Alteration of skin immune environment by sand fly saliva across progressive Leishmaniasis

白蛉唾液改变进行性利什曼病的皮肤免疫环境

基本信息

批准号：
10666688
负责人：
Christine A Petersen
金额：
$ 61.98万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666688
关键词：
Animal Model Antigens Arthropods B-Lymphocytes Biological Models Biopsy Bite CD8-Positive T-Lymphocytes Canis familiaris Cells Cessation of life Clinical Complex Data Dermal Dermis Disease Environment Epidemiology Erythrocytes Event Exposure to Female Hour Human Immune Immune response Immunity Immunotherapy Infection Infection Control Inflammation Inflammatory Integration Host Factors Intervention Intervention Studies Laboratories Lead Leishmania Leishmania donovani Leishmania infantum Leishmaniasis Ligands Lutzomyia genus Macrophage Mediating North America Organ Outcome Parasitemia Parasites Phlebotominae Phlebotomus Productivity Property Public Health Rupture Saliva Salivary Salivary Proteins Sand Flies Site Skin South America Time Trauma Visceral Leishmaniasis Work Zoonoses cohort exhaust experimental study feeding heme oxygenase-1 immunoregulation innovation prevent programmed cell death ligand 1 programmed cell death protein 1 response transcriptome transmission process vector

项目摘要

Summary Visceral leishmaniasis (VL), caused by Leishmania donovani complex spp. causes between 20,000- 40,000 deaths a year. L. infantum is the cause of VL in the Mediterranean basin and imported to both South and North America. L. infantum is zoonotic with canid reservoirs. Leishmania spp. are transmitted primarily between mammalian hosts by female Lutzomyia or Phlebotomus sand flies. It has been established that both sand fly and host factors modulate local dermal immunity when and where parasites first encounter skin, guiding immunity locally and systemically and impacting infection outcomes. Relatively little is known about the skin immune environment during progressive VL, how dermal immune changes alter host infectiousness or responses to immunomodulatory sand fly salivary components. Skin parasite burden in dogs with L. infantum infection correlates with transmission efficiency, more so than parasitemia, though dogs with late-stage disease were less infectious than those with mild-moderate disease. We have shown that asymptomatic VL clinical status was associated in dogs, as in humans, with productive Th1 type responses, while symptomatic infection correlated with presence of exhausted CD4+ and CD8+ T cells, significant expression of Programmed Death 1 (PD-1) and its ligand, PD-L1 on both B cells and macrophages and loss of macrophage parasite clearance. These findings collectively lead us to hypothesize that immune cell responses in subclinical or clinically infected hosts’ skin, whether from dogs or humans, dictate host infectiousness. We will address this hypothesis through three specific aims in this proposed work, 1) Identify unique dermal immune environments in subclinical vs. clinical hosts that alter infectiousness to naïve sand flies, 2) Evaluate how the functions of sand fly salivary proteins are impacted by skin changes during progressive VL leading to new understanding of vector saliva-host interactions and how they contribute to infectiousness to sand flies and 3) Evaluate how alteration of the dermal immune environment through dermal immunotherapy alters bite-site inflammation and transmission. The work proposed here is therefore significant, as it provides infection control relevant evidence regarding the dermal microenvironment and how it alters infectivity during progressive L infantum infection. The studies proposed here are significantly innovative as they quantitatively on a spatial level assess how parasite burden and different dermal inflammatory states alter infectiousness to sand flies. Using purified salivary antigens, skin biopsy, histopathologic and transcriptome analysis and a key unique natural infection cohort, we will determine how progressive VL alters the landscape in which vector salivary proteins operate with consequences for understanding both host infectiousness and the epidemiology of VL. When completed, findings from these proposed studies will both underscore how progressive dermal inflammation impacts reservoir host infectiousness and provide critical data to further assess appropriate interventions to prevent canine-sand fly-human transmission.

概括内脏利什曼病 (VL)，由杜氏利什曼原虫复合体引起，可引起 20,000- 婴儿乳杆菌每年造成 40,000 人死亡，是造成地中海盆地和南部地区 VL 的原因。婴儿利什曼原虫是人畜共患的，主要传播犬科动物利什曼原虫。已经确定，雌性 Lutzomyia 或 Phlebotomus 沙蝇在哺乳动物宿主之间传播。白蛉和宿主因素在寄生虫首次接触皮肤的时间和地点调节局部皮肤免疫力，对于局部和系统性免疫以及影响感染结果的了解相对较少。进行性 VL 期间的皮肤免疫环境，真皮免疫变化如何改变宿主传染性或患有婴儿乳杆菌的狗对免疫调节白蛉唾液成分的反应。感染与传播效率的相关性比寄生虫血症更相关，尽管处于晚期的狗我们已经证明，无症状 VL 的传染性低于轻中度疾病的传染性。与人类一样，狗的临床状态与有效的 Th1 型反应相关，而有症状的感染与耗尽的 CD4+ 和 CD8+ T 细胞的存在相关，Programmed 的显着表达 B 细胞和巨噬细胞上的死亡 1 (PD-1) 及其配体 PD-L1 以及巨噬细胞寄生虫的丧失这些发现共同引导我们重新认识亚临床或免疫细胞的反应。临床感染宿主的皮肤，无论是来自狗还是人类，决定了宿主的传染性。通过这项拟议工作中的三个具体目标提出假设，1）识别独特的真皮免疫环境在改变幼稚沙蝇传染性的亚临床宿主与临床宿主中，2) 评估白蛉唾液蛋白在进行性 VL 过程中受到皮肤变化的影响，从而导致对白蛉唾液蛋白的新认识媒介唾液与宿主的相互作用以及它们如何促进白蛉的传染性以及 3) 评估如何通过皮肤免疫疗法改变皮肤免疫环境，从而改变咬伤部位的炎症，因此，这里提出的工作意义重大，因为它提供了相关的感染控制。关于真皮微环境及其如何改变进行性婴儿乳杆菌感染性的证据这里提出的研究具有显着的创新性，因为它们在空间水平上进行了定量研究。评估寄生虫负担和不同的皮肤炎症状态如何改变白蛉的传染性。纯化的唾液抗原、皮肤活检、组织病理学和转录组分析以及关键的独特天然感染队列，我们将确定进展性 VL 如何改变载体唾液蛋白的景观操作对了解宿主传染性和 VL 流行病学具有重要意义。完成后，这些拟议研究的结果都将强调进展性皮肤炎症如何影响储存宿主的传染性并提供关键数据以进一步评估适当的干预措施防止犬-沙蝇-人传播。