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

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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.