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〜2000病例。每年。莱姆病是由疏螺旋体螺旋体引起的，而原生动物寄生虫则引起 Babesia Microti（此处称为BM）是美国Babesiosis的主要病因。出现 B. burgdorferi-BM在北美和欧洲不断扩展的地区的共同感染已成为主要过去十年的健康关注。共同感染期间这些病原体的协同作用或对抗具有尚未描述。 B. Burgdorferi-BM共同感染的患者表现出更广泛的症状比单独感染B. burgdorferi的患者长。共同感染的患者通常需要住院，并且在某些情况下，疾病是致命的。了解这些病原体对彼此和宿主的影响最终将导致发展更好的诊断，保护和治疗策略。到目前为止进行的少鼠研究有限显示BM-B的矛盾结果。伯格多尔菲利（Burgdorferi）共同不同小鼠菌株的感染。 C3H小鼠是研究共感染的影响的理想选择菌株既表现出莱姆病，又表现出类似于人类的巴氏病表现。我们的初步数据表明BM感染会引起C3H小鼠的贫血，肝肿大和脾肿大，并导致脾脏T和B细胞的耗竭。这些变化与BM和B的减少有关。共同感染的小鼠中的勃艮第特异性抗体，两者都会增加各种组织的定殖和增加炎症性莱姆病增强。如果BM感染仍未发现且未经治疗，则此类变化共感染的人可能会导致患者的长期痛苦，并有可能导致后治疗莱姆病综合征。我们建议进行第一个广泛的研究，以了解 BM对易感C3H小鼠的B. burgdorferi基因表达，生存和持久性的影响 B. burgdorferi对减少BM寄生虫血症的影响。根据我们的初步研究，我们假设：（i）宿主性别和年龄是BM-B期间发病机理中的重要生物学变量。 Burgdorferi共感染，（ii）BM耗尽脾脏T和B细胞可减少总体抗体产生影响B. burgdorferi清除率的动力学，并增加莱姆病的严重程度，同时刺激 B. burgdorferi的先天免疫反应减少了BM寄生虫病，（iii）调节宿主反应 BM通过B.b。brgdorferi诱导特定的基因表达允许螺旋体长期存活，组织定植和炎症性疾病。我们将：（1）确定小鼠的性别和年龄对莱姆的影响 BM-B期间的疾病和Babesiosis。 Burgdorferi共感染，（2）确定顺序B的影响。 Burgdorferi/BM感染有关莱姆病的感染，（3）鉴定在专门生产的抗原蛋白可能有助于长期B. burgdorferi持久性的共同感染。更好地了解共同感染将提供有关人类疾病的见解，并确定持续性莱姆病的有用抗原标记。