Rickettsia

Rickettsiae were named after the English pathologist Howard Taylor Ricketts, who, among other things, described Rocky Mountains spotted fever. He was able to detect its pathogen in the blood of infected people. Howard Taylor Ricketts became infected with rickettsiae during his research work and died of this infection in 1910.

Rickettsiae were previously thought to be close relatives of viruses because they are smaller than bacteria and because, like viruses, their reproduction occurs only within living cells. However, apart from the fact that rickettsiae are extremely fastidious in their growth conditions, it is now certain that rickettsiae are small, obligately parasitic, true bacteria, in which all structural features of bacteria, furthermore all enzymes as well as all building elements of the bacterial cell wall can be detected . Thus, they oxidize intermediate metabolic products such as pyruvic acid, succinic acid and glutamic acid and can convert glutamic acid into aspartic acid.

The genera Rickettsia /and Orientia comprise pleomorphic, coccoid or short rod bacteria with a size of 0.5-1.5μm. Their cell structure is similar to that of Gram-negative bacteria. Rickettsiae reproduce exclusively intracellularly in the cytoplasm of endothelial cells and macrophages. Propagation by transverse division also occurs inside the host cell. The bacteria are subsequently released by strangulation from the cell membrane (exocytosis) or by lysis, which destroys the host cell. Due to their dependence on the host cell, bacteria cannot be kept in artificial culture media in the laboratory. They are therefore grown either in biological tissues or embryo cultures (typically chicken embryos are used). Human pathogenic rickettsiae are transmitted exclusively by arthropods.

Rickettsiae multiply in different parts of the cell. Species belonging to the spotted fever group can generally be detected in the cytoplasm of cells, whereas species belonging to the spotted fever group can be detected in the nucleus. However,the physiological basis for the obligate parasitism of the rickettsiae has remained a mystery for more than 90 years.

The natural reservoir of these microorganisms is arthropods, in which they can live without causing any tangible disease in this host. If, on the other hand, they are transferred to a "false host" such as humans, they can have a pathogenic effect on this false host. Humans as the final host only play a role in the late relapses of classical spotted fever (Brill-Zinsser disease ). Cultivation and enrichment succeed in cell cultures or in animal experiments, but require the safety standards of a high-security laboratory (BSL 3). Isolation is not possible on standard microbiological culture media.

In the order Rickettsiales, the family Rickettsiaceae is found with diverse genera and important human pathogenic representatives. The human pathogenic species of the genus Rickettsia can be grouped into 3(4) groups (see also Rickettsioses):

typhoid fever group (typhus-group)

• Rickettsia prowazeckii (classical typhus)
• Rickettsia typhi (murine typhus)

Tick-bite fever (spotted fever group)

• Rickettsia akari (rickettsial pox)
• Rickettsia africae (African tick bite fever)
• Rickettsia australis (Queensland tick bite fever)
• Rickettsia conorii (Mediterranean spotted fever/Boutonneuse fever)
• Rickettsia rickettsii (Rocky Mountain spotted fever)
• Rickettsia sibiricae (North Asian or Siberian tick-bite fever/sibirian tick typhus)
• Rickettsia japonica (Japanese spotted fever)
• Rickettsia felis (cat flea typhus)

Tsutsugamushi fever group

• Orientia tsutsugamsuhi (Japanese spotted fever; scrub typhus)

Coxiella burnetti (Q fever): taxonomically listed as a separate group

Rickettsioses in a broader sense

Ehrlichia, Anaplasma and Neorickettsiosis are considered to be rickettsioses in a broader sense.

Rickettsia is transmitted in the faeces of arthropods, and in the saliva of ticks. To invade eukaryotic cells, rickettsia apparently use the protein kinase Ku 70 in endothelial cells, which is a receptor for OmpB proteins on the cell wall of rickettsia. This receptor enables the invasion of the endothelial cell of the host with subsequent severe damage up to apoptosis. The pathogens mainly attack the endothelial cells of the small blood vessels. Within the host cell, the rickettsiae lie in a vacuole in which they can multiply. This leads to an expansion of the vacuole, which can take up the entire cytoplasm. The cell dies. The pathogen enters the bloodstream in batches where they are phagocytosed by macrophages. Small endothelial lesions result, leading to focal vasculitis with thrombosis of the capillaries and hyperplasia of the endothelia. The result of vasculitis is focal necrosis.

The pathophysiology of the very severe rickettsial diseases, such as classical spotted fever or Rocky Mountain spotted fever, can be explained in a similar way. In these cases, disseminated multiple vasculitides occur in the skin, brain, myocardium, kidneys and many other organs, which are accompanied by microthrombosis and consecutive necrosis, thus explaining the severity of these diseases and their high lethality. Rickettsial diseases leave a long-lasting, probably cell-mediated immunity. The causes of the sometimes very marked differences in virulence within the rickettsial species are not yet known in detail.

All rickettsial diseases have a similar clinical course: incubation period 3 - 20 days, onset with general signs of illness: high fever, chills, headache, myalgias, arthralgias, abdominal pain, lymphadenopathy, general feeling of illness, nausea, possible hepatosplenomegaly, increased transaminases, thrombocythemia.

Complications: pulmonary, neurological, ocular, hepatic, cardiac in varying degrees. Course depends on cardiac and CNS involvement.

Untreated lethality rates:

• classic spotted fever 40
• Rocky mounted spotted fever > 20
• Mediterranean tick-bite fever < 3 %
• with adequate treatment 1 - 2 %.

The infections leave long-term immunity.

In the early phase of the infection, the pathogens can be detected by means of real time PCR from EDTA blood of the patient, after the development of the eschar (in spotted fever) by means of real time PCR also in this necrotic skin lesion, which corresponds to the inoculation site of the pathogens. For this purpose, a small sample of the eschar can be sent to the laboratory; good results are also obtained with a moist smear of the eschar. If the PCR is positive, the responsible rickettsial species is sequenced and determined. Ticks, clothes lice and fleas from patients with corresponding symptoms can also be examined for these pathogens using real time PCR and, if positive, subsequent sequencing.

Serology: In addition to PCR, the patient's blood can also be examined serologically for the presence of rickettsialpox. However, seroconversion often takes more than 5 days. In indirect immunofluorescence , IgM and IgG antibodies against rickettsiae (tick-bite fever rickettsiae and against spotted fever rickettsiae) are determined.

Eschar: Histopathologically, a necrotizing vasculitis is seen at the site of entry, which manifests clinically with central necrosis in a livid red infiltrate. This primary lesion, which is covered with blackisheschar, is known as "eschar" or "tache noir" in tropical medicine and is often accompanied by lymphangitis. It is, for example, the leading symptom of African tick-bite fever.

Tetracyclines, e.g. two-week administration of doxycycline.

Alternatively, quinolones can be used.

For central nervous system infections, chloramphenicol or (the tetracycline) doxycycline in combination with quinolones and/or rifampicin may be considered as antimicrobial drugs.

In moist media, killing occurs at 50 °C in 15 minutes. The pathogens can also be effectively destroyed with conventional disinfectants.

Because of their cell dependency and their reduced metabolism, rickettsiae were grouped in the past between the viruses and the bacteria, as it were as an "intermediate species". For a long time, they were also referred to as "large viruses".

In Europe, millions of people were still dying of spotted fever at the time of the two world wars. As a result of the destruction of the clothes louse, the disease disappeared in Europe. Retrospectively, according to US epidemiologists, about 40-45% of the 225000 "lost man days" caused by fever of uncertain origin (FUO) during the Vietnam War 1966 -1969 can be attributed to rickettsiosis. In some Andean valleys, rickettsioses are still endemic.

Coxiella burnetii, Rickettsia prowazekii, Rickettsia typhi, and Rickettsia rickettsii are particularly important because they can survive longer outside their vector and are extremely infectious. They are considered potential agents for bioterrorist attacks.

1. Badger LF (1993) Rocky Mountain spotted fever and boutonneuse fever. A study of their immunological relationship. Publ Hlth Rep (Wash.) 48: 507
2. Caron J et al (2008) Rickettsia sibirica subsp. mongolitimonae infection and retinal vasculitis. Emerg Infect Dis 14:683-684.
3. Fournier PE et al. (2005) Lymphangitis-associated rickettsiosis, a new rickettsiosis caused by Rickettsia sibirica mongolotimonae: Seven new cases and review of the literature. Clin Infect Dis 40:1435-1444.
4. Hackstadt T (1996) The biology of rickettsiae. Infect Agents Dis 5:127-143.
5. Loftis AD et al (2006) Rickettsial agents in Egyptian ticks collected from domestic animals. Exp Appl Acarol 40:67-81.
6. Parola P et al. (2005) Tick borne rickettsioses around the world: emerging diseases challenging old concepts. Clin Microbiol Rev18:719-56.
7. Ricketts HT (1906) The study of "Rocky Mountain spotted fever" (tick fever?) by means of animal inoculations. J Amer Med Ass 47: 33
8. Ricketts HT (1909): A micro-organism which apparently has a relationship to Rocky Mountain spotted fever. J Amer Med Ass 52: 379
9. Wilson ME et al (2007) Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis 44:1560-1568.