Eosinophils sustain chronic nematode infection

描述(申请人提供)：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。当第一期幼虫感染骨骼肌细胞时，就会被旋毛虫慢性感染。我们发现，嗜酸性粒细胞促进了随后的肌炎，同时促进了对幼虫的保护，使其免受免疫介导的破坏。具体地说，我们发现，在两个嗜酸性粒细胞缺乏的小鼠品系中，肌肉幼虫被大量杀死。这些新的观察结果促使人们重新评估在线虫感染过程中嗜酸性粒细胞功能的长期范式。我们的假设是，嗜酸性粒细胞阻止巨噬细胞的经典激活，以保存肌肉中的幼虫。这可能是直接或间接完成的，我们的目标是阐明嗜酸性粒细胞对渗入感染部位的细胞的影响。这些影响的重要性将通过在寄生虫存活分析中操纵相关介质来检验。我们已经确定了幼虫容易被杀死的发育阶段，我们的具体目标是辨别嗜酸性粒细胞缺陷小鼠的浸润物的功能偏差，并通过过继转移的嗜酸性粒细胞来拯救幼虫。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，同时促进宿主群体内寄生虫的生存，实现了微妙的平衡。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生存。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，线虫感染以一种类似于过敏性疾病的方式影响免疫系统。因此，我们的研究可能会对慢性过敏和慢性感染产生洞察力。

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.