Host-pathogen-vector interactions of R. amblyommatis for spotted fever pathogenesis

R. amblyommatis 的宿主-病原体-载体相互作用对斑疹热发病机制的影响

• 批准号: 10431123
• 负责人: Hwan Keun Kim
• 金额: $ 23.25万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431123
• 关键词: Address; Adult; Amblyomma; Ambylomma americanum; American; Animals; Antibodies; Area; Arthropod Vectors; Bacteremia; Behavior; Biology; Black-legged Tick; Blood Circulation; Blood Vessels; Borrelia lonestari; Bourbon virus; CCL14 gene; CRISPR screen; Canis familiaris; Cavia; Characteristics; Child; Clinical; Cutaneous; Cytopathology; Cytoplasm; Dermacentor; Diagnosis; Disease; Ehrlichia chaffeensis; Ehrlichia ewingii; Ehrlichiosis; Endothelial Cells; Etiology; Exanthema; Exhibits; Fever; Francisella tularensis; Frequencies; Gene Mutation; Generations; Genes; Genetic; Genetic study; Genome; Genotype; Geographic Locations; Geography; Habitats; Headache; Heartland virus; Hemostatic function; High Prevalence; Human; Immune response; Immunity; Infection; Integration Host Factors; Knowledge; Laboratories; Life; Long Island; Microarray Analysis; Midgut; Midwestern United States; Modeling; Mus; Myalgia; Necrosis; New England; Organ; Ovary; Pathogenesis; Pathogenicity; Pathology; Patients; Phenotype; Population; Prevalence; Probability; Public Health; Reporting; Resistance; Rickettsia; Rickettsia Infections; Rickettsia parkeri; Rickettsia rickettsii; Rocky Mountain Spotted Fever; Role; Saliva; Salivary Glands; Sepsis; Serology; Sociology; Southeastern United States; Southern Tick Associated Rash Illness; Surveys; Symptoms; Texas; Tick-Borne Diseases; Ticks; Tissues; Tularemia; United States; Universities; Vascular Endothelial Cell; Vasculitis; Virulence; Virus Diseases; Work; base; cell injury; comparative; environmental change; epidemiology study; genome-wide; human pathogen; insight; member; novel; offspring; pathogen; spotted fever; surveillance study; tick bite; tick saliva; tissue culture; transmission process; vascular inflammation; vector; whole genome

Ticks are the most important arthropod vectors capable of transmitting a diverse array of pathogens to humans. Several environmental and sociological factors have contributed to the range and population expansion of ticks, resulting in an increased number of tick-borne diseases (TBDs) in the United States. Recent tick surveillance studies have demonstrated that Amblyomma americanum (lone star tick) has rapidly expanded northward and become the dominant tick species, displacing local tick species such as Ixodes scapularis (deer tick) and Dermacentor variabilis (American dog tick) in the Northeast and Midwest, where the increased number of patients with TBDs of unknown etiology has been observed. A. americanum poses a public health threat as the tick presents non-discriminating aggressive biting behavior and serves as a vector and reservoir for diverse human pathogens, including Rickettsia amblyommatis (rickettsiosis), Ehrlichia chaffeensis and E. ewingii (human ehrlichiosis), Francisella tularensis (tularemia), Heartland virus (Heartland virus disease), Bourbon virus (Bourbon virus disease), and Borrelia lonestari (Southern tick-associated rash illnesses). R. amblyommatis, a Gram-negative pathogen that belongs to the spotted fever group of Rickettsia, has been frequently identified from A. americanum in several parts of the United States. In contrast, the current prevalence of R. rickettsii (Rocky Mountain spotted fever, RMSF) in D. variabilis is estimated to be less than 1%. The high prevalence of R. amblyommatis, combined with the aggressive biting behavior of A. americanum, enhances the probability of human infections with R. amblyommatis. Within ticks, R. amblyommatis exhibits obligatory intracellular lifecycle in multiple organ tissues such as ovaries, midgut, and salivary glands, enabling R. amblyommatis transmission to offspring and mammalian hosts. Several lines of clinical and serological evidence suggest that R. amblyommatis is the etiological agent of RMSF-like illness. Analysis of paired sera from patients diagnosed with probable RMSF revealed that some patients developed antibodies to R. amblyommatis, but not to R. rickettsii, corroborating that R. amblyommatis may cause RMSF-like illnesses in humans. Those patients with specific reactivity to R. amblyommatis presented typical clinical manifestations of a mild RMSF with fever, headache, and myalgia. However, there is a significant gap in our understanding of R. amblyommatis biology and its virulence potential to cause rickettsiosis in mammalian hosts. Based on the available evidence of 1) the invasion and expansion of A. americanum heavily infected with R. amblyommatis in the upper Midwestern and the Northeastern United States; 2) the increasing numbers of RMSF-like cases in the same areas; 3) experimental results from our laboratory for R. amblyommatis-induced cytopathology and pathogenesis, we will investigate the genetic basis of R. amblyommatis from one of the northernmost hotspots for this species, determine the virulence potential in tissue culture and animal infection models, and study the host-pathogen-vector interactions enabling R. amblyommatis rickettsiosis.

壁虱是能够将各种病原体传输到的最重要的节肢动物向量 人类。几个环境和社会学因素促成了范围和人口 tick虫的扩张，导致在美国的壁虱传播疾病（TBD）增加。 最近的tick监视研究表明，Amblyomma Americanum（Lone Star Tick）迅速 向北扩展并成为主要的壁虱物种，取代了当地的壁虱物种，例如ixodes 肩cap骨（鹿tick）和西北和中西部的Dermacentor variabilis（美国狗tick虫） 已经观察到患有未知病因的TBD的患者数量增加。 A. Americanum构成 公共卫生威胁tick提出了无歧视的侵略性咬人行为，并充当矢量 以及用于多样化人类病原体的水库，包括立克斯萨（Rickettsia） Chaffeensis和E. ewingii（人类Ehrlichiosis），Francisella tularensis（Tularemia），Heartland病毒（Heartland 病毒疾病），波旁病毒（波旁病毒疾病）和波雷利亚lonestari（南部tick相关皮疹 疾病）。 R. amblyommatis，一种属于斑点的人力体的革兰氏阴性病原体， 经常在美国几个地区的Americanum鉴定出来。相反，电流 D. variabilis中R. rickettsii（落基山斑点发烧）的患病率估计小于 1％。 R. amblyommatis的高流行，结合了A. americanum的侵略性咬人行为 增强了人类感染的可能性。在tick中，R。Amblyommatis展览 多个器官组织中的强制性细胞内生命周期，例如卵巢，中肠和唾液腺，使得能够 R. Amblyommatis向后代和哺乳动物宿主传播。几条临床和血清学系列 有证据表明，R。amblyommatis是RMSF样疾病的病因。配对血清的分析 从诊断患有RMSF的患者中表明，一些患者患有对R的抗体。 Amblyommatis，但不给R. Rickettsii，证实R. amblyommatis可能会导致RMSF样疾病 人类。那些针对R. amblyommatis的特异性反应性的患者呈现了典型的临床表现。 温和的RMSF发烧，头痛和肌痛。但是，我们对R的理解存在很大的差距。 Amblyommatis生物学及其在哺乳动物宿主中引起立克氏症的毒力潜力。基于 可用的证据1）大量感染了Amblyommatis的Amerimum侵袭和扩张 在中西部和美国东北部； 2）越来越多的RMSF样病例 相同的区域； 3）我们实验室的实验结果，用于炎症炎的细胞病理学和 发病机理，我们将研究来自最北端热点之一的R. amblyommatis的遗传基础 对于该物种，确定组织培养和动物感染模型中的毒力潜力，并研究 宿主 - 病原体矢量相互作用，使R. r. amblyommatis rickettsiosis。