INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France ; Universite Francois Rabelais, UMR1282 Infectiologie et Sante Publique, Tours, France.
Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France.
PLoS Pathog. 2013;9(12):e1003801. doi: 10.1371/journal.ppat.1003801. Epub 2013 Dec 19.
Cryptosporidium parvum is a zoonotic protozoan parasite found worldwide, that develops only in the gastrointestinal epithelium and causes profuse diarrhea. Using a mouse model of C. parvum infection, we demonstrated by conditional depletion of CD11c+ cells that these cells are essential for the control of the infection both in neonates and adults. Neonates are highly susceptible to C. parvum but the infection is self-limited, whereas adults are resistant unless immunocompromised. We investigated the contribution of DC to the age-dependent susceptibility to infection. We found that neonates presented a marked deficit in intestinal CD103+ DC during the first weeks of life, before weaning, due to weak production of chemokines by neonatal intestinal epithelial cells (IEC). Increasing the number of intestinal CD103+ DC in neonates by administering FLT3-L significantly reduced susceptibility to the infection. During infections in neonates, the clearance of the parasite was preceded by a rapid recruitment of CD103+ DC mediated by CXCR3-binding chemokines produced by IEC in response to IFNγ. In addition to this key role in CD103+ DC recruitment, IFNγ is known to inhibit intracellular parasite development. We demonstrated that during neonatal infection CD103+ DC produce IL-12 and IFNγ in the lamina propria and the draining lymph nodes. Thus, CD103+DC are key players in the innate immune control of C. parvum infection in the intestinal epithelium. The relative paucity of CD103+ DC in the neonatal intestine contributes to the high susceptibility to intestinal infection.
微小隐孢子虫是一种在全球范围内发现的动物源原生动物寄生虫，仅在胃肠道上皮细胞中发育，并导致大量腹泻。我们使用微小隐孢子虫感染的小鼠模型，通过条件性耗尽 CD11c+细胞证明，这些细胞对于控制感染是必不可少的，无论是在新生儿和成年人中。新生儿极易感染微小隐孢子虫，但感染是自限性的，而成年人则不易感染，除非免疫功能低下。我们研究了 DC 对感染的年龄依赖性易感性的贡献。我们发现，新生儿在生命的头几周，即断奶前，由于新生儿肠道上皮细胞 (IEC) 产生的趋化因子较少，肠道中 CD103+DC 明显减少。通过给予 FLT3-L 增加新生儿肠道中 CD103+DC 的数量，可显著降低感染的易感性。在新生儿感染期间，寄生虫的清除先于 CXCR3 结合趋化因子介导的 CD103+DC 的快速募集，这些趋化因子由 IEC 在 IFNγ 刺激下产生。除了在 CD103+DC 募集中的关键作用外，IFNγ 还已知可抑制细胞内寄生虫的发育。我们证明，在新生儿感染期间，CD103+DC 在固有层和引流淋巴结中产生 IL-12 和 IFNγ。因此，CD103+DC 是肠道上皮中微小隐孢子虫感染固有免疫控制的关键参与者。新生儿肠道中 CD103+DC 的相对缺乏导致对肠道感染的高度易感性。
