Neorickettsia sennetsu

by Julien Beauchamp

Introduction

Neorickettsia sennetsu, originally classified as Ehrlichia sennetsu, is the etiologic agent of the well-defined human syndrome known as Glandular or Sennetsu Fever. The first recognized infection was diagnosed in Japan in 1954. Cases of Sennetsu Fever seem to be restricted to parts of Western Japan and Southeast Asian countries. N. sennetsu is a member of the family Anaplasmataceae, a group of Gram-negative obligatory intracellular bacteria. This means that they cannot survive outside their eukaryotic host cell. The bacteria invade and multiply in host macrophages and monocytes (specialized white blood cells used to destroying invading microbes).

Disease

N. sennetsu is thought to be transmitted to humans through nematodes encysted in raw or improperly cooked fish. Nematodes are roundworms suited to living inside the digestive tracts of animals. Neorickettsia spp. lack common pili or capsules, used by normal bacteria to bind, and therefore bind to host cells via outer membrane proteins. These are proteins found on the outside surface of cells, used for interacting with the environment. The vector stimulates an inflammatory response when it clings to the intestinal wall. This faciliates the interaction between the bacteria and small veins, arteries, and capillaries. The endothelial cells are an important site of involvement in the disease process. Entry into the host phagocytes is mediated by transglutaminase activity, which is necessary for receptor-mediated endocytosis. Transglutaminase is an enzyme used to bind proteins together. The endocytosis allows the pathogen to successfully establish vacuoles for survival inside the host immune cell. These specialized compartments block the macrophage’s normal activity of fusing it with lysosomes. The appearance of inclusion bodies that appear on the surface of the host cell can lead to the disintegration of the macrophages or monocytes. If the infection progresses, Sennetsu Fever causes enlargement of the liver, spleen and lymph nodes. Other symptoms include fever, chills, headache, sore throat, muscle aches, nausea, vomiting, and insomnia, along with other non-specific flu-like symptoms. Signs of illness begin about 1-2 weeks after consumption.

Figure 1: N. sennetsu presumed life cycle. A, eggs deposited in feces. B, First intermediate host (musculus). C, Cercariae. D/E, Secondary intermediate host. F, Present within parasitic flukes found in the secondary intermediate hosts. H, Ingestion by humans leads to infection of the digestive tract. Source: Julien Beauchamp.

Epidemiology

Sennetsu is only reported in parts of Southeast Asia (Japan, Laos, Thailand, Philippines and Malaysia), where fish is a staple food and eating it raw is common. The disease is described as a type of Human Ehrlichioses. Many forms of veterinary Ehrlichioses have been identified since the early 1900s. In most cases the bacteria were transmitted by ticks, causing disease in horses, sheep, deer, cattle, rodents and dogs. It is known that N. sennetsu shares many antigenic qualities with E. canis, the causative agent of Canine Ehrlichioses. Ehrlichia sennetsu was renamed Neorickettsia sennetsu after being discovered as the first human form of the illness. Sennetsu Fever was first recognized in japan in 1954 on the island of Kyushu and continued to be prevalent in Japan during the rest of the 1950s-60s. Sennetsu Fever was shown to be transmittable to mice and then to humans in Japan. Consumption of grey mullet, a fish indigenous to Japan has been associated with the illness. Also, in Laos, documented cases were linked to eating raw climbing perch.

The disease was described as mononucleosis-like and is often confused for mono. Mononucleosis, or mono, applies to a group of symptoms associated with the Epstein-Barr virus (EBV), which had many similarities with N. sennetsu infection. Fortunately, Glandular Fever is not contagious and will not spread from one person to another. Individuals with reduced immunity, such as those with HIV or who are undergoing cancer treatment may be at a higher risk of contracting Sennetsu Fever.

Virulence factors

Neorickettsia species have complex life cycles involving trematodes and several hosts. Once entering a their human host, the bacteria look to infect the endothelial layers of the GI (gastrointestinal) tract so that they can eventually make their way into the bloodstream and lymphatic system. Despite a small genome of 0.9 Mb, Neorickettsia sennetsu has a wide range outer membrane proteins, dependant on different host cell environments. The internalization, or entering the cell, through specific binding sites is necessary for establishing infection. The binding signals disarm the host cell’s ‘alarm’ against pathogens, allowing entry into the cell. They enter the host phagocyte (macrophage or monocyte) without the help of small filaments used by other species. Therefore, there is no phagocytosis (engulfing by the macrophage); instead they rely on the mentioned transglutaminase activity. This activity allows for receptor-mediated endocytosis. Meaning, the cell can now be inside the cytoplasm of their new home the cells can replicate. The vacuoles they form are called ‘modified parasitophorous endosomes’ because they are negative for lysosomal glycoproteins. These unique containers protect the bacteria from the host cell’s ability to break them down by fusion with lysosomes because of the glycoproteins. The bacteria now looks for a method to acquire nutrients and compete with the host cell. N. sennetsu comes from a group of bacteria with a considerable need of iron. The pathogen helps the host cell regulate the amount of iron-transferrin (Tf) present by synthesizing toxins. Tf regulated the normal amount of iron available. These protein toxins inhibit certain restraining factors normally found in the phagocyte DNA, vastly increasing the amount of available iron. The changes made to the healthy cell’s metabolism and the exit of the bacterial cells through inclusion bodies leads to the death of the host. Both entering the cell and the creation of proteins are important steps in the infection. Additionally, if the white blood cell count decreases the bacteria may also grow in membrane-bound cavities inside bone marrow, lymph nodes, liver, spleen, kidneys, lungs or even cerebrospinal fluid.

Figure 2: Process of a N. sennetsu entering host cell. A, N. sennetsu approaching the cell surface . B, N. sennetsu is partially internalized, being engulfed by a cell ruffle. C, Two morulae are seen still connected by a membrane after division. Source: Julien Beauchamp.

Treatment

N. sennetsu is generally treated with a tetracycline antibiotic, such as doxycycline or minocycline. The antibiotics stop the synthesis of certain proteins, neutralizing the capability of N. sennetsu to inhibit the digestion process of the macrophage/monocyte. Pregnant women may be prescribed another antibiotic since the tetracycline class of antibiotics can be harmful for a fetus. In severe cases hospitalization may be required. Other treatment is largely supportive and symptomatic.

References

Dumler, J. S. (2011). Ehrlichioses and Anaplasmosis. Tropical Infectious Diseases 3, 339-343. doi: 10.1016/B978-0-7020-3935-5.00052-5

Hoilien, C. A., Ristic, M., Huxsoll, D. L. & Rapmund G. (1982). Rickettsia sennetsu in human blood monocyte cultures: similarities to the growth cycle of Ehrlichia canis. Infect. Immun. 35, 314-319.

Kelly, D. J., Lee, M. & Lewis, G. E. Jr. (1985). A light and electron microscopic examination of ehrlichia sennetsu in cultured human endothelial cells. Japan. J. Med. Sci. Biol. 38, 155-168.

Regan, J. J. & Nicholson, W. L. (2012). Etiologic Agents of Infectious Diseases. Principles and Practice of Pediatric Infectious Disease 4, 893-896. doi: 10.1016/B978-1-4377-2702-9.00172-0

Rikihisa, Y. (2003). Mechanisms to Create a Safe Haven by Members of the Family Anaplasmataceae. Annals 990, 548-555. doi: 10.1111/j.1749-6632.2003.tb07425.x

Tachibana N. (1986). Sennetsu fever: the disease, diagnosis, and treatment. Microbiology 1986, 205-208.

Walker, D., et al. (1998). Ultrastructural differentiation of the genogroups in the genus Ehrlichia. Journal of Medical Microbiology 47, 235-251. doi: 10.1099/00222615-47-3-235

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