralis tax-4 homolog abolishes heat seeking, providing the first evidence that parasitic host-seeking behaviors are generated through an adaptation of sensory cascades that drive environmental navigation in C. elegans [7-10]. Together, our results provide insight into the behavioral strategies and molecular mechanisms that allow skin-penetrating nematodes to target humans.
皮肤穿透性寄生线虫感染全球约 10 亿人，是被忽视的热带病的主要来源[1-6]。它们的生命周期包括感染性的第三幼虫（iL3）阶段，该阶段在一个理解甚少的过程中寻找宿主进行感染，该过程既涉及热刺激又涉及嗅觉线索。在这里，我们研究了皮肤穿透性 iL3 的温度驱动行为，包括人体寄生的丝虫 Strongyloides stercoralis 和人体寄生的钩虫 Ancylostoma ceylanicum。我们表明，人体寄生的 iL3 对温度梯度表现出强烈的反应。与自由生活的线虫秀丽隐杆线虫一样，人体寄生的 iL3 表现出正向和负向趋温性，它们之间的转换由最近的培养温度调节[7]。当进行正向趋温性时，iL3 向接近哺乳动物体温的温度迁移。将 iL3 暴露于新的培养温度会在数小时内改变正向和负向趋温性之间的热开关点，与 C. elegans 的热可塑性时间尺度相似[7]。iL3 的热可塑性可能使它们能够优化在昼夜温度周期中的宿主寻找。我们表明，温度驱动的反应在多感觉环境中可能占主导地位，因此，当热驱动力强时，iL3 会优先进行温度驱动的行为，尽管存在有吸引力的宿主气味。最后，靶向突变 S. stercoralis tax-4 同源物会消除热寻求，这首次提供了寄生虫宿主寻求行为是通过适应驱动 C. elegans 环境导航的感觉级联产生的证据[7-10]。总之，我们的结果提供了对允许皮肤穿透性线虫靶向人类的行为策略和分子机制的深入了解。
