Vector-Borne Infectious Diseases & One Medicine
ACVIM 2008
David H. Walker, MD; Edward B. Breitschwerdt, DVM, DACVIM
Galveston, TX, USA; Raleigh, NC, USA

Ehrlichioses and Anaplasmoses

In 2001 a group of veterinary and human medical scientists reorganized the classification of the family Anaplasmataceae, which contains agents of diseases of mutual concern in One Medicine, including Anaplasma phagocytophilum, Ehrlichia chaffeensis, E. ewingii, and E. canis.1 Human medicine was late in joining the investigation of these obligately intracellular bacteria as the first case of human ehrlichiosis was only reported in 1987.2 Prior veterinary contributions included the discoveries of A. marginale by Theiler in 1910 and E. ruminantium by Cowdry in 1925 in South Africa, E. canis by Lestoquard and Donatien in 1935 in Tunisia, A. phagocytophilum by Gordon in 1940 in the United Kingdom, and E. ewingii by Ewing in 1971 in the United States.

Until 1994 infections with A. phagocytophilum were known to affect horses in the United States under the name E. equi and sheep and cattle in the United Kingdom and Europe under the name E. phagocytophila. An observant physician in Duluth, Minnesota, Johann Bakken, pursued the idea that some of his patients were suffering from infection with ehrlichiosis by collaborating with Steve Dumler, then a research fellow in Galveston3. Using a combination of clinical, hematologic, molecular, serologic, and ultrastructural evidence, Bakken, Chen, Dumler and I identified the etiology as A. phagocytophilum.4 Soon Swedish scientists had independently identified A. phagocytophilum as the cause of infections of horses, and canine infections were detected in Minnesota.5,6 Tick vectors, Ixodes scapularis, I. pacificus, I. ricinus, and I. persulcatus, transmit the anaplasma from a wide variety of persistently infected wild ruminants and rodents to humans, cattle, sheep, cats and dogs. The challenges of diagnosis, treatment, and prevention strongly emphasize the importance of One Medicine.

A. phagocytophilum infects neutrophils and prolongs the survival of these short-lived cells by upregulating a bcl-1 family anti-apoptotic gene bf1-1, thus enabling further bacterial growth.7,8 Direct detoxification of preformed superoxide by a heat-labile surface protein enables A. phagocytophilum to evade reactive oxygen species-mediated killing.9,10 These bacteria also have a transcriptionally active superoxide dismutase B gene, and after engulfment, they inhibit the respiratory burst by downregulation of NADPH oxidase gene expression.11-13 Adaptive immunity is critical for clearance of infection as SCID mice become persistently infected with A. phagocytophilum.14 IFN-γ is important for clearance of these organisms, but also contributes to the tissue pathology.15-17 NADPH phagocyte oxidase, tumor necrosis factor, inducible nitric oxide synthase, and Toll-like receptor signaling do not play important roles in anaplasma clearance but do contribute to hepatic inflammation and injury in a mouse model of HGA.18 Infected humans have elevated serum concentrations of ferritin, IL-10, IL-12p70, and IFN-γ, and severity of illness correlates with ferritin and IL-12p70 levels with some severely ill patients meeting the criteria of the macrophage activation syndrome.19 These anaplasmae have evolved these mechanisms to survive in rodents, ruminants, equines, carnivores, and primates alike.

My research on immunity and immunopathogenesis of monocytotropic ehrlichiosis relies heavily on murine models of fatal acute disease caused by an unnamed Ehrlichia recovered from Japanese I. ovatus ticks, of persistent asymptomatic infection with E. muris, and of crossprotective immunity.20-22 Both organisms are very closely related to E. chaffeensis.23,24 The pathogenesis of toxic shock-like illness involves overproduction of TNF-α by CD8+ T lymphocytes,22 and protective immunity against the fatal infection requires a combination of antibodies, CD4+ and CD8+ T lymphocytes. These observations are potentially important to the development of vaccines for acute canine monocytic ehrlichiosis and for heartwater. We have identified a large portion of the proteins and the genes encoding them that are recognized by the humoral immune response to E. canis.25,26 These proteins include the most sensitive antigens for the specific diagnosis of E. canis infection early in the course of illness, and they are strong candidates for development of a protective vaccine for dogs. Conceived as a project to develop vaccines against emerging infectious diseases, this project is an example of One Medicine being a pathway with potential benefits for both human and veterinary medicine.

As a beneficiary of developing into a scientist under the mentorship of an outstanding veterinarian, Frederick A. Murphy, and collaborating with many colleagues in veterinary medicine such as Edward Breitschwerdt, it is particularly ironic that I declined his invitation in the mid-1980s to study canine ehrlichiosis on the basis of my perception of its irrelevance to human medicine. Surely one can teach an old dog new tricks.

Rickettsioses and Bartonelloses

Sir William Osler alluded to the virtues of "One Medicine" in a Presidential Address Lecture to the Classical Association at Oxford entitled "The Old Humanities and the New Science" on May 16, 1919.27 Subsequently this concept was essentially lost until the 1980s, when a veterinary epidemiologist and parasitologist, Dr. Calvin Schwabe coined the phrase "One Medicine."28 However, until very recently "One Medicine" remained conceptually and financially synonymous with "human medicine." As a result, the vast majority of governmental infrastructure support and biomedical research funding was appropriated and directed toward the management of diseases in one species, Homo sapiens. This philosophy generated a political agenda that resulted in the creation and consolidation of a large human medical research infrastructure in the United States, supported annually through the National Institutes of Health and other governmental resources. During the later part of the 20th century the term "Comparative Medicine" gained acceptance in the fields of human and veterinary medicine. Unfortunately, this term was used primarily to promote the use of animals in biomedical research for the medical benefit of one species, Homo sapiens. Veterinary pathologists and laboratory animal veterinarians became an important and integral component of comparative medicine, however, regardless of the animal model, the primary goal remained the enhanced medical well-being of a single species, Homo sapiens. Although comparative medical benefits were derived for other animal species, this clearly was not the primary goal, nor the agenda that sustained the comparative medicine infrastructure.

In recent years, the term "One Medicine" has been resurrected by proponents in human and veterinary medicine.29 Depending upon the context of various philosophical discussions, and for obvious reasons, "ecosystem health" has been added to the health care concerns of animals and human beings. Clearly, this expanded concept of "One Medicine," which incorporates animals, Homo sapiens, and the environment in which we all live, makes philosophical, financial and biomedical sense. However, resource allocation will ultimately determine the success or failure of the "One Medicine" concept in the future. If 97% of the national biomedical research budget continues to be devoted solely to the health care priorities of a single species, all other animal species and the environment will suffer. As veterinary medicine is responsible for the health care of every animal on this planet except for one species, Homo sapiens, it is incumbent upon every veterinarian to join in the efforts to redefine the concept of "One Medicine" in our society in the future. As 75% of human emerging infectious diseases are zoonotic, those individuals who are responsible for infectious disease surveillance and public health are providing leadership in promoting the "One Medicine" philosophy.30 At the time of graduation from a College of Veterinary Medicine, the veterinary medical curriculum has provided each student with the most comprehensive biomedical education of any profession that exists in the world today. This would suggest that all veterinarians should play a more central role in the future relative to the health care of animal species, human beings, and the ecosystem in which we all exist.

As a veterinarian whose research has focused on vector-borne infectious diseases, I have been fortunate to interact with human medical colleagues who share a far greater appreciation for the concept of One Medicine and Ecosystem Health than the average physician or those individuals who are responsible for biomedical research funding priorities in the United States. Clearly, this is because animals and human beings share the same environment; are exposed to many of the same vectors, can be infected by the same pathogens and develop the same diseases. Dr. David Walker has just discussed anaplasmosis and ehrlichiosis, two emergent tick-borne infectious diseases of animals and human beings. It is clearly an honor to share this segment of the 2008 ACVIM symposium on One Medicine, with my friend and long time colleague, David Walker. If it were not for his support and guidance when I joined the faculty at North Carolina State University in 1982, it is most probable that I would not be standing before you today. Despite the discovery and scientific validation of Rocky Mountain spotted fever as a tick-borne infectious disease in the Bitterroot Valley of Montana by Ricketts in 1906, it was not until 1980 that the first documented case of canine Rocky Mountain spotted fever was reported in the veterinary literature.31,32 It is perhaps pertinent to point out that many animal species, including dogs, were experimentally infected by Ricketts, Wolbach and others in an effort to clarify the cause and pathogenesis of Rocky Mountain spotted fever.31 Also of historical importance, the US military demonstrated a dose-dependent response in the severity of illness during experimental infection of dogs with Rickettsia rickettsii in 1977.33 Research performed in my laboratory in collaboration with Dr. Walker, indicates that dogs and human patients infected with R. rickettsii develop clinical, hematological, biochemical abnormalities and pathology that are identical in most respects.34,35 This makes the dog an exceptional natural or experimental model for study of rickettsial diseases. Since pet dogs share the same environment as their owners, dogs are also an excellent sentinel for Rocky Mountain spotted fever in human beings.36 In many instances, documented in the medical literature, RMSF in a dog predates the diagnosis of RMSF in a child or adult in the same household.36 As with other infectious diseases, veterinarians can and should play an important role in the public health infrastructure in our country and the world.

To a substantial degree, rickettsiologists in human and veterinary medicine are responsible for the recognition of members of the genus Bartonella as a highly prevalent and potentially insidious animal and human pathogens.37,38 As is true of rickettsial infection, dogs and human patients develop highly similar disease manifestations and pathological abnormalities when infected with a Bartonella species. It is very clear that this genus has evolved to induce persistent intravascular infections in a spectrum of animal species. For over a decade, our research group has generated novel information relative to infections with Bartonella species in pets (cats, dogs and horses), wildlife (large felids, wild canines, marine mammals and sea turtles) and cattle. More recently, our research efforts have focused on the potentially unrecognized, zoonotic transmission of these organisms from pets to their owners or to animal health professionals. Currently, based upon the historical association with cat scratch disease, physicians generally assume that B. henselae and B. vinsonii subsp. berkhoffii induce self-limiting infections in immunocompetent individuals or antibiotic responsive infections accompanied by fever or vasoproliferative disease in immunocompromised individuals. Based upon evolving data, this paradigm may represent only the tip of the Bartonella iceberg.

Similar to humans, dogs infected with B. henselae or B. vinsonii subsp. berkhoffii develop endocarditis, peliosis hepatis, localized or generalized granulomatous lymphadenitis, cutaneous vasculitis, anterior uveitis, polyarthritis, meningoencephalitis, immune-mediated thrombocytopenia and immune-mediated hemolytic anemia. PCR detection or microbiological isolation of Bartonella species from a dog is as challenging as detecting these organisms in human diagnostic samples. For the past six years, our research group has worked diligently to enhance the diagnostic detection of Bartonella species, particularly in dog blood and tissue samples.39 Fortunately, the same methods used in dogs are applicable for the enhanced detection of some Bartonella species in human patient samples.40 As a result we have documented persistent infections in veterinarians, veterinary technicians and wildlife biologists, who may be at risk for occupational exposure to various Bartonella spp. Although there are only a few reports in the world literature implicating dogs in the transmission of B. henselae to people, we have detected B. henselae DNA in blood, lymph nodes and saliva from dogs.41 The extent to which dogs can serve as a reservoir host for B. henselae has not been established, but B. henselae seroreactivity in healthy and sick dogs in the southeastern US is much higher than seroreactivity to B. vinsonii subsp. berkhoffii, in comparable dog populations.42 In addition, we have recently detected infection with a Bartonella spp. in 18% of healthy Golden retrievers as well as in Golden retrievers with lymphoma.43

Dogs serve as the primary reservoir host for B. vinsonii subsp. berkhoffii and may also transmit B. henselae to people. Currently, there are 60 million dogs living in US households. Contact between dogs and their owners is more intimate than at any point in history. As a veterinary professional, it is my hope that infection of immunocompetent humans with B. henselae and B. vinsonii subsp. berkhoffii is more often the result of exposure to arthropods, as compared to contact with a beloved pet. Based upon recent and ongoing research findings, it will be absolutely critical for physicians and veterinarians to work together to define and manage diseases induced by members of the genus Bartonella.44

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Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Edward Breitschwerdt, DVM, DACVIM
North Carolina State University
Raleigh, NC

David Walker, MD
University of Texas Medical Center
Galveston, TX


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