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In 2018, an immunosuppressed woman in southern Taiwan had onset of fever, chills, myalgia, malaise, thrombocytopenia, lymphocytopenia, and elevated hepatic transaminases. Investigation revealed infection with Ehrlichia chaffeensis. This autochthonous case of human monocytotropic ehrlichiosis was confirmed by PCR, DNA sequencing, and seroconversion.

Human ehrlichiosis and anaplasmosis are acute febrile tick-borne infectious diseases caused by various members from the genera Ehrlichia and Anaplasma. Ehrlichia chaffeensis is the major etiologic agent of human monocytotropic ehrlichiosis (HME), while Anaplasma phagocytophilum is the major cause of human granulocytic anaplasmosis (HGA). The clinical manifestations of HME and HGA ranges from subclinical to potentially life-threatening diseases associated with multi-organ failure. Macrophages and neutrophils are the major target cells for Ehrlichia and Anaplasma, respectively. The threat to public health is increasing with newly emerging ehrlichial and anaplasma agents, yet vaccines for human ehrlichioses and anaplasmosis are not available, and therapeutic options are limited. This article reviews recent advances in the understanding of HME and HGA.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation that occurs as either a familial disorder or as a sporadic condition in association with a variety of triggers. Infections are the most common cause of HLH in adults and should be searched for as early treatment usually results in a favorable outcome. Human monocytotropic ehrlichiosis (HME) is a very rare cause of HLH. Failure to consider ehrlichiosis can result in misdiagnosis and an increased length of hospitalization and healthcare cost as described in our report. Treatment for secondary HLH is aimed at reducing hypercytokinemia and eradicating inflammatory and infected cells. It is important to promptly initiate doxycycline when tick-borne diseases are being entertained as a possible trigger, as the antibiotic is effective, safe and inexpensive.

Cases of tick-borne diseases, including spotted fever rickettsioses, borreliosis, babesiosis, anaplasmosis and ehrlichiosis, in the United States and territories have more than doubled from 2004 to 2016 and account for 77% of all vector-borne disease reports. In an effort to inform control efforts, the presence of tick-borne pathogens and their vectors was assessed in a recreational park in Walker County, Texas. Here we report data from questing ticks collected on three dates from June 2017 to June 2018. The majority of ticks collected were Amblyomma americanum (96.69%) followed by three additional tick species: Dermacentor variabilis (2.59%), Ixodes scapularis (0.52%), and A. maculatum (0.21%). Ticks were pooled and tested for molecular evidence of bacterial and viral pathogens, respectively. All of the 68 pools of A. americanum had molecular evidence of the spotted fever group rickettsia, Rickettsia amblyommatis. Additionally, six (8.82%) of the A. americanum pools contained sequences matching Ehrlichia chaffeensis, the pathogen responsible for human monocytotropic ehrlichiosis, and 11 (16.18%) for E. ewingii. Three of the A. americanum pools demonstrated evidence of Borrelia lonestari. The presence of etiologic agents of known human disease in this study merits the continued surveillance efforts of ticks and their pathogens in areas where they could pose risks to public health.

Ehrlichia chaffeensis is a small, gram negative, obligately intracellular bacterium that preferentially infects mononuclear phagocytes. It is the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. Mechanisms by which E. chaffeensis establishes intracellular infection, and avoids host defenses are not well understood, but involve functionally relevant host-pathogen interactions associated with tandem and ankyrin repeat effector proteins. In this review, we discuss the recent advances in our understanding of the molecular and cellular mechanisms that underlie Ehrlichia host cellular reprogramming strategies that enable intracellular survival.

Human ehrlichiosis and anaplasmosis are acute febrile tick-borne diseases caused by various members of the genera Ehrlichia and Anaplasma (Anaplasmataceae). Human monocytotropic ehrlichiosis has become one of the most prevalent life-threatening tick-borne disease in the United States. Ehrlichiosis and anaplasmosis are becoming more frequently diagnosed as the cause of human infections, as animal reservoirs and tick vectors have increased in number and humans have inhabited areas where reservoir and tick populations are high. Ehrlichia chaffeensis, the etiologic agent of human monocytotropic ehrlichiosis (HME), is an emerging zoonosis that causes clinical manifestations ranging from a mild febrile illness to a fulminant disease characterized by multiorgan system failure. Anaplasma phagocytophilum causes human granulocytotropic anaplasmosis (HGA), previously known as human granulocytotropic ehrlichiosis. This article reviews recent advances in the understanding of ehrlichial diseases related to microbiology, epidemiology, diagnosis, pathogenesis, immunity, and treatment of the 2 prevalent tick-borne diseases found in the United States, HME and HGA.

Ehrlichioses and anaplasmoses are caused by alpha-proteobacteria within the family of Anaplasmataceae. These diseases have been known for a long time in veterinary medicine and recently in human medicine. These tick-borne zoonoses are considered as emerging diseases. The first case of human monocytotropic ehrlichiosis occurred in 1986. Human granulocytic anaplasmosis was described as a separate entity in 1994 and ehrlichiosis caused by Ehrlichia ewingii was reported in humans in 1999. The number of cases has been rising steadily due to better diagnostic techniques and better surveillance worldwide. In this review, we will present human and animal ehrlichioses and anaplasmoses as emerging diseases and present candidate(s) for the future.

In the U.S.A., human monocytotropic ehrlichiosis (HME) caused by Ehrlichia chaffeensis is an emerging tick-transmitted zoonosis. In Cameroon, where E. canis, E. chaffeensis and E. ewingii have recently been detected in dogs and/or ticks (Rhipicephalus sanguineus), the potential exists for human infections. Patients from the coastal region of Cameroon who had acute fevers of unknown aetiology were therefore checked for ehrlichial infection, using a real-time PCR that amplifies part of a genus-specific gene (dsb) that codes for a disulphide-bond formation protein. Ehrlichial blood was detected in the peripheral blood from 12 (10%) of the 118 patients investigated by PCR. When the 12 amplicons from the positive cases were sequenced, they were found to be identical to each other and to the corresponding dsb sequence of an Arkansas strain of E. chaffeensis. The 12 patients who were PCR-positive for E. chaffeensis suffered from fever (100%), headache (67%), myalgia (42%), arthralgia (58%), pulmonary involvement (17%) and/or a diffuse rash (17%).

Human monocytotropic ehrlichiosis (HME), an emerging and often life-threatening tick-transmitted disease, is caused by the obligately intracellular bacterium Ehrlichia chaffeensis. HME is modeled in C57BL/6 mice using Ehrlichia muris, which causes persistent infection, and Ixodes ovatus Ehrlichia (IOE), which is either acutely lethal or sublethal depending on the dose and route of inoculation. A persistent primary E. muris infection, but not a sublethal IOE infection, protects mice against an ordinarily lethal secondary IOE challenge. In the present study, we determined the role of persistent infection in maintenance of protective memory immune responses. E. muris-infected mice were treated with doxycycline or left untreated and then challenged with an ordinarily lethal dose of IOE. Compared to E. muris-primed mice treated with doxycycline, untreated mice persistently infected with E. muris had significantly greater numbers of antigen-specific gamma interferon-producing splenic memory T cells, significant expansion of CD4 CD25 T regulatory cells, and production of transforming growth factor 1 in the spleen. Importantly, E. muris-primed mice treated with doxycycline showed significantly greater susceptibility to challenge infection with IOE compared to untreated mice persistently infected with E. muris. The study indicated that persistent ehrlichial infection contributes to heterologous protection by stimulating the maintenance of memory T-cell responses. Human monocytotropic ehrlilchiosis (HME), an emerging tick-borne disease in the United States, is caused by the obligately intracellular bacterium Ehrlichia chaffeensis, which resides in the host mononuclear phagocytic cells (24, 34). HME manifests initially as a mild flulike illness with nonspecific symptoms (12, 22), and the disease can progress to a severe life-threatening condition resulting from liver dysfunction, multiorgan failure, meningoencephalitis, and adult respiratory distress syndrome (11, 25, 26, 28). Immune-mediated pathology is attributed in severe cases of HME to the severity of inflammation observed in the absence of high numbers of ehrlichiae in the tissues (28). It is unknown whether E. chaffeensis establishes persistent infection in humans, although a few studies reported prolonged infection with E. chaffeensis (9, 27). It is also unknown whether immunocompetent patients recovered from HME are immune to reinfection with a genetically identical or distinct E. chaffeensis strain. However, a case of reinfection with a distinct strain of E. chaffeensis after a 2-year interval in a liver transplant patient who was receiving immunosuppressive therapy has been reported (21). In a previous study, using murine models of persistent ehrlichiosis and fatal ehrlichiosis, we have established that ehrlichial species that differ in their ability to cause acute or chronic persistent infection also differ in stimulation of a longterm protective memory immune response (33). Ehrlichia muris, a mildly virulent Ehrlichia which causes persistent infection in C57BL/6 mice, but not sublethal infection with highly virulent Ixodes ovatus Ehrlichia (IOE), which causes acute infection only, induces strong memory immune responses and confers protection against an ordinarily lethal IOE challenge. The cross-protection induced by persistent E. muris infection is associated with the generation and maintenance of strong Ehrlichia-specific IFN--producing CD4 and CD8 memory Tcell responses in the spleen and production of Ehrlichia-specific serum immunoglobulin G (IgG) responses (33). The correlation between persistent primary E. muris infection and heterologous protection against secondary lethal IOE challenge suggested that persistent infection or antigen persistence could play a role in the maintenance of protective immunity. Antigen persistence or continuous exposure to low levels of antigen is thought to be required for maintenance of protective memory immune responses (3, 14, 37). In the present study we addressed the role of persistent ehrlichial infection in conferring protection against lethal heterologous ehrlichiosis. The results suggested that persistence of E. muris infection in C57BL/6 mice contributes to protective heterologous immunity against IOE infection by stimulating maintenance of memory T-cell and Ehrlichia-specific antibody responses.

The obligate intracellular bacterium Ehrlichia chaffeensis that resides in mononuclear phagocytes is the etiologic agent of human monocytotropic ehrlichiosis (HME). HME is an emerging and often life-threatening zoonotic, tick-transmitted infectious disease in the USA. Lack of early diagnosis and treatment of HME are the main factors that lead to severe and fatal disease. Ehrlichia also causes diseases in companion animals and domesticated ruminants. E. chaffeensis and E. canis cause canine ehrlichioses in dogs, whereas E. ruminantium causes heartwater in cattle, sheep, and goats. As yet there are no commercially available vaccines to protect against these pathogens. This chapter describes a protocol to develop a structure-based vaccine for Ehrlichia based on the antigenic proteins P28-19 and Ehrlichia Hsp60.

Human monocytotropic ehrlichiosis (HME), caused by the bacterium Ehrlichia chaffeensis, and human granulocytic anaplasmosis (HGA), caused by the bacterium Anaplasma phagocytophilum, are two emerging tick-borne zoonoses of concern. Factors influencing geographic distributions of these pathogens are not fully understood, especially at varying spatial extents (regional versus landscape) and resolutions (counties versus smaller land units). We used logistic regression to compare influences of physical environment, land cover composition, and landscape heterogeneity on distributions of A. phagocytophilum and E. chaffeensis at multiple spatial extents. Pathogen presence or absence was determined from white-tailed deer (Odocoileus virginianus) serum samples collected from 1981 to 2005. Ecological predictor variables were derived from spatial datasets that represented deer density, elevation, land cover, normalized difference vegetation index (NDVI), hydrology, and soil moisture. We used three strategies (a priori, exploratory, and spatial extent) to develop models. Best fitting models were applied within a geographic information system to create predictive probability surfaces for each bacterium. Ecological predictor variables generally resulted in better fitting models for E. chaffeensis than A. phagocytophilum (90.5% and 68% sensitivity, respectively), possibly as a result of differences in the natural histories of tick vectors. Although alternative model development strategies produced different models, in all cases bacteria presence or absence was affected by a combination of soil moisture or flooding variables (thought to affect primarily tick vectors) and forest cover or NDVI variables (thought to affect primarily mammalian hosts). This research demonstrates the potential for modeling the distributions of microscopic tick-borne pathogens using coarse regional datasets and emphasizes the importance of forest cover and flooding as environmental constraints, as well as the importance of considering ecological variables at multiple spatial extents.

Ehrlichia chaffeensis was detected for the first time in blood samples from Brazilian marsh deers (Blastocerus dichotomus) captured in the marshes of Parana River in Southeast Brazil in 1998. Seven EDTA-blood samples from deers were analyzed by PCR and nested PCR for presence of Ehrlichia chaffeensis, Ehrlichia ewingii, Ehrlichia canis, Neoriickettsia risticii, Anaplasma phagocytophilum and Anaplasma marginale. Three samples showed positive reactions for E. chaffeensis and Anaplasma marginale. None contained detectable A. phagocytophilum, E. ewingii, E. canis or Neorickettsia risticii DNA. In Brazil, the wild marsh deer may be a natural reservoir of the agents that cause human monocytotropic ehrlichiosis and ruminant erythrocytic anaplasmosis.

While bacterial transformation has evolved since the early 20th century to allow for the genetic manipulation of a variety of microbial agents, rickettsial organisms have proved resistant to such advances until only recently. The Ehrlichia are small, gram-negative, obligately intracellular bacterial parasites, which belong to the family Anaplasmataceae and cause a variety of infections in human and animal hosts. E. chaffeensis is the causative agent of human monocytotropic ehrlichiosis and is transmitted by Amblyomma americanum, the Lone Star tick. In this work, we describe the first report of successful transformation of a closely related ehrlichial species, the murine monocytotropic species E. muris. Application of these techniques should allow for a wide variety of molecular studies to be performed that were previously impossible. This heralds the beginning of a new era in ehrlichial research.

Ehrlichia chaffeensis, which causes human monocytotrophic ehrlichiosis (HME), is an important emerging tick-borne pathogen in the southeastern and southcentral United States. The endemnicity probability of E. chaffeensis and, by implication, locations with risk for HME, was predicted by using two modeling methods. This is first large-scale study to use geospatial analyses to estimate the distribution of E. chaffeensis, and it was conducted using data from a prototypic surveillance system that used white-tailed deer as natural sentinels. Analyses included the E. chaffeensis serostatus for 563 counties from 18 states. Both kriging and logistic regression models provided very reliable portrayals of E. chaffeensis occurrence and predicted that E. chaffeensis distribution had good concordance with human case data. The integration of a deer surveillance system with geospatial analyses was useful in developing HME risk maps that will be useful for identifying high-risk areas for public health interventions such as prevention and control efforts.

Human monocytotropic ehrlichiosis caused by Ehrlichia chaffeensis was reported in 1987. An animal model to study acute fatal ehrlichiosis in mice that has been developed closely resembles the fatal form of human monocytotropic ehrlichiosis. However, animal models for persistent infection in the genus Ehrlichia in immunocompetent mice have not been characterized. We report the histopathological progression of Ehrlichia muris infection in immunocompetent mice (AKR and C57BL/6 strains) correlated with their antibody response determined by indirect immunofluorescence and Western immunoblotting, and the distribution and quantity of the ehrlichial load by immunohistochemistry, polymerase chain reaction (PCR), and real-time PCR in lungs, liver, and spleen. Mild to moderate correlation was observed between histopathological grading in these organs and relative ehrlichial loads. The highest ehrlichial loads were present between days 4 and 14 after infection. E. muris was detected in tissues examined up to 150 days after infection by real-time PCR. Analysis of the serological response revealed several immunodominant antigens, including 200-, 180-, 100-, 73/75-, 45-, and 28-kd proteins. In conclusion, we have provided for the first time a complete histopathological, serological, immunohistochemical, and quantitative analysis of an animal model for the study of persistent ehrlichial infection.

To determine the incidence, clinical and laboratory characteristics, and utility of molecular diagnosis of human monocytotropic ehrlichiosis (HME) in the primary care setting, we conducted a prospective study in an outpatient primary care clinic in Cape Girardeau, Missouri. One hundred and two patients with a history of fever for 3 days (37.7 degrees C), tick bite or exposure, and no other infectious disease diagnosis were enrolled between March 1997 and December 1999. HME was diagnosed in 29 patients by indirect immunofluorescent antibody assay and polymerase chain reaction (PCR). Clinical and laboratory manifestations included fever (100%), headache (72%), myalgia or arthralgia (69%), chills (45%), weakness (38%), nausea (38%), leukopenia (60%), thrombocytopenia (56%), and elevated aspartate aminotransferase level (52%). Hospitalization occurred in 41% of case-patients. PCR sensitivity was 56%; specificity, 100%. HME is a prevalent, potentially severe disease in southeastern Missouri that often requires hospitalization. Because clinical presentation of HME is nonspecific, PCR is useful in the diagnosis of acute HME.

SUMMARY Ehrlichia chaffeensis is an obligately intracellular, tick-transmitted bacterium that is maintained in nature in a cycle involving at least one and perhaps several vertebrate reservoir hosts. The moderate to severe disease caused by E. chaffeensis in humans, first identified in 1986 and reported for more than 1,000 patients through 2000, represents a prototypical “emerging infection.” Knowledge of the biology and natural history of E. chaffeensis, and of the epidemiology, clinical features, and laboratory diagnosis of the zoonotic disease it causes (commonly referred to as human monocytic ehrlichiosis [HME]) has expanded considerably in the period since its discovery. In this review, we summarize briefly the current understanding of the microbiology, pathogenesis, and clinical manifestations associated with this pathogen but focus primarily on discussing various ecological factors responsible for the recent recognition of this important and potentially life-threatening tick-borne disease. Perhaps the most pivotal element in the emergence of HME has been the staggering increases in white-tailed deer populations in the eastern United States during the 20th century. This animal serves as a keystone host for all life stages of the principal tick vector (Amblyomma americanum) and is perhaps the most important vertebrate reservoir host for E. chaffeensis. The contributions of other components, including expansion of susceptible human populations, growth and broadening geographical distributions of other potential reservoir species and A. americanum, and improvements in confirmatory diagnostic methods, are also explored.

Human ehrlichioses are emerging, often life-threating, tick-borne diseases caused by obligately intracellular Gram-negative bacteria belonging to the genus Ehrlichia. Ehrlichiae lack cell wall components, lipopolysaccharide and peptidoglycan. Ehrlichiae are maintained in the enzootic cycle involving persistently infected vertebrate hosts such as deer and the vector tick. Human monocytotropic ehrlichiosis (HME), caused by Ehrlichia chaffeensis, is highly prevalent in the south-central, southeastern and mid-Atlantic regions of the United States. Molecular and serological evidence suggest a worldwide distribution of ehrlichiae. Ehrlichia chaffeensis resides in monocytes and causes moderate-to-severe flu-like illness characterised by non-specific symptoms such as fever, headache, myalgia, etc. The disease can progress to a severe toxic-shock-like syndrome with multiorgan failure, liver injury, meningoencephalitis, acute respiratory distress syndrome and myocarditis. Aberrant host inflammatory responses are implicated in the disease pathogenesis. Frequent laboratory findings in HME patients include leukopenia, thrombocytopenia and elevated hepatic transaminases. Clinical diagnosis frequently requires application of appropriate molecular diagnostics. Ehrlichia ewingii and newly discovered Ehrlichia muris-like agent (EMLA) also cause human disease. Currently no vaccine is available against ehrlichiosis. Doxycycline is the drug of choice, and initiation of antibiotic therapy early during the infection is critical for its effectiveness.

Human monocytic ehrlichiosis is an emerging tick-borne disease caused by the rickettsiaEhrlichia chaffeensis. We investigated the impact of two genes that control macrophage and T-cell function on murine resistance toE. chaffeensis. Congenic pairs of wild-type and toll-like receptor 4 (tlr4)- or major histocompatibility complex class II (MHC-II)-deficient mice were used for these studies. Wild-type mice cleared the infection within 2 weeks, and the response included macrophage activation and the synthesis ofE. chaffeensis-specific Th1-type immunoglobulin G response. The absence of a functionaltlr4gene depressed nitric oxide and interleukin 6 secretion by macrophages and resulted in short-term persistent infections for ≥30 days. In the absence of MHC-II alleles,E. chaffeensisinfections persisted throughout the entire 3-month evaluation period. Together, these data suggest that macrophage activation and cell-mediated immunity, orchestrated by CD4+T cells, are critical for conferring resistance toE. chaffeensis.

Ehrlichioses are emerging tick-borne diseases that affect several mammals, including humans. The genus Ehrlichia comprises Ehrlichia chaffeensis, Ehrlichia canis, Ehrlichia ewingii, Ehrlichia ruminantium, Panola Mountain Ehrlichia, and Ehrlichia muris; however, a new species closely related to E. muris, designated E. muris–like agent (EMLA), has been identified in human patients and ticks [1, 2]. All ehrlichial species except E. muris have been reported to cause infection in humans, which can lead to life-threatening disease, such as human monocytotropic ehrlichiosis (HME) caused by E. chaffeensis [2–6]. E. chaffeensis infection does not provide a relevant animal model, since it does not induce progressive infection in laboratory animals. E. chaffeensis infection in immunocompromised mice with severe combined immunodeficiency does not provide an ideal model for studying pathogenesis or immunity. Other murine models have been developed to better understand the mechanisms of ehrlichial infection and disease mechanisms: E. muris, a nonlethal agent inducing persistent infection, and Ixodes ovatus Ehrlichia (IOE), a lethal model [7, 8]. IOE has been detected only in I. ovatus ticks in Japan [9]. EMLA has been detected in patients from the upper Midwestern United States since 2009 [2]. The new bacterium has been identified in different stages of Ixodes scapularis ticks collected from the same region as the human patients. The disease caused by EMLA is similar to E. chaffeensis infection, with fever, malaise, fatigue, headache, nausea, and vomiting. Clinical laboratory findings include elevated hepatic aminotransferase levels, thrombocytopenia, and lymphopenia [2, 10]. An ideal animal model to study monocytotropic ehrlichiosis infection should use a human pathogen and induce dose-dependent sublethal and lethal infection [11–13]. The objective of this research was to develop and characterize a better mouse model of human ehrlichiosis, using EMLA, which will be used for future studies of the vector-host-pathogen interaction, ehrlichial pathogenesis, and immunity.

Phylogenetic analysis based on 16S rRNA gene homology places organisms currently designated Ehrlichia spp. within three different clusters. The theme of evolution for survival as obligately intracellular organisms within insects and ticks seems to characterize most of those bacteria well, except for those in the group containing Ehrlichia sennetsu and Neorickettsia helminthoeca. The etiologic organisms of human monocytotropic ehrlichiosis (HME) and human granulocytotropic ehrlichiosis (HGE) have surely been present on Earth for eons. The body of knowledge provided by veterinary scientists, including techniques to cultivate some of the Ehrlichia spp. as antigens for immunofluorescence serology and descriptions of their microscopic and ultrastructural appearance, facilitated the identification of the etiologic agent of HME as an Ehrlichia sp. Increasing numbers of commercial laboratories are offering serologic and PCR diagnostic assays for the diagnosis of the human ehrlichioses. A commercial laboratory with the most experience in the diagnosis of HME, demonstrated the presence of antibodies to E. chaffeensis in 1,136 serum specimens between October 1991 and May 1996. Cell culture recovery of the HGE agent in HL60 cells (a human myeloid cell line) has yielded more isolates than recovery of E. chaffeensis has in DH82 cells. HGE is treated successfully with doxycycline with the same doses as for HME. Based on cell culture antimicrobial susceptibility studies, rifampin, rifabutin, and selected fluoroquinolones show promise as alternative drugs that might prove useful in situations such as pregnancy.

This chapter first gives a brief history of human monocytotropic ehrlichiosis (HME), which is a zoonotic disease. From this brief history of HME, it is clear that rapid progress in understanding this newly emerged tick-borne zoonosis was facilitated both by its successful cultivation and by experimental studies of ticks linked to field observations. Epidemiological studies were furthered through the use of molecular techniques, and knowledge of HME expanded rapidly in the early to mid-1990s. Next, the chapter talks about biology of the etiologic agent. In the eastern United States, Ehrlichia chaffeensis is maintained in an epizootic cycle involving the lone star tick (Amblyomma americanum) as the principal vector and the white-tailed deer (Odocoileus virginianus) as a major vertebrate reservoir. This critical vector-host association places these two species at the core of E. chaffeensis epizootiology and strongly influences its geographic distribution and seasonality of transmission. HME caused by E. chaffeensis is endemic to the United States, with residents in the southeastern and south-central states at highest risk. The clinical recognition of HME can be difficult, since the spectrum of manifestations is broad and nonspecific, ranging from asymptomatic infection to mild self-limited symptoms to rapidly fatal disease. HME typically presents as an uncomplicated, acute, nonspecific febrile illness that resolves rapidly if treated with doxycycline, characteristic of many rickettsial infections. The chapter ends with a discussion on laboratory diagnosis, treatment and prevention of HME.

This chapter reviews information on the geographic distributions of tick-borne diseases and their primary tick vectors. It first addresses tick-borne encephalitis (TBE); Crimean-Congo hemorrhagic fever (CCHF); Colorado tick fever (CTF); tularemia; the tick-borne rickettsioses, including the rickettsial spotted fevers, tick typhuses, and Q fever; human granulocytic anaplasmosis (HGA) (previously called human granulocytic ehrlichiosis), human monocytotropic ehrlichiosis (HME), and ehrlichiosis caused by Ehrlichia ewingii; the tick-borne borrelioses, including Lyme borreliosis (LB) and tick-borne relapsing fever (TBRF); and babesiosis. Causative agents are identified, and principal ecological and epidemiological determinants of the diseases are outlined, providing information on vectors and vertebrate hosts, as well as features of the diseases useful in understanding exposures and spread and in framing case definitions. Modes of transmission other than tick bite are noted. The chapter describes primary tick vectors and their distributions. It specifically addresses 35 ixodid species and 10 argasid species of the 867 recognized species of ticks that commonly bite people. Risk of transmission to humans in foci of tick-borne diseases is determined by such factors as the density of competent vectors and reservoir hosts, infection thresholds of the pathogens, and the behaviors of humans that place them at risk of bites by infective ticks.

Introduction Ehrlichiosis is a bacterial zoonosis transmitted by hematophagous arthropods - ticks. In humans, it occurs as monocytic, granulocytic, and ewingii ehrlichiosis. Pathological process is based on parasitic presence of Ehrlichia organisms within peripheral blood cells - monocytes and granulocytes. Case Outline Fifty-two year old patient was admitted to hospital due to high fever of over 40°C that lasted two days, accompanied with chills, muscle aches, malaise, loss of appetite, headache, confusion, breathing difficulties, and mild dry cough. The history suggested tick bite that occurred seven days before the onset of disease. Doxycycline was introduced and administered for 14 days, causing the disease to subside. Indirect immunofluorescence assay was used to analyze three serum samples obtained from this patient for Ehrlichia chaffeensis antibodies, and peripheral blood smear was evaluated for the presence of Ehrlichia and Ehrlichia aggregation into morulae. Conclusion Ehrlichiosis should be considered in each case where there is a history of tick bite together with the clinical picture (high fever, chills, muscle aches, headache, generalized weakness and malaise, and possible maculopapular rash). The presence of Ehrlichia chaffeensis antibodies was confirmed in a patient with the history of tick bite, appropriate clinical picture and indirect immunofluorescence assay. This confirmed the presence of human monocytotropic ehrlichiosis, a disease that is uncommonly identified in our country. Uvod Erlihioza je bakterijska zoonoza koja se prenosi hematofagnim artropodama - krpeljima. Kod ljudi se javlja kao monocitna, granulocitna i ewingii erlihioza. Patološki proces je posledica unutar ćelijskog parazitiranja erlihije u monocitima i granulocitima periferne krvi. Prikaz bolesnika Bolesnik star 52 godine primljen je na odeljenje zbog visoke dvodnevne febrilnosti (preko 40°C) koja je praćena drhtavicom, bolovima u mišićima, malaksalošću, gubitkom apetita, glavoboljom, konfuznošću, otežanim disanjem i oskudnim suvim kašljem. U anamnezi je dobijen podatak o ujedu krpelja sedam dana pre prijema. Laboratorijski nalazi su ukazali na trombocitopeniju, leukopeniju, anemiju i povećanje aktivnosti transaminaza u serumu. Bolesnik je lečen doksiciklinom 14 dana, nakon čega su se tegobe povukle. Metodom indirektne imunofluorescencije analizirana su tri uzorka seruma ovog bolesnika na prisustvo antitela na bakteriju Ehrlichia chaffeensis i pregledan je uzorak razmaza periferne krvi na prisustvo erlihija i konglomerata erlihije u morule, koje predstavljaju citoplazmatske vakuole. Zaključak Kod bolesnika s podatkom o ubodu krpelja, odgovarajućom kliničkom slikom i serološkim testom indirektne imunofluorescencije dokazana su antitela za bakteriju Ehrlichia chaffeensis, što ukazuje na humanu monocitotropnu erlihiozu, bolest koja se kod nas retko dokazuje. Na erlihiozu treba misliti kada uz kliničku sliku (visoka febrilnost, groznica, bolovi u mišićima, glavobolja, opšta slabost i malaksalost, eventualno makulopapulozna ospa) postoji podatak o ubodu krpelja.

The clinical course and laboratory evaluation of 21 patients coinfected with human immunodeficiency virus (HIV) and Ehrlichia chaffeensis or Ehrlichia ewingii are reviewed and summarized, including 13 cases of ehrlichiosis caused by E. chaffeensis, 4 caused by E. ewingii, and 4 caused by either E. chaffeensis or E. ewingii. Twenty patients were male, and the median CD4(+) T lymphocyte count was 137 cells/microL. Exposures to infecting ticks were linked to recreational pursuits, occupations, and peridomestic activities. For 8 patients, a diagnosis of ehrlichiosis was not considered until > or =4 days after presentation. Severe manifestations occurred more frequently among patients infected with E. chaffeensis than they did among patients infected with E. ewingii, and all 6 deaths were caused by E. chaffeensis. Ehrlichiosis may be a life-threatening illness in HIV-infected persons, and the influence of multiple factors, including recent changes in the epidemiology and medical management of HIV infection, may increase the frequency with which ehrlichioses occur in this patient cohort.

Summary Tick-transmitted ehrlichiae are small obligately intracellular bacteria that are maintained in zoonotic cycles involving persistently ehrlichaemic rodents, ruminants, or canids. Ehrlichiae grow as clusters within a cytoplastic vacuole in monocytes, macrophages, and neutrophils, and in animal ehrlichioses also in platelets, erythrocytes, and endothelial cells. Ongoing reclassification of ehrlichiae will place the agent of human granulocytic ehrlichiosis (HGE), Ehrlichia phagocytophila , in the genus Anaplasma , whereas E chaffeensis , the agent of human monocytotropic ehrlichiosis (HME), and E ewingii , which also grows in neutrophils, remain in the genus Ehrlichia . HGE is transmitted by Ixodes species ticks in the upper midwestern and northeastern USA, northern California, and northwestern and eastern Europe. Ranging in severity from mild or symptomless to fatal (0·7%), HGE presents nonspecifically except for frequent thrombocytopenia, leucopenia, and elevated hepatic transaminases. HME presents similarly in the southwestern and south-central USA, but more often manifests as meningoencephalitis, adult respiratory distress syndrome, acute renal failure, rash, and death (2·7%). Diagnosis of human ehrlichioses is usually achieved by a four-fold rise in antibody immunofluorescence titre or by species-specific PCR. Detection of ehrlichiae in leucocytes in peripheral blood smears is achieved more often in HGE than HME. Doxycycline is the drug of choice for human ehrlichioses in most clinical situations. Higher recognised incidences, additional clinical manifestations, wider worldwide geographic distribution, and further discoveries of new human ehrlichioses are likely.

A nested polymerase chain reaction assay was used to determine the presence of Ehrlichia chaffeensis, E. canis, and E. ewingii DNA in blood samples of free-ranging coyotes from central and north-central Oklahoma. Of the 21 coyotes examined, 15 (71%) were positive for E. chaffeensis DNA; none was positive for E. canis or E. ewingii. Results suggest that E. chaffeensis infections are common in free-ranging coyotes in Oklahoma and that these wild canids could play a role in the epidemiology of human monocytotropic ehrlichiosis.

Seven Ehrlichia strains (six HF strains and one Anan strain) that were obtained from laboratory mice by intraperitoneally inoculating homogenates of adult Ixodes ovatus collected in Japan were characterized. 16S rRNA sequences of all six HF strains were identical, and the sequences were 99.7, 98.2, and 97.7% identical to those of Anan strain, Ehrlichia chaffeensis (human monocytic ehrlichiosis agent), and E. muris , respectively. Partial GroEL amino acid sequencing also revealed that the six HF strains had identical sequences, which were 99.0, 98.5, and 97.3% identical to those of E. chaffeensis , the Anan strain, and E. canis , respectively. All HF strains were lethal to mice at higher dosages and intraperitoneal inoculation, whereas the Anan or E. muris strain induced only mild clinical signs. Light and electron microscopy of moribund mice inoculated with one of the HF strains revealed severe liver necrosis and the presence of numerous ehrlichial inclusions (morulae) in various organs. The study revealed that members of E. canis genogroup are naturally present in Ixodes ticks. HF strains that can cause severe illness in immunocompetent laboratory mice would be valuable in studying the pathogenesis and the roles of both cellular and humoral immune responses in ehrlichiosis caused by E. canis genogroup.

Ehrlichia chaffeensis was sought among patients with a history of tick exposure and fever, and the accuracy of other diagnostic tests was compared with that of primary isolation. Among the 38 patients enrolled, E. chaffeensis was isolated from the blood of 7 (18%) and from cerebrospinal fluid specimens of 2 of these 7. All 7 patients also were positive by polymerase chain reaction (PCR) of blood, and 6 patients developed diagnostic titers of antibody to E. chaffeensis. The isolates were characterized by molecular analysis of the 16S rRNA gene, the 120-kDa protein gene, and the variable-length PCR target (VLPT) of E. chaffeensis. On the basis of the 120-kDa and VLPT genotypes, the cerebrospinal fluid and blood isolates from the same patients were identical. This study demonstrates that both PCR and culture of blood for E. chaffeensis have high diagnostic yields. More frequent isolation of E. chaffeensis from patients with infection should further our understanding of the pathogenesis of this infection.

Red foxes (Vulpes vulpes) and gray foxes (Urocyon cinereoargenteus) were evaluated for their susceptibility to experimental infection with Ehrlichia chaffeensis, the causative agent of human monocytotropic ehrlichiosis. Two red foxes and three gray foxes were inoculated intravenously with E. chaffeensis (15B-WTD-GA strain) and were monitored at 7, 14, 21, and 28 days post inoculation (DPI) for evidence of infection using an indirect fluorescent antibody (IFA) assay, light microscopy, polymerase chain reaction (PCR), and cell culture methods. One red fox and one gray fox served as negative controls. Red foxes were susceptible to infection based on reisolation of E. chaffeensis from blood at 7 and 14 DPI, seroconversion by 7 DPI, and positive PCR assays on spleen and lymph nodes at 28 DPI. Morulae were not found in circulating leukocytes and clinical signs or lesions of ehrlichiosis were not observed. In contrast, gray foxes were refractory to infection based on negative results on all culture, PCR, serologic, and microscopic examinations. These findings imply that red foxes, but not gray foxes, are potential vertebrate reservoirs for E. chaffeensis. These findings also illustrate the need to verify serologic evidence of E. chaffeensis infection among wild animals.

Diagnosis of human monocytotropic ehrlichiosis (HME) generally depends on serology that detects the antibody response to immunodominant proteins of Ehrlichia chaffeensis . Protein immunoblotting was used to evaluate the reaction of the antibodies in patients’ sera with the recombinant E. chaffeensis 120- and 28-kDa proteins as well as the 106- and the 37-kDa proteins. The cloning of the genes encoding the latter two proteins is described in this report. Immunoelectron microscopy demonstrated that the 106-kDa protein is located at the surfaces of ehrlichiae and on the intramorular fibrillar structures associated with E. chaffeensis . The 37-kDa protein is homologous to the iron-binding protein of gram-negative bacteria. Forty-two serum samples from patients who were suspected to have HME were tested by immunofluorescence (IFA) using E. chaffeensis antigen and by protein immunoblotting using recombinant E. chaffeensis proteins expressed in Escherichia coli . Thirty-two serum samples contained IFA antibodies at a titer of 1:64 or greater. The correlation of IFA and recombinant protein immunoblotting was 100% for the 120-kDa protein, 41% for the 28-kDa protein, 9.4% for the 106-kDa protein, and 0% for the 37-kDa protein. None of the recombinant antigens yielded false-positive results. All the sera reactive with the recombinant 28- or the 106-kDa proteins also reacted with the recombinant 120-kDa protein.

Human ehrlichiosis is a recently recognized tick-borne infection. Four species infect humans: Ehrlichia chaffeensis, E. sennetsu, E. canis, and the agent of human granulocytic ehrlichiosis.We tested peripheral-blood leukocytes from 413 patients with possible ehrlichiosis by broad-range and species-specific polymerase-chain-reaction (PCR) assays for ehrlichia. The species present were identified by species-specific PCR assays and nucleotide sequencing of the gene encoding ehrlichia 16S ribosomal RNA. Western blot analysis was used to study serologic responses.In four patients, ehrlichia DNA was detected in leukocytes by a broad-range PCR assay, but not by assays specific for E. chaffeensis or the agent of human granulocytic ehrlichiosis. The nucleotide sequences of these PCR products matched that of E. ewingii, an agent previously reported as a cause of granulocytic ehrlichiosis in dogs. These four patients, all from Missouri, presented between May and August 1996, 1997, or 1998 with fever, headache, and thrombocytopenia, with or without leukopenia. All had been exposed to ticks, and three were receiving immunosuppressive therapy. Serum samples obtained from three of these patients during convalescence contained antibodies that reacted with E. chaffeensis and E. canis antigens in a pattern different from that of humans with E. chaffeensis infection but similar to that of a dog experimentally infected with E. ewingii. Morulae were identified in neutrophils from two patients. All four patients were successfully treated with doxycycline.These findings provide evidence of E. ewingii infection in humans. The associated disease may be clinically indistinguishable from infection caused by E. chaffeensis or the agent of human granulocytic ehrlichiosis.

The emerging tick-borne zoonoses human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE) are under reported in the United States. From 1986 through 1997, 1,223 cases (742 HME, 449 HGE, and 32 not ascribed to a specific ehrlichial agent) were reported by state health departments. HME was most commonly reported from southeastern and southcentral states, while HGE was most often reported from northeastern and upper midwestern states. The annual number of reported cases increased sharply, from 69 in 1994 to 364 in 1997, coincident with an increase in the number of states making these conditions notifiable. From 1986 through 1997, 827 probable and confirmed cases were diagnosed by serologic testing at the Centers for Disease Control and Prevention, although how many of these cases were also reported by states is not known. Improved national surveillance would provide a better assessment of the public health importance of ehrlichiosis.

Serological testing at the New York State Department of Health for human granulocytic ehrlichiosis in the residents of Westchester County, N.Y., was performed with specimens from 176 patients by the indirect fluorescent-antibody (IFA) technique with Ehrlichia equi MRK-infected neutrophils. To understand whether human monocytotropic ehrlichiosis also occurs in this northeastern geographic region, specimens were also tested for antibodies to Ehrlichia chaffeensis Arkansas. Screening tests and immunoblots for Lyme disease (Borrelia burgdorferi infection) were also performed. Thirty-two patients had antibodies only to E. equi and 21 patients had antibodies to both E. equi and E. chaffeensis, whereas 12 patients had only E. chaffeensis antibodies by the IFA technique. The remaining patients did not have antibodies to either ehrlichia. Eighteen serum samples from 13 of these patients were coded and sent to the Ehrlichia Research Laboratory (Baltimore, Md.) for repeat analysis by the IFA test and for E. equi and E. chaffeensis immunoblots. Immunoblot analysis for E. equi in samples with positive IFA test results confirmed the results for eight of the nine specimens. Immunoblot analyses for E. chaffeensis were negative for all 18 serum samples. Borrelia-reactive antibodies were found in sera both from patients with granulocytic ehrlichiosis and from patients with monocytotropic ehrlichiosis from New York State. Our results suggest that E. equi antigen is an appropriate substrate for identifying human granulocytic ehrlichiosis. E. chaffeensis antigen lacks appropriate sensitivity to serve as a surrogate substrate for the detection of human granulocytic ehrlichiosis and should be used solely for the diagnosis of human monocytotropic ehrlichiosis. Heat shock proteins may, in some cases, cause cross-reactivity between B. burgdorferi and ehrlichiae.

Field and experimental studies have implicated white-tailed deer (Odocoileus virginianus) as probable reservoir hosts for Ehrlichia chaffeensis, the causative agent of human monocytic ehrlichiosis, but natural infection in deer has not been confirmed through isolation of E. chaffeensis. Thirty-five white-tailed deer collected from three Amblyomma americanum-infested populations in Georgia were examined for evidence of E. chaffeensis infection by serologic, molecular, cell culture, and xenodiagnostic methods. Twenty-seven deer (77%) had E. chaffeensis-reactive indirect fluorescent-antibody assay titers of > or = 1:64; and the blood, spleens, or lymph nodes of seven (20%) deer were positive in a nested PCR assay with E. chaffeensis-specific primers. E. chaffeensis was isolated in DH82 cell cultures from the blood of five (14%) deer, including two deer that were PCR negative. Combination of culture and PCR results indicated that six (17%) deer were probably rickettsemic and that nine (26%) were probably infected. Restriction digestion of PCR products amplified from deer tissues and cell culture isolates resulted in a banding pattern consistent with the E. chaffeensis 16S rRNA gene sequence. The sequences of all PCR products from deer tissues or cell culture isolates were identical to the sequence of the Arkansas type strain of E. chaffeensis. Xenodiagnosis with C3H mice inoculated intraperitoneally with deer blood, spleen, or lymph node suspensions was unsuccessful. When viewed in the context of previous studies, these findings provide strong evidence that E. chaffeensis is maintained in nature primarily by a tick vector-vertebrate reservoir system consisting of lone star ticks and white-tailed deer.

Ehrlichia chaffeensis is the tick-borne, obligately intracellular bacterium that causes human monocytic ehrlichiosis. A 120-kDa protein is one of the immunodominant proteins of E. chaffeensis that stimulates production of specific antibodies in infected humans. A genomic library of E. chaffeensis was constructed in a λZAP II phage vector, and a clone expressing the 120-kDa protein of E. chaffeensis was identified using canine anti- E. chaffeensis serum. DNA sequence analysis of the cloned 120-kDa protein gene of E. chaffeensis identified a 1884-bp open reading frame with an ehrlichial promoter. Five identical 240-bp tandem repeat units were identified in the 120-kDa protein gene of E. chaffeensis , comprising 60% of the entire gene. Aside from the first repeat unit, all the other repeat units are identical. In the first repeat unit there are four nucleotides that are different from the other repeats. Hydropathy analysis of the deduced amino-acid sequence demonstrated that the repeat domain contains highly hydrophilic segments. The 120-kDa protein should be evaluated for a role in stimulating protective immunity.

Ehrlichia chaffeensis is an obligately intracellular gram negative bacterium with a small genome that thrives in mammalian mononuclear phagocytes by exploiting eukaryotic processes. Herein, we discuss the latest findings on moonlighting tandem repeat protein effectors and their secretion mechanisms, and novel molecular interkingdom interactions that provide insight into the intracellular pathobiology of ehrlichiae.

Description of the pathobiology of the recently described zoonotic agent of human ehrlichiosis ( Ehrlichia chaffeensis ) would be greatly facilitated by the availability of a convenient experimental animal model of infection. We determined whether C3H/HeJ mice could sustain persistent infection by this predominantly monocyte-inhabiting rickettsia. Such mice rapidly produced an intense specific IgG response upon inoculation of ehrlichiae, and high titers were demonstrable for more than 6 months thereafter. Ehrlichiae were reisolated from the peripheral blood and spleen of 1 mouse at day 11 after inoculation. DNA of E. chaffeensis was more frequently detected within these tissues by polymerase chain reaction. Other candidate rodent models appeared to be poor hosts for this pathogen. About half of intact and virtually all splenectomized white-footed mice that were inoculated seroconverted. Sera from inoculated voles and hamsters did not react to antigens of E. chaffeensis . The C3H/HeJ mouse becomes persistently infected by this rickettsia, and may serve as a useful model for studies of the immune response to the agent of human ehrlichiosis.

Since 1989, we have confirmed the diagnosis of human ehrlichiosis in 57 patients. Although routine radiological studies of the central nervous system (CNS) or analyses of cerebrospinal fluid (CSF) samples were not done for these patients, primary care physicians detected symptoms or signs that prompted them to perform such studies. CSF samples were examined for 15 of the 57 patients. Findings in eight of the 15 CSF samples were abnormal, and the most common abnormalities were lymphocytic pleocytosis and elevated protein levels. A search of the English-language literature revealed 21 additional cases in which CSF examinations were performed; in 13 of these cases, CSF findings were abnormal. The most common clinical finding that predicted CSF abnormalities was a change in mental status. A total of 14 patients underwent computerized tomographic studies, and none of these studies showed abnormalities. Four (19%) of the 21 patients with CNS manifestations of ehrlichiosis and abnormal CSF findings died.

Human granulocytic ehrlichiosis is a potentially fatal tick-borne infection that has recently been described. This acute febrile illness is characterized by myalgias, headache, thrombocytopenia, and elevated serum aminotransferase levels. The disease is difficult to diagnose because the symptoms are non-specific, intraleukocytic inclusions (morulae) may not be seen, and the serologic results are often initially negative. Little is known about the causative agent because it has never been cultivated.We studied three patients with symptoms and laboratory findings suggestive of human granulocytic ehrlichiosis, including unexplained fever after probable exposure to ticks, granulocytopenia, and thrombocytopenia. Peripheral blood was examined for ehrlichia microscopically and with use of the polymerase chain reaction (PCR). Blood was inoculated into cultures of HL60 cells (a line of human promyelocytic leukemia cells), and the cultures were monitored for infection by Giemsa staining and PCR.Blood from the three patients, only one of whom had inclusions suggestive of ehrlichia in neutrophils, was positive for human granulocytic ehrlichiosis on PCR. Blood from all three patients was inoculated into HL60 cell cultures and caused infection, with intracellular organisms visualized as early as 5 days after inoculation and cell lysis occurring within 12 to 14 days. The identity of the cultured organisms was confirmed by immunofluorescence microscopy, PCR analysis, and DNA sequencing. DNA from the infected cells was sequenced in regions of the 16S ribosomal gene reported to differ between the agent of human granulocytic ehrlichiosis and closely related species, including Ehrlichia equi and E. phagocytophila which cause infection in animals. The sequences from all three human isolates were identical and differed from the strain of E. equi studied in having guanine rather than adenine at nucleotide 84.We describe the cultivation of the agent of human granulocytic ehrlichiosis in cell culture. The ability to isolate this organism should lead to a better understanding of the biology, treatment, and epidemiology of this emerging infection.

Ehrlichiae are small, gram-negative, obligately intracellular bacteria that reside within a phagosome. The first human ehrlichial infection was recognized in the United States in 1987. It was later shown to be caused by a new species, Ehrlichia chaffeensis. In 1994, an ehrlichial pathogen within neutrophils that is closely related to the known veterinary pathogens E. equi and E. phagocytophila was found to infect humans. Molecular methods were required to detect, characterize, and identify these fastidious and uncultivated bacteria. Subsequently, E. chaffeensis infection was documented in more than 400 patients in 30 states, Europe, and Africa. Likewise, approximately 170 cases of human granulocytic ehrlichiosis have been diagnosed, most since 1994, predominantly in the upper midwestern and northeastern states, but also in northern California. The disease caused by ehrlichiae is generally undifferentiated but is often associated with leukopenia, thrombocytopenia, and elevated serum hepatic transaminase levels in tick-exposed patients. Infection ranges from subclinical to fatal; tetracycline appears to be an effective therapy. The emergence of these two newly recognized tickborne infections as threats to human health is probably due to increased clinical cognizance, but as in other emerging tickborne infections, it is likely that the rapid increase in identified cases signals a true emergence of disease associated with a changing vector-host ecology.

Ehrlichioses are caused by obligately intracellular bacteria that are maintained subclinically in a persistently infected vertebrate host and a tick vector. The most severe life-threatening illnesses, such as human monocytotropic ehrlichiosis and heartwater, occur in incidental hosts. Ehrlichia have a developmental cycle involving an infectious, nonreplicating, dense core cell and a noninfectious, replicating reticulate cell. Ehrlichiae secrete proteins that bind to host cytoplasmic proteins and nuclear chromatin, manipulating the host cell environment to their advantage. Severe disease in immunocompetent hosts is mediated in large part by immunologic and inflammatory mechanisms, including overproduction of tumor necrosis factor α (TNF-α), which is produced by CD8 T lymphocytes, and interleukin-10 (IL-10). Immune components that contribute to control of ehrlichial infection include CD4 and CD8 T cells, natural killer (NK) cells, interferon-γ (IFN-γ), IL-12, and antibodies. Some immune components, such as TNF-α, perforin, and CD8 T cells, play both pathogenic and protective roles. In contrast with the immunocompetent host, which may die with few detectable organisms owing to the overly strong immune response, immunodeficient hosts die with overwhelming infection and large quantities of organisms in the tissues. Vaccine development is challenging because of antigenic diversity of E. ruminantium, the necessity of avoiding an immunopathologic response, and incomplete knowledge of the protective antigens.

From 1981 through 1993, tick infestations and serum antibodies reactive to Ehrlichia chaffeensis, the causative agent of human ehrlichiosis, were monitored among white-tailed deer (Odocoileus virginianus) at Whitehall Experimental Forest, Clarke County, Georgia (USA). Neither ticks nor E. chaffeensis antibodies were detected during the first two years of the study. Infestations of the lone star tick (Amblyomma americanum), a suspected vector of E. chaffeensis, first were noted on deer in 1983. Prevalence and intensity of A. americanum sharply increased from 1985 to 1989, and prevalence was 100% from 1990 to 1993. Antibodies reactive to E. chaffeensis were first detected in 7% of deer sampled in 1986. Antibody prevalence increased to 21% in 1987 and was 100% from 1988 to 1993. This temporal association between the establishment of A. americanum and the appearance of E. chaffeensis antibodies provides evidence to support the concept that A. americanum could be a natural vector of E. chaffeensis. The high prevalence of antibodies among all age classes of deer also reaffirms that white-tailed deer may be sensitive natural sentinels for monitoring the distribution of E. chaffeensis.

Human ehrlichioses and rickettsioses are important arthropod borne infectious diseases which are transmitted by ticks, mites, lice and fleas. Infections result in mild to fatal outcomes, with clinical presentations that resemble other tropical infectious diseases such as malaria making clinical diagnosis difficult. Despite recognition as important causes of lifethreatening diseases in the United States, the geographic distribution of these diseases worldwide remains undefined due to their recent emergence, challenges in diagnosis and lack of comprehensive epidemiological studies needed to determine incidence in developing countries. Recently, the transfer of technological developments to other parts of the world especially developing countries has encouraged basic epidemiological inquiry and generated scientific interest in understanding the epidemiology of these tick borne diseases and their role as causes of undifferentiated febrile illnesses. In this chapter, we review the current knowledge of human monocytotropic ehrlichiosis (HME) and spotted fever rickettsiosis (African tick bite fever) in Cameroon.

Background Ehrlichia chaffeensis is a bacterial pathogen that causes fatal human monocytic ehrlichiosis (HME) that mimic toxic shock-like syndrome. Murine studies indicate that over activation of cellular immunity followed by immune suppression plays a central role in mediating tissue injury and organ failure during fatal HME. However, there are no human studies that examine the correlates of resistance or susceptibility to severe and fatal HME. Results In this study, we compared the immune responses in two patients with mild/non fatal and severe/fatal HME who had marked lymphopenia, thrombocytopenia and elevated liver enzymes. The levels of different immunological factors in the blood of those patients were examined and compared to healthy controls. Our data showed that fatal HME is associated with defective production of Th1 cytokines such as ( IFNγ and IL-2), increased anti-inflammatory (IL-10 and IL-13) and pro-inflammatory (TNF-α, IL-1α, IL-1β, and IL-6) cytokines, increased levels of macrophages, T cells, and NK cells chemokines such as MCP-1, MIP-1α, MIP-1β, but not RANTES and IP-10, increased levels of neutrophils chemokine and growth factor (IL-8 and G-CSF), and elevated expression of tumor necrosis factor receptor (TNFR), and toll like receptors 2 and 4 compared to patients with non fatal HME and healthy controls. Conclusions Fatal Ehrlichia-induced toxic shock is associated with defective Th1 responses, possible immune suppression mediated by IL-10. In addition, marked leukopenia observed in patients with fatal disease could be attributed to enhanced apoptosis of leukocytes and/or elevated chemokine production that could promote migration of immune cells to sites of infection causing tissue injury.

We determined the antibody prevalence to Ehrlichia spp., in white-tailed deer (Odocoileus virginianus) and the geographic distribution of seropositive animals in 84 counties in Alabama, Arkansas, Florida, Georgia, Illinois, Kentucky, Louisiana, Maryland, Massachusetts, Mississippi, Missouri, North Carolina, South Carolina, Tennessee, Texas, Virginia, and West Virginia (USA). Using an indirect fluorescent antibody test we detected antibodies (or = 1:128) to this bacterium in 544 (43%) of 1269 deer. Presence of antibodies to Ehrlichia spp. was related to a southerly latitude, low elevation, and resulting milder climatic conditions. It appears that white-tailed deer were naturally infected with Ehrlichia spp.; the infection was widely distributed throughout the southeastern United States. Based on these data, we propose that white-tailed deer play a role in the natural history of Ehrlichia spp. infection in the United States.