Bartonella spp. - a chance to establish One Health concepts in veterinary and human medicine

The threat of infectious diseases to mankind has never been greater than today. For the first time, political leaders of the 41^st “G7 summit” in Schloss Elmau/Germany on June 7–8, 2015, set the topic “global health” (including infectious diseases) as one of the key issues on their agenda. In the past, health issues played only a minor part in such international economic summits. However, governments have now realized that public health is an essential prerequisite for education, working capacity and therefore the economic prosperity of societies.

In this regard, it is important to recognize that human health and animal health are closely linked. An estimated 75 % of emerging infectious diseases are zoonotic and 28 % vector-borne [1]. Global warming represents an additional factor promoting the spread of these diseases as the geographic range of some vectors and reservoir hosts expands in response to a changing climate [2].

To respond to these challenges, the One Health concept aims to establish interdisciplinary collaborations between medical, veterinary and environmental researchers as well as public health officials for the early detection of health hazards affecting both humans and animals and to fight them on multiple levels. The genus Bartonella represents a prototypical example for zoonotic pathogens as Bartonella species are infectious agents for humans and animals. High pathogen prevalence and severe courses of infection raise the importance to investigate possible routes of transmission and to combat infections.

The bacterial genus of Bartonella is comprised of Gram-negative, slow growing and facultative intracellular pathogens that infect mainly mammalian hosts and are often transferred via blood sucking arthropod vectors. Bartonella infections of humans and animals are often characterized by an intraerythrocytic bacteremia. At least 20 species are known to cause host-specific intraerythrocytic infections in their specific mammalian reservoir hosts, including the human-specific pathogens Bartonella quintana and Bartonella bacilliformis, the agents of trench fever and Oroya fever, respectively. A secondary tissue phase can be associated with development of vasculoproliferative lesions, e.g. bacillary angiomatosis (Bartonella henselae, B. quintana) or verruga peruana (B. bacilliformis) and may play a role in various other dermal conditions [3–7].

Molecular epidemiology techniques have revealed a remarkable diversity within the genus Bartonella. A wide variety of Bartonella spp. specialized to various mammalian hosts and transferred by specific arthropod vectors have been identified over the years and the prevalence of infection appears to be widespread across species and geographic regions. At least 13 species of Bartonella have been identified as pathogenic to humans with three species responsible for most of the clinically relevant infections in humans: B. bacilliformis, B. quintana and B. henselae [6].

Bartonella spp. infections are often chronic or asymptomatic in their reservoir hosts. Bacteria have been shown to infect erythrocytes, endothelial cells, macrophages and even human stem cells [8–17]. The infection of erythroctyes is host-specific and mediated by the so-called “Trw”-type 4 secretion system which facilitates host-restricted adhesion to erythrocytes [18]. Localized tissue manifestations may occur in reservoir and incidental hosts and the growth of bacteria in vascular tissue can lead to angioproliferative tumors and inflammation [5, 6, 12, 19]. The ability of Bartonella spp. to persist within immunoprivileged intracellular habitats is probably a key factor contributing to the establishment of chronic infections; however, the cyclic release of bacteria to the blood stream or the hemolytic activity of some species can also result in dramatic illnesses such as trench fever or Oroya fever, respectively [20]. The presence of Bartonella spp. in the blood stream of infected hosts or within the erythrocytes also facilitates their transfer via ingestion along with the blood meal of arthropod vectors [5, 21].

Dogs represent an incidental host for Bartonella and two species are known to cause clinically apparent infections: B. vinsonii subsp. berkhoffii, causing endocarditis, arrhythmias, myocarditis, granulomatous lymphadenitis and granulomatous rhinitis, and B. henselae causing peliosis hepatis [66–71]. In a study from the United States surveying Bartonella bacteremia in dogs, B. henselae was found in 30 of 61 infected dogs [72]; however, there are also rare cases in which other Bartonella spp. have caused disease in dogs: B. clarridgeiae, B. washoensis and B. quintana were isolated from dogs suffering from endocarditis [8, 22, 23]. To date, all Bartonella spp. identified in sick dogs are also known as pathogenic or potentially pathogenic infectious agents for humans and this observation led to the suggestion that dogs might act as useful sentinel species and important comparative models for human infections [22, 73].

Domestic dogs are generally incidental hosts for B. henselae with a reported seroprevalence of ~10 % in healthy dogs in the United States and ~27 % in sick dogs [30, 74]. Similar to cat epidemiology, seroprevalence increases in warmer regions [30]. Bartonella henselae, B. quintana, B. vinsonii subsp. berkhoffii and B. bovis have been detected in mouth swabs from dogs and there is some evidence that dogs may be able to transmit B. henselae to humans via bites [22, 30, 37, 75]. Because of the prolonged bacteremia of B. vinsonii subsp. berkoffii in dogs, they are suspected to represent the reservoir host of these bacteria and seroreactivity of dogs against B. vinsonii subsp. berkoffii is found worldwide [22, 26, 32]. In Gabon, B. clarridgeiae was also isolated from ~2 % of the examined dogs indicating that these animals may represent a potential reservoir host for Bartonella spp. in Africa [76].

Serological surveys suggest that B. vinsonii subsp. berkhoffii may also cause immuno-mediated hemolytic anemia, neutrophil or granulomatous meningoencephalitis, neutrophil polyarthritis and uveitis in dogs [8, 22]. Bartonella vinsonii subsp. berkhoffii can cause endocarditis, especially in large breed dogs with a predisposition for aortic valve involvement. Intermittent lameness and fever of unknown origin can occur several months before endocarditis. Myocarditis without an associated endocarditis is also possible and may result in arrhythmias, syncope or sudden death [26, 67]. To detect Bartonella spp. as the causative agent of infectious endocarditis in dogs, diagnostic PCRs should be performed from blood or heart valve specimen as blood cultures often remain negative [77, 78]. High antibody-titers and characteristic lesions in echocardiography are also suspicious for Bartonella endocarditis. In most cases, Bartonella infect the aortic valve causing aortic insufficiency leading to severe chronic heart failure and arrhythmias [66–68, 77, 79, 80].

There are many publications describing Bartonella infections of numerous mammals and even reptiles. For instance, Bartonella spp. have been detected in a wide variety of wild and domestic animals throughout the world including, e.g. mountain lions, bobcats, coyotes, grey foxes, elks, mule deer, cougars, rabbits, several rodent species, cattle, belugas, bats and porpoises. However, it is unclear which diseases if any are associated with such infections and if these animals play a role as potential reservoir hosts. [26, 30, 81–92].

The first human pathogenic Bartonella species to be identified in the early 1900s was B. bacilliformis. This human-specific bacterium causes a biphasic disease characterised by a primary hemolytic fever (“Oroya fever”) with high mortality (up to 90 %), followed by a chronic vasculoproliferative tissue phase (“verruga peruana”). Pathogens are transmitted by the sand fly (Lutzomyia verrucarum). The human body louse (Pediculus humanus humanus) transmits B. quintana, a second human pathogenic Bartonella species which emerged as a major agent of disease causing debilitating cyclic fever (“trench fever“) during World War I. Today, trench fever occurs mainly in the homeless population or among drug addicts. Endocarditis, generalized lymphadenopathy and bacillary angiomatosis are symptoms of B. quintana infections in immunocompromised people [93–100].

Of the three most significant human pathogenic Bartonella species B. henselae is the most common symptomatic infection causing agent identified in the modern clinical setting. Bartonella henselae infection is the cause of multiple clinical entities in humans and infections result in differential disease outcomes often depending on the immune status of the patient. Humans become infected via the scratches or bites of infected cats contaminated with infected flea feces or are directly contaminated with infected blood. Dogs are also suspected to be an additional reservoir for B. henselae transmission to humans [41]. In immunocompetent patients, infections normally cause cat scratch disease which is often self-limiting with no need for antibiotic treatment. Typically, two to three weeks after infection, a unilateral lymphadenitis in the draining region of the lymph node near the site of inoculation can be observed. In ~10 % of the cases, the lymph node forms a fistula where pus is draining. Other symptoms include chronic lymph node swelling, fever, headache, skin and mucosal lesions near the inoculation site and splenomegaly. “Blood-culture negative”-endocarditis, oculoglandular involvement (“Parinaud’s syndrome”), encephalopathy, neuroretinitis and osteomyelitis are described as complications of infection [101]. Recurring or systemic infections can be treated with macrolides. In immunocompromised hosts, chronic infections can occur, leading to angioproliferative diseases like bacillary angiomatosis and peliosis hepatis which can be fatal if not treated [6, 19].

Several Bartonella spp. have been reported as cause of fever of unknown origin and culture-negative endocarditis in humans and animals [102–105]. In humans, endocarditis caused by B. henselae, B. quintana, B. elizabethae, B. vinsonii subsp. berkhoffii, B. vinsonii subsp. arupensis, B. koehlerae, B. alsatica, B. washoensis and Candidatus B. mayotimonensis have been reported [24, 106–114]; however, human endocarditis cases are most often associated with B. henselae and B. quintana [79, 80, 115]. In most cases, high anti-Bartonella-IgG antibody-titers can be detected [102, 116].

Co-infections with more than one Bartonella spp. (even in immunocompetent patients) [117–119] and with other zoonotic bacterial species have been reported. Co-infections with Borrelia burgdorferi (sensu lato) and B. henselae were described in patients with atypical neuroborreliosis [120–122]. Furthermore, surveys showed the occurrence of co-infections with B. henselae in people suffering from persistent symptoms after borreliosis treatment where ticks might have been the source of infection [121]. The transmission of multiple pathogens via co-infected vectors might contribute to atypical disease progression and should be considered for the diagnosis of tick-borne diseases [121, 123, 124]. However, it must be stated that the occurrence of chronic, atypical tick-borne co-infections in patients with chronic, nonspecific illnesses is highly controversially discussed. As reviewed by Lantos & Wormser, in most reported cases of Bartonella and Borrelia co-infections, laboratory diagnostics were not properly performed [125].

Different population groups are exposed to animals and arthropod vectors in variable dimensions. In particular, veterinarians, veterinary technicians or zookeepers might be at increased risk of infection with Bartonella spp. [119, 126]. For example, one case of B. vinsonii subsp. berkhoffii, transmission to a veterinarian was likely caused by a needle puncture injury [127]. Bartonella infections have even been suspected to have been a contributing factor in the death of two veterinarians in 2013 [128]. In an epidemiological study, Bartonella DNA was also detected in the blood of 28 % of veterinary workers whereas no Bartonella was detected in control subjects [126]. The prevalence of Bartonella infections has also been found to be elevated in other risk groups. In a recent study in Germany B. henselae IgG antibodies were found in ~45 % of forestry workers which may be due to a higher contact with arthropods which is inevitable during forest work [129]. From a One Health perspective, the identification of possible vectors and means of Bartonella transmission is crucial to reduce occupational hazards in certain risk groups and prevent such cases of Bartonella transmission in future.

Blood transfusion has also been identified as a risk factor for the transmission of Bartonella infections. The transmission of infection via blood transfusion was first shown 20 years ago in cats [58] and a very recent study from Brazil has also indicated a ~3 % prevalence of Bartonella spp. in asymptomatic human blood donors. Remarkably, the results of this study found that professionals with animal contact were seven times more likely to harbor Bartonella than other blood donors and individuals with cat contact or a history of tick bite were three to four times more likely to be infected with Bartonella spp. [130]. Considering that patients receiving blood transfusions are already in a state of weakened health, screening of blood donors for Bartonella infections, especially in certain risk groups should be considered to prevent transmission of infection.

The transmission cycle of bartonellosis is typical for vector-borne diseases. Typically, infections are characterized by persistent intraerythrocytic bacteremia within the reservoir host. Infected blood is ingested by the blood sucking arthropod vector and subsequently transmitted to a further reservoir or incidental host. To date, vector-competence of several arthropods has been proven for Bartonella spp. transmission and additional vectors competencies are suspected in many more.

The cat flea (Ctenocephalides felis) represents the main vector for B. henselae infection among cats. Its vector-competence for B. henselae transmission is experimentally proven and its presence is essential for the maintenance of B. henselae infection within the cat population. The contamination of the flea-feeding wound, or other wounds such as scratches or bites with contaminated flea feces has been identified as an important transmission route among hosts including cats and humans [30, 33, 96, 131–133]. Bacteria are replicating in the flea’s intestine and are secreted with the feces over the life-span of the flea (~12 days). The excreted flea feces contain B. henselae within 24 h of a blood meal [134].

Further supporting the importance of the flea as a vector of B. henselae transmission, epidemiological studies have shown an increased risk of B. henselae infection in cats suffering from flea infestation and the use of flea-prevention collars has also been shown to be effective in preventing the transmission of B. henselae infection from cat to cat [35]. Once infected, B. henselae bacteremia in cats can last for weeks, months or even longer than one year supporting further vector-transmission [22, 23, 29, 39, 132, 135, 136]. In addition to B. henselae, cats are susceptible to infections with B. quintana, B. koehlerae, B. clarridgeiae, B. vinsonii subsp. berkhoffii and B. bovis which have also been detected in cat fleas. With the exception of B. bovis, these species can also be pathogenic to humans [6, 30, 52, 137]. Flea control is highly recommended in endemic areas to reduce the pathogen exposition of cats and humans [39].

In addition to the cat flea various other flea species may also play important roles in Bartonella transmission. Bartonella spp. were detected in several flea species collected from bats and different rodents [30, 96, 138–144]. Vector-competence, however, has not been confirmed experimentally for these species.

The human body louse (Pediculus humanus humanus) represents the vector of human to human-transmission of B. quintana. Environmental factors supporting louse infestation such as unhygienic living conditions lead to an increased risk of infection. In the past, infections with B. quintana were a severe medical problem in the trenches and in prisoners of war camps of World War I from which the name “trench fever” arises. Today, mostly homeless people or drug addicts are affected resulting in the term “urban trench fever” [99, 145]. The vector becomes infected when adult lice feed on bacteremic hosts. Bartonella quintana reaches the louse gut and can infect humans when bite sites or other wounds are contaminated with infected louse feces [30, 64, 65, 96, 97, 146]. Bartonella spp. have also been detected from several other louse species (e.g. Neohaematopinus sciuri, Hoplopleura sciuricola, Pediculus humanus capitis and others) which may also serve as vectors [96, 139, 147, 148].

The sand fly (Lutzomyia verrucarum) transmits B. bacilliformis from humans to humans and its vector-competence has been proven experimentally [96, 98, 149–151]. The occurrence of the disease is strictly limited to the Peruvian Andes where the vector is endemic. However, it should be considered that climate change may extend the distribution area of this vector and thereby increase the spread of B. bacilliformis.

Ticks are known to act as vectors for many different bacterial, protozoan and viral pathogens. Hard ticks (e.g. Ixodes spp., Dermacentor spp.) usually feed three times during their life-cycle and can possibly be infected with different pathogens during every blood meal. Hosts can be bitten by ticks several times during their lifetime presenting multiple opportunities for pathogen transmission [152–154]. Several studies have detected the presence of Bartonella spp. in various tick species from around the world [26, 84, 93, 120, 121, 123, 138, 152, 155–168]. The prevalence of Bartonella DNA in hard ticks in Europe has been shown to be as high as 40 % [158]. In a recent study conducted in Finland, ticks were found to contain no detectable Bartonella DNA whereas DNA of Borrelia spp. was found frequently at ~ 19 % [169]. On the other hand, Bartonella DNA was detected in ~2 % of ticks collected in a recent study from Austria [170]. Figure 1 displays the percentage of ticks found to harbor Bartonella in different studies. Overall, in ~15 % of ticks studied Bartonella DNA was detectable.

Vector competence has been demonstrated experimentally by the use of artificial tick-feeding procedures for B. henselae [171] and a murine B. birtlesii infection model [172]; however, vector competence of naturally infected ticks has still not been confirmed.

Bartonella DNA has been detected in hard ticks removed from dogs. However, as DNA was detectable in only some but not all ticks removed from one particular dog, the infection of the tick may have been acquired from another source previously [173]. Furthermore, several studies indicate co-transmission of Bartonella with other tick-borne pathogens (e.g. Ehrlichia, Babesia) in dogs [66, 174–178]. In a study surveying dogs with endocarditis from California, all dogs that were infected with Bartonella were also seroreactive to Anaplasma phagocytophilum, another tick-borne pathogen [77].

In two cases, B. henselae DNA was detected in ticks collected from the home of patients which suffered from Lyme disease and which did not respond to a Borrelia-specific antibiotic therapy. In another study, Bartonella DNA was detectable in human blood after tick bites and recently, B. henselae and three other animal-associated Bartonella species (B. doshiae, B. schoenbuchensis and B. tribocorum) were isolated from patients suffering from undifferentiated chronic illness and who had reported tick bites [121, 179, 180].

Several case reports of B. henselae infections of humans have been published where no or very limited cat contact was reported, limiting the possibility of transmission via cats or cat fleas. Authors concluded that transmission via arthropod vectors (e.g. ticks) may provide an alternative explanation [96, 181].

The most important reservoir hosts for tick-borne pathogens are small rodents as they are the preferred hosts of tick larvae and nymphs. Several Bartonella spp. have been detected in these small mammals further supporting the possibility that ticks may represent a vector for Bartonella transmission [84, 87, 152–154, 162, 182, 183]. Bartonella spp. have also been isolated from cattle and mule deer in North America. As ruminants are rarely infested with fleas, ticks seem to be more likely to transmit these pathogens to these animals [81].

Nevertheless, it must be mentioned that the transmission of Bartonella spp. via ticks to humans and animals is still controversially discussed. Clearly, Bartonella DNA which was found in several tick species in multiple studies does not prove the presence of viable bacteria. Therefore, some researchers doubt heavily that Bartonella spp. are transmitted by ticks [125, 184]. Furthermore, concerns about the relevance of experimental tick transmission studies performed with an artificial feeding system [171] have been raised [184]: the amount of colony forming units in the blood was criticized to be much higher than it would be in natural infected bacteremic cats and the B. henselae strain that was used is not representative for Bartonella strains found in nature [184]. Building on these points, the authors conclude that neither of these studies demonstrated transmission of Bartonella spp. from ticks to mammalian hosts [125]. At least for B. birtlesii, tick transmission was proven in a murine infection model [172] whereas a bona fide tick transmission of B. henselae has not been demonstrated so far.

Bartonella species have been found in biting flies collected from cattle in California: B. bovis was detected in a horn fly (Haematobia spp.) and B. henselae was found in a stable fly (Stomoxy spp.) [185]. Several studies found Bartonella spp. in mites collected from rodents and bats from Korea, Egypt and Costa Rica [96, 162, 186]. Deer keds (Lipoptena mazamae and Lipoptena cervi) were shown to be infected with B. henselae and B. schoenbuchensis [30, 187–189]. Lipoptena species usually feed on deer but were also found on horses, cattle and humans. Bartonella schoenbuchensis was detected in Lipoptena cervi from a deer (Capreolus capreolus) in Germany and is suspected to be the causative agent of deer ked dermatitis in humans [190]. Bartonella was also found in several other species of the family Hippoboscidae indicating that they may play a role in the transmission of these bacteria [96, 191]. However, no experimental transmission studies with these species have been performed nor do any data exist on the transmission of B. schoenbuchensis by Lipoptena spp. to humans.

When discussing transmission of Bartonella spp. from animals to humans, e.g. via arthropod vectors, a more integrative approach elucidating Bartonella prevalence in vectors as well as the infection status of animals and humans would clearly help to increase understanding of Bartonella infection dynamics, infection risk and prevent speculative and non-evidence-based conclusions. Such an approach might, for instance, include the investigation of the prevalence of Bartonella DNA or (even more reliable) of viable Bartonella species in feeding ticks, combined with parallel detection of these pathogens via direct detection or seroprevalence in animals (e.g. pets) and humans (e.g. pet owners). Figure 2 shows this concept of such a One Health approach.

For instance, a coordinated set of data might include (i) the pathogen-DNA status of questing ticks (with bacterial, e.g. Bartonella 16S-rDNA sequences; analyzed by conventional PCRs or metagenomics analysis), (ii) the direct detection of these pathogen(s) or detection of pathogen-specific (e.g. Bartonella) antibodies in animals (arguing for infection of the pet), and (iii) the direct detection of these pathogen(s) if feasible or the determination of the respective pathogen-specific antibodies in humans (e.g. pet owner) in parallel (arguing for a previous or present infection).

First incidental results from a clinical case revealed interesting findings: In a female, adult, half-engorged I. ricinus tick (black forest, Germany) which was feeding for ~1–2 days on a cat, Bartonella-DNA was detected via nested-PCR. Sequence analysis revealed most likely the presence of B. henselae 16S-rDNA (99 % sequence homology). For medical reasons, a serum sample from the cat was taken (because of unspecific illness). Immunofluorescence testing revealed cat antibody titers of 1:640 whereas no specific B. henselae-antibodies were detected in the pet owner. This setting might be interpreted as follows: The questing I. ricinus tick was probably ingesting B. henselae-containing cat blood as anti-B. henselae IgG antibodies were detectable. The pet owner, however, had no serological evidence for having been exposed to B. henselae. As a further option, a chronic B. henselae infection of the cat might additionally be confirmed (e.g. via PCR-analysis of peripheral blood). The application of such One Health approaches in prospective scientific studies would be useful to assess the real risk of transmission of Bartonella spp. from pets to pet owners and to clarify the role of ticks in this process.

The cumulative data collected in many studies and conducted in several countries throughout the world indicate that infections with Bartonella spp. might represent an underappreciated danger for human and animal health. A great deal more research is needed to specify arthropod vectors and characteristics of diseases caused by Bartonella species. To date, strict ectoparasite-control is highly recommended to lower the risk of Bartonella infection from arthropod vectors to domestic animals and pets, thereby preventing pathogen transmission from animals to human owners. Overall, these results demonstrate that reliable data about vector transmission of Bartonella spp. from animals to humans can only be generated through the application of scientific One Health approaches which take into account the epidemiological factors and interactions of humans, animals and their environments as an integrated system.