Rickettsia Infection- Tick-Borne Rickettsioses And Spotted Fever

  • Rickettsia is small-sized intracellular bacteria about 0.3 to 2 µm and because of its small size, it was thought to be a virus.
  • These bacteria multiply in the cytoplasm of eukaryotic cells by binary fission and contain both DNA and RNA as genetic material.
  • These small gram-negative bacteria are found in the intestinal tract of ticks, flies, mites, and chiggers and cause Rocky Mountain spotted fever, rickettsialpox, epidemic typhus, and murine typhus.
  • It belongs to the Rickettsiaceae family and consists of three genera namely Rickettsia, Orientia, and Candidatus Cryptoprodotis.
  • Rickettsia and Orientia are closely related to each other while Candidatus Cryptoprodotis are detected in ticks and do not cause human infection.
  • In the genus Rickettsia25 species are recognized to date and are classified into four groups.
Rickettsia Infection- Tick-Borne Rickettsioses And Spotted Fever. Image Source: CDC.
  • The typhus group includes the fly-borne Rickettsia typhi and the louse-borne Rickettsia prowazekiithe spotted fever group is caused by 21 Rickettsiae species, the third is Rickettsia bellii and the fourth Rickettsia Canadensis group.
  • R. rickettsii rickettsiosis is the most prevalent tick-borne disease in the United States that causes Rocky Mountain spotted fever.
  • It has a high fatality rate of about 30% in untreated cases but even with proper treatment 72% are hospitalized and the fatality rate is 4% according to the report of the Center for Disease Control and Prevention.

Characteristics of Rickettsia

  • Gram-negative bacteria
  • Non-spore forming
  • Non-motile
  • Pleomorphic bacteria
  • Cocci (~0.1µm), bacilli (1 to 4µm) or thread (upto 10µm)
  • Circular genome (1 to 2.1 Mb)
  • Replicates by binary fission
  • Contains a microcapsular protein layer above the outer membrane
  • Cannot survive in an artificial nutrient environment
  • Can grow in tissue cells or chicken embryo culture

Ecology and Epidemiology of Rickettsia

  • Rickettsia is globally distributed throughout tropical, subtropical, and temperate regions based on the availability of small blood-sucking anthropods.
  • Rats are the primary reservoir of R. typhi which are transmitted to mammals by the vector rat flea and are responsible for causing murine typhus.
  • Ticks are also hematophagous arthropod vector that transmits tropical rickettsioses by biting humans and are transmitted through saliva.
  • The infection period takes 6 hours of attachment and feeding on the host skin surface before transmission.
  • Tick-borne rickettsioses and spotted fever groups are transmitted in ticks in two ways either by transtadially (stage to stage transmission) or transovarially (transfer of bacteria from adult female to eggs).
  • The infection can also be spread by scratching, itching, and rubbing the infectious tick feces into the skin.
  • Rickettsioses are emerging zoonotic diseases during international travel as the ticks are being carried out by birds, Northern American flying squirrels, and their ectoparasites.
  • It has been discovered that the alternative zoonotic cycle also plays an important role in the life cycle of typhus rickettsiae.
  • Most cases of human spotted fever rickettsioses occur in summer due to high exposure activity between humans and ticks.
  • Children aged 5 to 9 years old and older adults aged 40 to 64 years old are high-risk groups for Rocky Mountain spotted fever.
  • According to the analysis of the GeoSentinel database, about 3.1% of travelers have rickettsiosis.
  • An increase in the number of rickettsiosis infections and northward expansion of several tick species may be due to the cause of global warming.
Life cycle of tick-borne rickettsiae
The life cycle of tick-borne rickettsiae. Image Source: David H. Walker & Nahid Ismail 2008.

Pathogenesis of Rickettsioses

  • Human rickettsiosis occurs when an infected tick or mite bites on the surface of the skin or through the fecal-oral route from the ingestion of infected louse or flea feces.
  • Infection occurs after the Rickettsiae invades the vascular endothelium, multiply in the cytoplasm, and spread via the bloodstream to different parts of the body.
  • It then infects the vascular endothelium and smooth muscle cell with an increase in immune-effector responses.
  • The disseminated increases infection the permeability of vascular cells and fluids are assembled in the interstitial surroundings.
  • It leads to a decrease in blood volume which might cause hypovolemic shock and death.
  • Other affected vital organs are the brain, liver, lungs, heart, and adrenal glands causing diseases like meningoencephalitis and interstitial pneumonitis.
  • Infection can also occur by inhalation of the organisms or their feces which mainly occurs in laboratory workers due to poor hygienic practices.
  • When the kidney is infected, acute renal failure may occur due to a decrease in the perfusion of fluid.
  • The vascular leakage of plasma into the alveolar spaces leads to gas exchange in the lungs and causes hypoxemia.
  • Cellular immunity of the host cell is important for inhibition of intracellular rickettsiae by killing it in endothelial cells with the inducible nitric oxide production.
  • The inducible nitric oxide is activated by the cytokines gamma interferon and tumor necrosis factor.
  • Natural killer cells also produce immune responses against rickettsial disease and the humoral immune response produces antibodies against the outer membrane protein and prevents reinfection.
Host cell interactions of rickettsiae
Host cell interactions of rickettsiae. Image Source: David H. Walker & Nahid Ismail 2008.

Clinical syndrome of Rickettsioses

  • The incubation period is usually 7 days long with the early symptoms of severe headache, fever, chills, malaise, and myalgia.
  • A macular rash may develop after several days and typically appears on the wrist, ankles, palm, and soles at the initial stage and spreads throughout the trunk.
  • Diseases like Rocky Mountain spotted fever, rickettsialpox, epidemic typhus, and murine typhus are caused by Rickettsia species.
  • The disease has many complications such as respiratory failure, encephalitis, and acute renal failure through which the patient may die within 5 days of incision.

Diagnosis of Rickettsioses

  • The initial diagnosis is based on the clinical observation by immunohistochemical detection by taking skin biopsies of skin lesions for antigen detection.
  • Serological tests are done to confirm the diagnosis using serum samples but the antibodies might not be detected at the initial stage of infection.
  • Rickettsiosis is difficult to diagnose in an artificial culture therefore, they are isolated in viable eukaryotic host cells such as embryonated eggs, tissue cultures, antibiotic-free cell cultures, and many susceptible laboratory animals.
  • Rickettsia is grown on cell lines like HeLa, Hep2, Detriot-6, and mouse fibroblasts for their maintenance, and for isolation, they are cultivated in developing 5 to 6 days old chick embryos.
  • Laboratory animals like Guinea pigs and mice are used for the isolation of Rickettsia species from animal specimens.
  • For the diagnosis of Rocky Mountain spotted fever, a direct fluorescent antibody test is used as it is a rapid and specific method for confirmation.
  • IFA and ELISA are newly developed serological tests for the early diagnosis of Rickettsial disease.

Treatment of Rickettsiosis

  • Presumptive treatment of Rickettsioses is the use of antibiotics such as doxycycline, tetracycline, chloramphenicol, and fluoroquinolones.
  • Doxycycline is more effective and should be administered at an early stage of infection while chloramphenicol is less effective and is prescribed during pregnancy.

Prevention and Control of Rickettsioses

  • To limit the risk of infection, use protective clothing, insect repellent creams, and removal of attached ticks decreases the chance of transmission.
  • Avoid activities like bushwalking and camping where direct human contact might occur with ticks, lice, mites, and flas.
  • A vaccine is not available for Rickettsial infection to date therefore it is best to prevent direct contact with these vectors.

References

  1. Crossley, EC, Jordan, JM, & Walker, DH (2008). Rickettsia. International Encyclopedia of Public Health, 582–590.
  2. Walker, D. H. (2017). Rickettsia. International Encyclopedia of Public Health, 370–377.
  3. Socolovschi, C., Parola, P., & Raoult, D. (2013). Tick-borne Spotted Fever Rickettsioses. Hunter’s Tropical Medicine and Emerging Infectious Disease, 546–552.
  4. Silva-Ramos, CR, Hidalgo, M., & Faccini-Martínez, Á. A. (2021). Clinical, epidemiological, and laboratory features of Rickettsia parkeri rickettsiosis: A systematic review. Ticks and Tick-Borne Diseases, 12(4), 101734.
  5. Saito, TB, Bechelli, J., Smalley, C., Karim, S., & Walker, DH (2018). Vector tick transmission model of spotted fever rickettsiosis. The American Journal of Pathology.
  6. Walker, D., Ismail, N. Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Nat Rev Microbiol 6, 375–386 (2008). https://doi.org/10.1038/nrmicro1866

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