During most of the 20th century, the epidemiology of tick-borne rickettsioses could be summarized as the occurrence of a single pathogenic rickettsia on each continent. An element of this paradigm suggested that the many other characterized and noncharacterized rickettsiae isolated from ticks were not pathogenic to humans. In this context, it was considered that relatively few tick-borne rickettsiae caused human disease. This concept was modified extensively from 1984 through 2005 by the identification of at least 11 additional rickettsial species or subspecies that cause tick-borne rickettsioses around the world. Of these agents, seven were initially isolated from ticks, often years or decades before a definitive association with human disease was established. We present here the tick-borne rickettsioses described through 2005 and focus on the epidemiological circumstances that have played a role in the emergence of the newly recognized diseases.

Tick-Borne Rickettsioses around the World: Emerging Diseases Challenging Old Concepts

Rickettsioses are caused by species of Rickettsia, a genus comprising organisms characterized by their strictly intracellular location and their association with arthropods. Rickettsia species are difficult to cultivate in vitro and exhibit strong serological cross-reactions with each other. These technical difficulties long prohibited a detailed study of the rickettsiae, and it is only following the recent introduction of novel laboratory methods that progress in this field has been possible. In this review, we discuss the impact that these practical innovations have had on the study of rickettsiae. Prior to 1986, only eight rickettsioses were clinically recognized; however, in the last 10 years, an additional six have been discovered. We describe the different steps that resulted in the description of each new rickettsiosis and discuss the influence of factors as diverse as physicians' curiosity and the adoption of molecular biology-based identification in helping to recognize these new infections. We also assess the pathogenic potential of rickettsial strains that to date have been associated only with arthropods, and we discuss diseases of unknown etiology that may be rickettsioses.

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Rickettsioses as paradigms of new or emerging infectious diseases.

▪ Abstract Until the 1990s, Amblyomma americanum was regarded primarily as a nuisance species, but a tick of minor importance as a vector of zoonotic pathogens affecting humans. With the recent discoveries of Ehrlichia chaffeensis, Ehrlichia ewingii, and “Borrelia lonestari,” the public health relevance of lone star ticks is no longer in question. During the next 25 years, the number of cases of human disease caused by A. americanum-associated pathogens will probably increase. Based on current trajectories and historic precedents, the increase will be primarily driven by biological and environmental factors that alter the geographic distribution and intensity of transmission of zoonotic pathogens. Sociologic and demographic changes that influence the likelihood of highly susceptible humans coming into contact with infected lone star ticks, in addition to advances in diagnostic capabilities and national surveillance efforts, will also contribute to the anticipated increase in the number of recognized cases...

The Ascendancy of Amblyomma Americanum as a Vector of Pathogens Affecting Humans in the United States

Rickettsia are best known as strictly intracellular vector-borne bacteria that cause mild to severe diseases in humans and other animals. Recent advances in molecular tools and biological experiments have unveiled a wide diversity of Rickettsia spp. that include species with a broad host range and some species that act as endosymbiotic associates. Molecular phylogenies of Rickettsia spp. contain some ambiguities, such as the position of R. canadensis and relationships within the spotted fever group. In the modern era of genomics, with an ever-increasing number of sequenced genomes, there is enhanced interest in the use of whole-genome sequences to understand pathogenesis and assess evolutionary relationships among rickettsial species. Rickettsia have small genomes (1.1-1.5 Mb) as a result of reductive evolution. These genomes contain split genes, gene remnants and pseudogenes that, owing to the colinearity of some rickettsial genomes, may represent different steps of the genome degradation process. Genomics reveal extreme genome reduction and massive gene loss in highly vertebrate-pathogenic Rickettsia compared to less virulent or endosymbiotic species. Information gleaned from rickettsial genomics challenges traditional concepts of pathogenesis that focused primarily on the acquisition of virulence factors. Another intriguing phenomenon about the reduced rickettsial genomes concerns the large fraction of non-coding DNA and possible functionality of these "non-coding" sequences, because of the high conservation of these regions. Despite genome streamlining, Rickettsia spp. contain gene families, selfish DNA, repeat palindromic elements and genes encoding eukaryotic-like motifs. These features participate in sequence and functional diversity and may play a crucial role in adaptation to the host cell and pathogenesis. Genome analyses have identified a large fraction of mobile genetic elements, including plasmids, suggesting the possibility of lateral gene transfer in these intracellular bacteria. Phylogenetic analyses have identified several candidates for horizontal gene acquisition among Rickettsia spp. including tra, pat2, and genes encoding for the type IV secretion system and ATP/ADP translocase that may have been acquired from bacteria living in amoebae. Gene loss, gene duplication, DNA repeats and lateral gene transfer all have shaped rickettsial genome evolution. A comprehensive analysis of the entire genome, including genes and non-coding DNA, will help to unlock the mysteries of rickettsial evolution and pathogenesis.

Rickettsial evolution in the light of comparative genomics

Morbidity and mortality caused by rickettsioses have had a major influence on military activities and public health for >2000 years. The threat posed by the rickettsioses is reviewed, focusing on the impact and epidemiology of those that have adversely influenced wartime operations and the current challenges posed by these diseases. With their uneven worldwide distribution, the discovery of drug-refractory strains of Orientia tsutsugamushi, the increased threat of their use in acts of bioterrorism, frequent deployment of troops to regions of endemicity, and exposures due to increased humanitarian missions, these diseases continue to be a threat to military personnel in the field. Effective strategies to reduce the impact of these diseases include development of effective vaccines, enhanced surveillance, and development of new safe, effective, and odorless repellants. The continuation of a proven, highly productive military infectious disease research program is essential for providing solutions to these daunting tasks.

The past and present threat of rickettsial diseases to military medicine and international public health.

The authors have presented evidence through work done 25-30 years ago for the rickettsial etiology of Bullis fever, a forgotten epidemic which occurred with over a 1,000 cases among World War II troops in training at Camp Bullis, Texas. Rickettsiae were recovered from blood and lymph nodes of patients and from ticks, Amblyomma americanum, collected in the area. All patients gave a history of tick-bites. The human and tick strains of rickettsiae, carried in chick embryo culture and in animal passage, were found to produce the characteristic syndrome of Bullis fever in human volunteers inoculated with either strain, indicating identity and specificity of infection. Wildlife in the area was found to support the stages in the life cycle of A. americanum. Deer were implicated as supporting the most abundant adult tick population, the stage which attacks man. Serologic studies eliminated othe rickettsial diseases, Colorado tick fever, dengue and many other diseases. The name Rickettsia texiana is suggested for the hitherto un-named member of the rickettsia group of organisms.

D Anigstein

Papers

A review of the evidence in retrospect for a rickettsial etiology in Bullis fever.