Emerging bartonellosis Christoph Dehio & Anna Sander

Bartonellae are arthropod-borne pathogens of they cause a long-lasting infection within the red blood growing medical importance. Until the early cells (intraerythrocytic bacteraemia). Blood-sucking 1990s, only two species of this bacterial genus, arthropod vectors transmit the bacteria from this reservoir B. bacilliformis and B. quintana, were recognized as caus- to new hosts. Incidental infection of non-reservoir hosts ing disease in humans. In addition to re-emergence of the (e.g. humans by the zoonotic species) may cause disease, human-specific B. quintana, a number of zoonotic but does not result in intraerythrocytic infection. Bartonella species have now been recognized as causative agents for a broadening spectrum of diseases that can be Natural history and epidemiology transmitted to humans from their animal hosts. Most Humans are the only known reservoir for two Bartonella prominently, B. henselae is an important zoonotic species, B. bacilliformis and B. quintana. pathogen that is frequently passed from its feline B. quintana was a leading cause of infectious morbidity reservoir to humans. among soldiers during World War I, and recurred on the Bacteria of the genus Bartonella are Gram-negative, East European front in World War II. The disease, pleomorphic, fastidious bacilli that belong to the α-2 Trench fever, is rarely fatal and is characterized by an subclass of Proteobacteria. All Bartonella species appear intraerythrocytic bacteraemia with recurrent, cycling to have a specific mammalian species as a host, in which fever. It is transmitted among humans by the human body louse Pediculus humanus. Although almost forgotten Table 1. Bartonella species, their natural reservoir, mode of by medical science since the end of World War II, B. transmission, and human diseases quintana re-emerged as an agent of disease among Bartonella species Reservoir Vector Human diseases homeless people and those with a lowered immune Human-specific species: response towards the end of the 20th century, exhibiting novel symptoms. B. bacilliformis Human Sandfly Carrión’s disease: B. bacilliformis was described by the Peruvian Oroya fever and verruga peruana physician Alberto Barton in 1909. He observed the B. quintana Human Body louse Trench fever, endocarditis, presence of intraerythrocytic bacilli in blood smears of bacillary angiomatosis peliosis patients suffering from Carrión’s disease. This biphasic disease is transmitted by the sandfly Lutzomyia Zoonotic species: verrucarum and occurs endemically in the valleys of the B. clarridgeiae Cat Cat flea CSD South American Andes of Peru, Columbia and Ecuador. B. elizabethae Rat Endocarditis, neuroretinitis The infection can manifest as the life-threatening B. grahamii Mouse, vole Neuroretinitis condition called Oroya fever, where the patient suffers from anaemia and a high temperature. If the patient B. henselae Cat Cat flea CSD, endocarditis, bacillary survives, this may be followed by a condition called angiomatosis peliosis, neuroretinitis verruga peruana, which is a less dangerous chronic illness B. vinsonii subsp. arupensis Mouse Ticks Fever, bacteraemia characterized by benign wart-like vascular lesions on the ‘B. washoensis’ Ground squirrels Myocarditis skin. In recent years, the appreciation of the widespread Animal-specific species: occurrence of Bartonella species in the bloodstream of B. alsatica Rabbit – mammals has resulted in the description of several new B. birtlesii Mouse – Bartonella species. In several instances this has allowed B. bovis (=‘B. weissii’) Cattle / cat – researchers to connect the presence of these bacteria with human diseases of previously unknown origin. Table 1 B. capreoli Roe deer – lists the 20 species of the genus Bartonella. So far, eight of B. chomelii Cattle – them are known to be zoonotic species that can act as B. doshiae Vole – pathogens in humans, although the preferred host is B. koehlerae Cat – another mammal. B. peromysci Deer, mouse – B. henselae: a major zoonotic pathogen B. schoenbuchensis Roe deer Deer ked – B. henselae (Fig. 1) is the most important zoonotic species B. talpae Mole – to cause human disease. This pathogen is distributed B. taylorii Mouse, vole – worldwide and causes intraerythrocytic bacteraemia in the feline reservoir host. Between 40 and 70 % of cats B. tribocorum Rat – living in warm, humid geographic regions have either an B. vinsonii subsp. berkhoffii Dog Ticks – active infection within their bloodstream, or have B. vinsonii subsp. vinsonii Vole Vole ear mite – antibodies, indicating that they have been infected in the past. Feral cats are more likely to be infected than pet cats

168 MICROBIOLOGYTODAY VOL 30/NOV03 Pathogenesis UPPER LEFT: During infection of their mammalian hosts, bartonellae Fig. 1. Colonies of B. henselae (large) and B. clarridgeiae (small) migrate towards two cell types, the red blood cells isolated from cat blood. (erythrocytes) and the cells lining the blood vessels COURTESY A. SANDER (vascular endothelium). The invasion and long-lasting intracellular colonization of erythrocytes occurs LOWER LEFT: exclusively in the normal reservoir host (i.e. humans for Fig. 2. Regional swelling of the B. bacilliformis and B. quintana; other mammals for other lymph nodes is a common clinical Bartonella species). In contrast, vascular endothelial cells manifestation of CSD. COURTESY A. SANDER are targets in both reservoir and incidental hosts, and their infection by bartonellae may result in the formation BELOW: of proliferative tumours. This ability to stimulate Fig. 3. Coloured scanning uncontrolled growth of vascular tissue is unique to electron micrograph of B. henselae bartonellae. Cultured human vascular endothelial cells bacteria (blue) infecting a human provide an in vitro system to study the interaction of cell (brown). REPRODUCED FROM DEHIO ET AL., B. henselae with the human vascular endothelium. J CELL SCI 110, 2141–2154 WITH THE The bacteria are tinternalized by endothelial cells and KIND PERMISSION OF THE COMPANY from the same region. Although some of these animals activate a proinflammatory phenotype. Moreover, OF BIOLOGISTS LTD. may be bacteraemic over a period of more than 1 year, cats the infection inhibits programmed cell death (apoptosis) usually appear healthy and asymptomatic. Transmission and stimulates multiplication of the endothelial to humans occurs by the cat flea Ctenocephalides felis, or cells (Fig. 3), thereby facilitating the formation of vaso- directly by cat scratch or bite. proliferative lesions. Recent evidence has demonstrated B. henselae can cause a variety of clinical manifest- that most of these dramatic ations. Cat-scratch disease (CSD) was first described in changes in endothelial 1950 by the French physician Debré in patients suffering cell physiology are medi- from inflamed lymph nodes following cat scratches. CSD ated by bacterial proteins occurs worldwide in all age groups. In the US, B. henselae that are delivered into causes 22,000 diagnosed cases of CSD per year, requiring infected endothelial cells hospitalization of about 10 % of the patients. Most cases by the bacterial type IV occur in October to March, when a closer and more secretion system VirB. prolonged contact with cats occurs indoors. Regional Since animal models of swelling of the lymph nodes (Fig. 2) is the most common Bartonella infection have clinical manifestation of CSD, but atypical symptoms shown that the VirB system with involvement of the eyes, liver, spleen, central is essential for establishing nervous system, skin, bones or other organs may occur, an infection, and many of particularly in immunocompromised individuals. its components are on the In recent years a large number of Bartonella infections bacterial cell surface, it of the heart (endocarditis) have been reported in the is a promising target for literature, indicating that it may cause 3–4 % of all cases. vaccine development. One Homeless and chronically alcoholic individuals are component of VirB, the particularly susceptible to the disease. In the immuno- 17 kDa antigen, has compromised, especially HIV-infected, patients already been shown to bacillary angiomatosis peliosis is the most common be immunogenic, and clinical manifestation of an infection with B. henselae. indicates a way forward. The symptoms are red, blood-filled lesions on the patient’s skin due to proliferation of surface blood vessels, Dr Christoph Dehio is Assistant Professor for and resemble pyogenic granulomas, haemangiomas or Molecular Microbiology at the Biozentrum of the Kaposi’s sarcoma. University of Basel, Switzerland. Laboratory diagnosis of B. henselae and other Bartonella Tel. +41 61 267 2140; Fax +41 61 267 2118; infections uses the most recent developments in email [email protected] serological testing [indirect immunofluorescent Dr Anna Sander is Assistant Professor in Medical antibody assay, enzyme-linked immunosorbent assay Microbiology, Department of Medical Microbiology (ELISA), Western blot analysis], histopathological and Hygiene, University of Freiburg, Germany. investigation of lymph node specimens, skin biopsies, Tel. +49 761 203 6529; Fax +49 761 203 6529; or other clinical material, and PCR amplification of email [email protected] Bartonella DNA from human specimens.

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