Etiology
Ehrlichiosis and anaplasmosis are tick-borne zoonotic infections that are maintained in nature through a cycle that involves an arthropod tick biting a mammalian host.
The main causative organisms are:
Ehrlichia chaffeensis: the cause of human monocytotropic/monocytic ehrlichiosis (HME)[2]
Anaplasma phagocytophilum: the cause of human granulocytotropic/granulocytic anaplasmosis (HGA)[3]
E ewingii: the cause of human ewingii ehrlichiosis (HEE).[4]
Two other bacteria in this family have been sporadically associated with human disease: Neorickettsia sennetsu and E canis, the etiologic agent of canine ehrlichiosis. Since 2009, two more pathogens associated with human cases have been identified: Ehrlichia muris eauclairensis(formerly known as Ehrlichia muris-like agent, EMLA) and Candidatus neoehrlichia mikurensis.
The lone star tick (Amblyomma americanum) is the primary vector of both E chaffeensis and E ewingii in the US, while A phagocytophilum is transmitted by the black-legged tick (Ixodes scapularis) and the western black-legged tick (Ixodes pacificus).[21] The American dog tick (Dermacentor variabilis) and the invasive Asian longhorned tick (Haemaphysalis longicornis) in the eastern US are also possible vectors for ehrlichiosis and anaplasmosis.[22][27] In Europe and eastern Europe/Asia, I ricinusand I persulcatus ticks are common vectors.[26]
Between 1997 and 2020, a total of 12 transfusion-related cases and 120 cases in transplant recipients were identified due to ehrlichiosis or anaplasmosis.[28] The majority of transfusion-related cases were due to A phagocytophilum, although a single case was attributed to E chaffeensis and a second to E ewingii.[28] Of the 120 cases in solid-organ transplant recipients, 113 cases were diagnosed as ehrlichiosis and 7 as anaplasmosis.[28] Cases occurring in solid-organ recipients include donor-derived or infections acquired via tick bites after transplantation.
Pathophysiology
Pathogenesis has been elucidated based on in vitro studies using animal- and human-derived hematopoietic cells and murine animal models developed for acute lethal and chronic infections.[29][30][31][32][33][34]
Ehrlichia and Anaplasma species are obligate intracellular Alphaproteobacteria that reside in phagosomal vacuoles in their target cells, which typically include leukocytes (neutrophils and monocytes) for Ehrlichia species and bone marrow-derived cells of all lineages (leukocytes, red blood cells, and platelets) for Anaplasma species.
In ticks, the bacteria are transmitted transstadially (i.e., pass within the tick vector through its developmental stages as larvae molt into nymphs and nymphs into adults). The bacteria enter the human body via a tick bite by an infected nymph or adult; 24 to 48 hours of attachment is needed in order for infection to take place. Disease may or may not result from infection. During this time, the tick engorges with blood and injects saliva infected with bacteria into the host. Glycoproteins from bothE chaffeensis and A phagocytophilum have been shown to translocate to the host cell’s nucleus and bind the promoter and intronic regions, and modulate gene expression of the host cell.[35][36]
Human monocytotropic/monocytic ehrlichiosis (HME)
E chaffeensis attaches to the host cell via E and L selectin through a 120-kD surface-exposed glycoprotein (TRP120).[37]
The bacterium is internalized via receptor-mediated endocytosis. It survives in the intracellular milieu via inhibition of phagosomal fusion with lysosomes and inhibition of reactive oxygen radical production.[38][39][40] Survival inside the phagosome requires iron acquisition from intracellular sources.[41]
Other survival mechanisms inside the cell include inhibition of interferon-gamma signaling pathways (Janus kinases and STAT pathways), which are required for activation of intracellular killing mechanisms.[42][43]
Modulation of gene expression has been clearly demonstrated in vitro using macrophage cell lines. Tandem repeat protein (TRP) effectors are important bacterial proteins that influence numerous cell processes including cytoskeletal reorganization, apoptosis, transcription, vesicle trafficking, autophagy, etc. These protein modulators include TRP120 (most studied), TRP32, TRP47, and TRP75.[44]
Anaplasmataceae (includes Ehrlichia and Anaplasma genre) have developed mechanisms to exploit intracellular autophagic pathways to obtain nutrients.[45]
Based on scant human data and the murine animal models of disease, the histopathology is in large part related to the immune response leading to lymphohistiocytic perivascular infiltrates and poorly formed granulomata in the liver, microvesicular fatty metamorphosis, and granulomata/focal necrosis in the spleen and the liver.
Bone marrow is normocellular or hypercellular with myeloid hyperplasia; few cases are hypocellular.
Severe cases reveal interstitial pneumonitis, hemophagocytosis, and diffuse alveolar damage.
When the central nervous system is involved, meningoencephalitis with perivascular lymphohistiocytic infiltrates can be demonstrated.[46][47][48][49]
In the animal model of fatal HME, high levels of tumor necrosis factor (TNF)-alpha produced by CD8 cytotoxic T lymphocytes has been demonstrated.[50]
Human granulocytotropic/granulocytic anaplasmosis (HGA)
A phagocytophilum attaches to polymorphonuclear neutrophils via P selectin.[51][52]
Phagolysosomal fusion is inhibited, and intracellular survival is enhanced by inhibition of superoxide dismutase, which decreases the concentration of bactericidal reactive oxygen intermediates.[40]
Apoptosis is inhibited via stabilization of bcl-2 proteins.[53][54][55]
Inhibition of interferon-gamma signaling pathways has also been demonstrated.[43]
Histopathologically, patchy inflammatory lesions composed of polymorphonuclear neutrophils and mononuclear cells can be demonstrated in the liver associated with focal hepatocyte necrosis.
Other inflammatory foci can be demonstrated in other organs such as the lungs and spleen as in HME.[46][56]
Human ewingii ehrlichiosis (HEE)
Pathophysiology in humans is unknown; however, in humans, the target cell is also the polymorphonuclear neutrophil.
Classification
Taxonomic classification[1]
The taxonomic organization of bacteria in the Anaplasmataceae family:
Ehrlichia chaffeensis: the cause of human monocytotropic/monocytic ehrlichiosis (HME)[2]
Anaplasma phagocytophilum: the cause of human granulocytotropic/granulocytic anaplasmosis (HGA)[3]
E ewingii: the cause of human ewingii ehrlichiosis (HEE).[4]
Since 2009, two more pathogens associated with human cases have been identified: Ehrlichia muris eauclairensis(formerly known as Ehrlichia muris-like agent, EMLA) and Candidatus neoehrlichia mikurensis.
EMLA has been described in Minnesota, Wisconsin, Indiana, Michigan, and North Dakota.[5] All cases reported tick exposure in Minnesota or Wisconsin. A murine animal model for this bacterium has also been reported, and the histopathology is very similar to what has been described in cases of HME.[6] The pathogen is transmitted by Ixodes scapularis ticks.
Eight cases of C neoehrlichia mikurensis have been reported in Europe and six had evidence of immunosuppression. Five of the patients recovered with doxycycline therapy and there was one fatality. Cases were diagnosed by polymerase chain reaction (PCR) using primers for the 16S rRNA gene. No isolates were obtained from any of the cases. The organism belongs to the family Anaplasmataceae, and their target cell appears to be circulating granulocytes.[7][8][9][10][11] Infections have also been documented in Asia; seven cases were reported in China.[12] In August 2014, five cases of asymptomatic infection were reported from Poland. The cases were diagnosed by PCR amplification from blood samples collected from asymptomatic individuals working in forested areas where Ixodes ricinus is prevalent.[8]
Two other bacteria in this family have been sporadically associated with human disease: Neorickettsia sennetsu and E canis, the etiologic agent of canine ehrlichiosis. These bacteria are not sufficiently investigated as human pathogens and will not be discussed here.
Use of this content is subject to our disclaimer