Eosinophils sustain chronic nematode infection

描述（由申请人提供）：建立慢性感染是许多寄生虫病的重要特征。支持寄生虫在受感染宿主中长期存活的免疫调节机制仍然知之甚少。当第一阶段的幼虫感染骨骼肌细胞时，旋毛虫线虫的慢性感染就建立起来了。我们发现嗜酸性粒细胞有助于随后的肌炎，同时促进保护幼虫免受免疫介导的破坏。具体来说，我们发现，肌肉幼虫被大量杀死在两个小鼠品系是缺乏嗜酸性粒细胞。这些新的观察提示重新评估线虫感染期间嗜酸性粒细胞功能的长期范式。我们的假设是，嗜酸性粒细胞防止经典的激活巨噬细胞，以保存幼虫在肌肉中。这可以直接或间接地完成，我们的目标是阐明嗜酸性粒细胞对浸润感染部位的细胞的影响。将通过操纵寄生虫存活测定中的相关介质来测试这些效应的显著性。我们已经确定了幼虫容易被杀死的发育阶段，我们的具体目标是识别嗜酸性粒细胞缺陷小鼠中浸润细胞的功能偏差，并用过继转移的嗜酸性粒细胞拯救幼虫。提出的研究将推进我们的长期目标，以确定慢性线虫感染期间的免疫调节机制。这些机制通过控制受感染宿主的疾病强度，同时促进寄生虫在宿主群体中的存活，达到微妙的平衡。公共卫生相关性：慢性感染是人类疾病和痛苦的重要原因。病原体必须逃避免疫系统，才能在宿主体内长期存活。寄生线虫特别擅长建立慢性感染，但它们部署的免疫逃避机制仍然知之甚少。重要的是，线虫感染以与过敏性疾病相似的方式参与免疫系统。因此，我们的研究可能会产生对慢性过敏以及慢性感染的见解。

DESCRIPTION (provided by applicant): Establishment of chronic infection is an important feature of many parasitic diseases. The immune regulatory mechanisms that support the long-term survival of parasites in infected hosts remain poorly understood. Chronic infection by the nematode Trichinella spiralis is established when first-stage larvae infect skeletal muscle cells. We have discovered that eosinophils contribute to the ensuing myositis while simultaneously promoting protection of larvae against immune-mediated destruction. Specifically, we find that muscle larvae are killed in large numbers in two mouse strains that are deficient in eosinophils. These novel observations prompt a re-evaluation of the long-standing paradigm for eosinophil function during nematode infection. Our hypothesis is that eosinophils prevent classical activation of macrophages in order to preserve larvae in muscle. This may be accomplished directly or indirectly and our goal is to elucidate the influence of eosinophils on cells that infiltrate sites of infection. The significance of these effects will be tested by manipulating the relevant mediators in assays of parasite survival. We have identified the developmental stage at which larvae are susceptible to killing, and our specific aims are to discern the functional deviation of infiltrates in eosinophil deficient mice and to rescue larvae with adoptively transferred eosinophils. The studies proposed will advance our long-term goal to define mechanisms of immune regulation during chronic nematode infection. These mechanisms strike a delicate balance by controlling the intensity of disease in infected hosts while simultaneously promoting parasite survival within the host population. PUBLIC HEALTH RELEVANCE: Chronic infections are important causes of human disease and suffering. Pathogens must evade the immune system in order to survive in their hosts for long periods. Parasitic nematodes are particularly adept at establishing chronic infections, yet the mechanisms of immune evasion they deploy remain poorly understood. Importantly, nematode infection engages the immune system in a way that parallels allergic disease. Thus, our studies are likely to generate insight into chronic allergy as well as chronic infection.