Introduction
Anaplasma phagocytophilum is an obligate intracellular, gram-negative bacterium that primarily parasitizes neutrophils. It can be transmitted by ticks and causes various diseases in mammals, including human granulocytic anaplasmosis (HGA) in humans. The clinical manifestations of this disease include fever, malaise, headache, myalgia, leukopenia, thrombocytopenia, elevated transaminases, and multi-organ dysfunction. Although the pathology of HGA resembles that of certain viral diseases, making it easily confusable with other infectious diseases, its actual harm should not be underestimated. Therefore, it is crucial to study the morphology, and genomic characteristics of Anaplasma phagocytophilum, as well as its interactions with host animals and vectors.
Fig. 1 Proposed life cycle of A. phagocytophilum. (Rikihisa Y. 2011)
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Progress in Pathogen Research
Discovery and Classificationof the Anaplasma phagocytophilum
The earliest complete description of Anaplasma phagocytophilum dates back to 1932 in Scotland, related to tick-borne fever in sheep. In 1940, the pathogen was identified in sheep. Subsequently, the same pathogen was found in cattle and sheep infected with tick-borne fever in the UK, Ireland, Scandinavia, and other parts of Europe. In the United States, equine and canine granulocytic anaplasmosis were discovered in 1969 and 1982, respectively. In 1994, Chen et al. in the United States first detected the pathogen of HGA in patients using PCR methods. In 1996, Goodman et al. successfully isolated the HGA pathogen in vitro using human promyelocytic cells.
Anaplasma phagocytophilum belongs to the order Rickettsiales, family Anaplasmataceae, and genus Anaplasma. This pathogen is widely distributed in Europe, Asia, and the United States, capable of infecting the granulocytes of various mammals. Due to significant genetic variations among pathogens from different sources, its biological characteristics are highly diverse. Currently, the family Anaplasmataceae primarily includes three genera (Anaplasma, Ehrlichia, and Neoerickettsia) and 14 species, as well as one tentative genus (Candidatus Neoehrlichia). At least six pathogens within the Anaplasmataceae family are known to cause human diseases.
Morphology and Structure of the Anaplasma phagocytophilum
Anaplasma phagocytophilum exhibits various shapes, including spherical, ovoid, and fusiform, with diameters ranging from 0.2 to 1.0 μm. It mainly parasitizes the cytoplasmic vacuoles of granulocytes, proliferating in membrane-bound inclusions, often forming chains near the cell membrane in clusters. Each inclusion contains several to dozens of bacterial bodies. When stained with Giemsa, the inclusions appear purple in the cytoplasm, resembling mulberries.
Under laboratory conditions, Anaplasma phagocytophilum can be isolated and cultured in HL-60 cells, primarily existing in vacuoles connected to the membrane structure within HL-60 cells, where it grows and proliferates rapidly. The vacuoles infected by Anaplasma phagocytophilum do not contain the fibrous structures formed by Ehrlichia chaffeensis infection. Early forms are mostly round, densely packed reticulated bodies, while later stages show smaller, denser bacterial bodies with more folds in the outer membrane compared to Ehrlichia chaffeensis.
Genetic Characteristics of the Anaplasma phagocytophilum
The genome of Anaplasma phagocytophilum consists of a circular chromosome that is 1,478,282 bp in length, with a G + C content of 41.6%. The genome includes multiple functional genes that have been lost through reductive evolution. However, it retains key genes for the biosynthesis of nucleotides, vitamins, and cofactors, as well as several major surface protein genes such as P44, HGE-14, and HGE-2 antigen protein genes.
Vectors and Hosts
Anaplasma phagocytophilum is primarily transmitted through ticks. The main vectors are the Ixodes persulcatus and Ixodes scapularis ticks. Ticks spread the pathogen by biting their hosts in natural environments. Infected ticks can transmit the pathogen at all life stages (larva, nymph, and adult).
The host range of Anaplasma phagocytophilum is broad and includes ruminants (such as cattle and sheep), dogs, horses, rodents (such as the white-footed mouse), cats, and others. Humans can also become hosts after being bitten by infected ticks. Research has found that Anaplasma phagocytophilum from different hosts exhibits significant genetic variation, leading to differences in their biological characteristics and pathogenicity.
Clinical Characteristics of Anaplasma phagocytophilum
The clinical manifestations of HGA patients are diverse. Most patients exhibit mild or no symptoms. Typical symptoms include acute high fever, headache, myalgia, and malaise. Some severe patients may develop complications such as septic shock, acute respiratory distress syndrome, and acute renal failure. Untreated patients have a disease course that ranges from 6 to 60 days, with most recovering spontaneously within 1 to 2 weeks. However, severe cases require timely antibiotic treatment.
Infection Prevention and Control of Anaplasma phagocytophilum
To prevent and control anaplasmosis, targeted prevention and control measures should be implemented. Major preventive measures include strengthening health education, personal protection, physical and chemical protective measures, controlling vectors and host animals, and conducting systematic epidemic monitoring. For suspected and clustered cases, timely epidemiological investigations should be organized to trace the infection source and transmission routes and propose targeted control measures. Conducting seroepidemiological studies in human populations and specialized monitoring of host animals and vectors is particularly important for the formulation and implementation of control strategies.
Conclusion
Human granulocytic anaplasmosis (HGA) caused by Anaplasma phagocytophilum is an emerging tick-borne zoonotic disease. This disease is widely distributed globally and can infect a variety of mammalian species. Although there has been some understanding of the pathogen and epidemiology of Anaplasma phagocytophilum in recent years, laboratory-confirmed case reports are still very limited in many countries. Systematic investigations are needed to better understand the distribution of infection in human populations. Additionally, the disease is often misdiagnosed or underdiagnosed, posing a significant threat to public health. Therefore, enhancing research on Anaplasma phagocytophilum and related diseases is of great importance for their prevention and control.
References
- Stuen S., et al. Anaplasma phagocytophilum-a widespread multi-host pathogen with highly adaptive strategies. Frontiers in Cellular and Infection Microbiology. 2013, 3: 31.
- Rikihisa Y. Mechanisms of obligatory intracellular infection with Anaplasma phagocytophilum. Clinical Microbiology Reviews. 2011, 24 (3): 469-489.
- Woldehiwet Z. The natural history of Anaplasma phagocytophilum. Veterinary Parasitology. 2010, 167 (2-4): 108-122.
- Chen S. M., et al. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. Journal of Clinical Microbiology. 1994, 32 (3): 589-595.
- Goodman J. L., et al. Direct cultivation of the causative agent of human granulocytic ehrlichiosis. New England Journal of Medicine. 1996, 334 (4): 209-215.
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