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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.

疾病预防控制中心估计，在美国发生了约30万例莱姆病和约2000例巴贝虫病每年莱姆病是由伯氏疏螺旋体螺旋体引起的，在美国，巴贝西虫（Babesiophyti）（这里简称为Bm）是巴贝西虫病的主要病原体。出现的B。在北美和欧洲不断扩大的地区，伯氏菌-Bm合并感染已成为主要的近十年来的健康问题。在合并感染期间，这些病原体的协同或拮抗作用尚未被描述。B。Burgdorferi-Bm合并感染的患者表现出持续存在的更广泛的症状比感染了B的病人要长。伯多菲力一个人。合并感染的患者通常需要住院治疗，疾病在某些情况下是致命的。了解这些病原体相互之间以及对宿主的影响将最终导致制定更好的诊断、保护和治疗战略。迄今为止进行的有限的小鼠研究显示Bm-B的结果相互矛盾。布格多费里公司不同品系小鼠的感染。C3 H小鼠是研究合并感染影响的理想选择，因为这菌株表现出与人类相似的莱姆病和巴贝西虫病表现。我们的初步数据显示Bm感染引起C3 H小鼠贫血、肝肿大和脾肿大，并导致脾T和B细胞耗竭。这些变化与Bm-和B的降低有关。共感染小鼠和两者中的伯氏特异性抗体：各种组织的定殖增加，增强的炎症性莱姆病如果Bm感染仍然未被发现和治疗，合并感染的人类可能导致患者长期痛苦，并可能导致治疗莱姆病综合征。我们建议进行第一次广泛的研究，以了解 Bm对B影响。易感C3 H小鼠中的burgdorferi基因表达、存活率和持久性， B的影响。burgdorferi对降低Bm寄生虫血症的作用。根据我们的初步研究，假设：（i）宿主性别和年龄是Bm-B发病过程中重要生物学变量。（ii）Bm对脾T和B细胞的消耗降低了总体抗体产生影响B的动力学。伯氏菌清除，并增加莱姆病的严重程度，而刺激先天性免疫反应由B。burgdorferi减少Bm寄生虫血症，和（iii）调节宿主反应通过Bm诱导B中的特异性基因表达。使螺旋体、组织定植和炎性疾病。我们将：（1）确定小鼠性别和年龄对莱姆病的影响 Bm-B期间的疾病和巴贝虫病。（2）测定序贯B治疗的效果。莱姆病的伯氏菌/Bm感染，以及（3）鉴定莱姆病期间特异性产生的抗原蛋白可能促进长期B的合并感染。burgdorferi持久性更好地了解合并感染将提供对人类疾病的深入了解，并确定持续性莱姆病的有用抗原标记。