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Interactions of tick-borne pathogens, Borrelia burgdorferi and Babesia microti with the mammalian host using rodent model of co-infections

使用啮齿动物共感染模型研究蜱传病原体、伯氏疏螺旋体和田鼠巴贝虫与哺乳动物宿主的相互作用

基本信息

批准号：
10467070
负责人：
Nikhat Parveen
金额：
$ 39.25万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-09 至 2024-07-31
项目状态：
已结题

项目摘要

The CDC estimates that ~300,000 cases of Lyme disease and ~2000 cases of babesiosis occur in the USA every year. Lyme disease is caused by Borrelia burgdorferi spirochetes while the protozoan parasite Babesia microti (referred to as Bm here) is the major causative agent of babesiosis in the USA. Emergence of B. burgdorferi-Bm co-infections in expanding regions of North America and Europe has become a major health concern in the last decade. Synergism or antagonism of these pathogens during co-infections has not yet been described. B. burgdorferi-Bm co-infected patients show more extensive symptoms that persist longer than patients infected with B. burgdorferi alone. Co-infected patients often need hospitalization, and disease in some cases is fatal. Understanding the effects of these pathogens on each other and on the host will ultimately lead to development of better diagnostic, protective and treatment strategies. Limited murine studies conducted until now showed contradictory outcomes of Bm-B. burgdorferi co- infections in different mouse strains. C3H mice are ideal to study the impact of co-infections because this strain exhibits both Lyme disease and babesiosis manifestations similar to humans. Our preliminary data shows that infection with Bm causes anemia, hepatomegaly, and splenomegaly in C3H mice and results in depletion of splenic T and B cells. These changes are associated with a decrease in Bm- and B. burgdorferi-specific antibodies in co-infected mice and both: increased colonization of various tissues and enhanced inflammatory Lyme disease. If Bm infection remains undetected and untreated, such changes in co-infected humans could result in prolonged suffering of patients and could potentially contribute to post- treatment Lyme disease syndrome. We propose to carry out the first extensive study to understand the impact of Bm on B. burgdorferi gene expression, survival and persistence in the susceptible C3H mice and the effect of B. burgdorferi on reducing Bm parasitemia. Based upon our preliminary studies, we hypothesize that: (i) host sex and age are significant biological variables in pathogenesis during Bm-B. burgdorferi co-infection, (ii) depletion of splenic T and B cells by Bm reduces overall antibody production affecting kinetics of B. burgdorferi clearance and increases severity of Lyme disease while stimulation of innate immune response by B. burgdorferi reduces Bm parasitemia, and (iii) modulation of host response by Bm induces specific gene expression in B. burgdorferi to allow long-term survival of spirochetes, tissues colonization, and inflammatory disease. We will: (1) determine the effect of sex and age of mice on Lyme disease and babesiosis during Bm-B. burgdorferi co-infections, (2) determine the effect of sequential B. burgdorferi/Bm infections on Lyme disease, and (3) identify antigenic proteins produced specifically during co-infections that may facilitate long-term B. burgdorferi persistence. A better understanding of co-infections will provide an insight into human disease and identify useful antigenic markers for persistent Lyme disease.

美国疾病控制与预防中心估计，美国约有30万例莱姆病病例和约2000例巴贝斯病病例每年都有。莱姆病是由伯氏疏螺旋体引起的，而原虫是寄生虫微小巴贝斯虫(BM)是美国巴贝斯虫病的主要病原体。浮现在北美和欧洲不断扩大的地区，伯氏杆菌和BM混合感染已成为主要的在过去的十年里，人们对健康问题感到担忧。这些病原体在合并感染过程中的协同或拮抗作用还没有被描述。Burgdorferi-BM混合感染的患者表现出更广泛的症状，并持续存在比单独感染伯氏杆菌的患者时间更长。合并感染的患者通常需要住院治疗，而且在某些情况下，疾病是致命的。了解这些病原体对彼此和对寄主的影响最终将导致制定更好的诊断、保护和治疗战略。到目前为止进行的有限的小鼠研究表明，BM-B的结果相互矛盾。Burgdorferi co. 感染不同品系的小鼠。C3H小鼠是研究混合感染影响的理想动物，因为菌株表现出与人类相似的莱姆病和巴贝斯虫病的表现。我们的初步数据研究表明，感染BM会导致C3H小鼠贫血、肝肿大和脾肿大，并导致脾T、B细胞耗竭。这些变化与BM-和B的减少有关。混合感染小鼠和两者中的伯氏杆菌特异性抗体：各种组织和组织的定植增加炎症性莱姆病加重。如果BM感染仍未被发现和治疗，这种变化在混合感染的人类可能导致患者长时间的痛苦，并可能导致后治疗莱姆病综合征。我们建议进行第一次广泛的研究，以了解 BM对伯氏杆菌在易感C3H小鼠和小鼠体内表达、存活和存活的影响白僵菌降低骨髓原虫血症的作用。根据我们的初步研究，我们假设：(I)宿主性别和年龄是BM-B发病机制中的重要生物学变量。 Burgdorferi混合感染，(Ii)BM耗尽脾T和B细胞减少总体抗体产生影响伯氏杆菌清除的动力学并增加莱姆病的严重程度伯氏杆菌的先天免疫反应可降低BM寄生虫血症，以及(Iii)调节宿主反应 BM在伯氏杆菌中诱导特异性基因表达以允许螺旋体、组织长期存活殖民和炎症性疾病。我们将：(1)测定小鼠的性别和年龄对莱姆病的影响 BM-B期间的疾病和巴贝斯虫病。Burgdorferi混合感染，(2)确定序贯B。伯氏杆菌/BM感染对莱姆病的影响，以及(3)鉴定在莱姆病期间产生的抗原蛋白。可能促进伯氏杆菌长期持续存在的混合感染。更好地了解合并感染将提供对人类疾病的洞察，并为持续性莱姆病识别有用的抗原标记物。