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

• 批准号: 10226964
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226964
• 关键词: Acute; Affect; Aftercare; Age; Anemia; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; Babesia microti; Babesiosis; Bacteria; Biological; Blood; Borrelia burgdorferi; Cause of Death; Centers for Disease Control and Prevention (U.S.); Data; Development; Diagnostic; Disease; Enzyme-Linked Immunosorbent Assay; Europe; Evaluation; Exhibits; Female; Foundations; Gene Expression; Geographic Locations; Health; Hepatomegaly; Hospitalization; Human; Immune response; Immune system; Immunocompetent; Immunologics; Inbred C3H Mice; Individual; Infection; Inflammatory; Innate Immune Response; Ixodes; Kinetics; Laboratories; Lead; Letters; Lyme Arthritis; Lyme Disease; Malaria; Monitor; Mouse Strains; Multiple Organ Failure; Mus; New England; New Jersey; North America; Order Spirochaetales; Outcome; Outcome Study; Parasitemia; Parasites; Pathogenesis; Pathologic; Patients; Phase; Plasma; Plasmodium; Plasmodium falciparum; Postdoctoral Fellow; Preventive measure; Proteins; Proteome; Relapsing Fever; Reporting; Residual state; Resolution; Rodent; Rodent Model; Sampling; Severities; Severity of illness; Splenomegaly; Symptoms; Syndrome; System; T-Lymphocyte; Testing; Tick-Borne Infections; Ticks; Tissues; Training; Transfusion; Treatment Protocols; United States; White Blood Cell Count procedure; Work; accurate diagnosis; base; co-infection; experience; experimental study; human disease; insight; male; pathogen; protein biomarkers; response; sex; synergism; tick-borne pathogen; treatment strategy; vector

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.

CDC 估计美国约有 300,000 例莱姆病病例和约 2000 例巴贝斯虫病病例 每年。莱姆病是由伯氏疏螺旋体螺旋体引起的，而原生动物寄生虫 田鼠巴贝斯虫（此处称为 Bm）是美国巴贝斯虫病的主要病原体。出现 在北美和欧洲不断扩大的地区，伯氏疏螺旋体 - 伯氏疏螺旋体混合感染已成为一个主要问题 过去十年的健康问题。这些病原体在共同感染期间的协同或拮抗作用 尚未被描述。伯氏疏螺旋体-Bm 共同感染的患者表现出更广泛的持续症状 比单独感染伯氏疏螺旋体的患者持续时间更长。合并感染的患者通常需要住院治疗，并且 在某些情况下，这种疾病是致命的。了解这些病原体对彼此以及对宿主的影响 最终将导致更好的诊断、保护和治疗策略的制定。 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。博格多弗里科 不同品系小鼠的感染。 C3H 小鼠是研究混合感染影响的理想选择，因为这 该菌株表现出与人类相似的莱姆病和巴贝斯虫病表现。我们的初步数据 表明感染 Bm 会导致 C3H 小鼠贫血、肝肿大和脾肿大，并导致 脾脏 T 细胞和 B 细胞耗竭。这些变化与 Bm- 和 B 的减少有关。 共感染小鼠中的伯氏疏螺旋体特异性抗体以及两者：各种组织的定植增加和 增强炎症莱姆病。如果 Bm 感染仍未被发现和治疗，这种变化 共同感染的人类可能会导致患者长期遭受痛苦，并可能导致后遗症 治疗莱姆病综合症。我们建议进行第一次广泛的研究以了解 Bm 对易感 C3H 小鼠中伯氏疏螺旋体基因表达、存活和持久性的影响 伯氏疏螺旋体对减少伯氏疏螺旋体寄生虫血症的作用。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。 伯氏疏螺旋体联合感染，(ii) Bm 消耗脾脏 T 细胞和 B 细胞，减少总体抗体产生 影响伯氏疏螺旋体清除动力学并增加莱姆病的严重程度，同时刺激 伯氏疏螺旋体的先天免疫反应可减少伯氏疏螺旋体寄生虫血症，以及 (iii) 调节宿主反应 by Bm 诱导伯氏疏螺旋体的特定基因表达，使螺旋体、组织能够长期存活 定植和炎症性疾病。我们将：（1）确定小鼠性别和年龄对莱姆病的影响 Bm-B 期间的疾病和巴贝斯虫病。伯氏疏螺旋体合并感染，(2) 确定序贯伯氏疏螺旋体的效果。 伯氏杆菌/Bm 感染对莱姆病的影响，以及 (3) 鉴定在莱姆病期间特异产生的抗原蛋白 可能促进伯氏疏螺旋体长期持续存在的共同感染。更好地了解合并感染 将提供对人类疾病的深入了解，并识别持续性莱姆病的有用抗原标记。