Bartonella spp. are facultative intracellular pathogens that employ a unique stealth infection strategy comprising immune evasion and modulation, intimate interaction with nucleated cells, and intraerythrocytic persistence. Infections with Bartonella are ubiquitous among mammals, and many species can infect humans either as their natural host or incidentally as zoonotic pathogens. Upon inoculation into a naive host, the bartonellae first colonize a primary niche that is widely accepted to involve the manipulation of nucleated host cells, e.g., in the microvasculature. Consistently, in vitro research showed that Bartonella harbors an ample arsenal of virulence factors to modulate the response of such cells, gain entrance, and establish an intracellular niche. Subsequently, the bacteria are seeded into the bloodstream where they invade erythrocytes and give rise to a typically asymptomatic intraerythrocytic bacteremia. While this course of infection is characteristic for natural hosts, zoonotic infections or the infection of immunocompromised patients may alter the path of Bartonella and result in considerable morbidity. In this review we compile current knowledge on the molecular processes underlying both the infection strategy and pathogenesis of Bartonella and discuss their connection to the clinical presentation of human patients, which ranges from minor complaints to life-threatening disease.

Intruders below the Radar: Molecular Pathogenesis of Bartonella spp.

Bacterial pathogens typically infect only a limited range of hosts; however, the genetic mechanisms governing host-specificity are poorly understood. The alpha-proteobacterial genus Bartonella comprises 21 species that cause host-specific intraerythrocytic bacteremia as hallmark of infection in their respective mammalian reservoirs, including the human-specific pathogens Bartonella quintana and Bartonella bacilliformis that cause trench fever and Oroya fever, respectively. Here, we have identified bacterial factors that mediate host-specific erythrocyte colonization in the mammalian reservoirs. Using mouse-specific Bartonella birtlesii, human-specific Bartonella quintana, cat-specific Bartonella henselae and rat-specific Bartonella tribocorum, we established in vitro adhesion and invasion assays with isolated erythrocytes that fully reproduce the host-specificity of erythrocyte infection as observed in vivo. By signature-tagged mutagenesis of B. birtlesii and mutant selection in a mouse infection model we identified mutants impaired in establishing intraerythrocytic bacteremia. Among 45 abacteremic mutants, five failed to adhere to and invade mouse erythrocytes in vitro. The corresponding genes encode components of the type IV secretion system (T4SS) Trw, demonstrating that this virulence factor laterally acquired by the Bartonella lineage is directly involved in adherence to erythrocytes. Strikingly, ectopic expression of Trw of rat-specific B. tribocorum in cat-specific B. henselae or human-specific B. quintana expanded their host range for erythrocyte infection to rat, demonstrating that Trw mediates host-specific erythrocyte infection. A molecular evolutionary analysis of the trw locus further indicated that the variable, surface-located TrwL and TrwJ might represent the T4SS components that determine host-specificity of erythrocyte parasitism. In conclusion, we show that the laterally acquired Trw T4SS diversified in the Bartonella lineage to facilitate host-restricted adhesion to erythrocytes in a wide range of mammals.

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The Trw Type IV Secretion System of Bartonella Mediates Host-Specific Adhesion to Erythrocytes

Adaptive radiation is the rapid origination of multiple species from a single ancestor as the result of concurrent adaptation to disparate environments This fundamental evolutionary process is considered to be responsible for the genesis of a great portion of the diversity of life Bacteria have evolved enormous biological diversity by exploiting an exceptional range of environments, yet diversification of bacteria via adaptive radiation has been documented in a few cases only and the underlying molecular mechanisms are largely unknown Here we show a compelling example of adaptive radiation in pathogenic bacteria and reveal their genetic basis Our evolutionary genomic analyses of the α-proteobacterial genus Bartonella uncover two parallel adaptive radiations within these host-restricted mammalian pathogens We identify a horizontally-acquired protein secretion system, which has evolved to target specific bacterial effector proteins into host cells as the evolutionary key innovation triggering these parallel adaptive radiations We show that the functional versatility and adaptive potential of the VirB type IV secretion system (T4SS), and thereby translocated Bartonella effector proteins (Beps), evolved in parallel in the two lineages prior to their radiations Independent chromosomal fixation of the virB operon and consecutive rounds of lineage-specific bep gene duplications followed by their functional diversification characterize these parallel evolutionary trajectories Whereas most Beps maintained their ancestral domain constitution, strikingly, a novel type of effector protein emerged convergently in both lineages This resulted in similar arrays of host cell-targeted effector proteins in the two lineages of Bartonella as the basis of their independent radiation The parallel molecular evolution of the VirB/Bep system displays a striking example of a key innovation involved in independent adaptive processes and the emergence of bacterial pathogens Furthermore, our study highlights the remarkable evolvability of T4SSs and their effector proteins, explaining their broad application in bacterial interactions with the environment

http://evolution.unibas.ch/salzburger/pub/048_PLoS_Genetics_2011.pdf

Parallel Evolution of a Type IV Secretion System in Radiating Lineages of the Host-Restricted Bacterial Pathogen Bartonella

Bartonella spp. are facultative intracellular bacteria that typically cause a long-lasting intraerythrocytic bacteremia in their mammalian reservoir hosts, thereby favoring transmission by blood-sucking arthropods. In most cases, natural reservoir host infections are subclinical and the relapsing intraerythrocytic bacteremia may last weeks, months, or even years. In this review, we will follow the infection cycle of Bartonella spp. in a reservoir host, which typically starts with an intradermal inoculation of bacteria that are superficially scratched into the skin from arthropod feces and terminates with the pathogen exit by the blood-sucking arthropod. The current knowledge of bacterial countermeasures against mammalian immune response will be presented for each critical step of the pathogenesis. The prevailing models of the still-enigmatic primary niche and the anatomical location where bacteria reside, persist, and are periodically seeded into the bloodstream to cause the typical relapsing Bartonella spp. bacteremia will also be critically discussed. The review will end up with a discussion of the ability of Bartonella spp., namely Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis, to induce tumor-like vascular deformations in humans having compromised immune response such as in patients with AIDS.

Persistence of Bartonella spp. stealth pathogens: from subclinical infections to vasoproliferative tumor formation

Bartonellosis is a vector-borne zoonotic disease with worldwide distribution that can infect humans and a large number of mammals including small companion animals (cats and dogs). In recent years, an increasing number of studies from around the world have reported Bartonella infections, although publications have predominantly focused on the North American perspective. Currently, clinico-pathological data from Europe are more limited, suggesting that bartonellosis may be an infrequent or underdiagnosed infectious disease in cats and dogs. Research is needed to confirm or exclude Bartonella infection as a cause of a spectrum of feline and canine diseases. Bartonella spp. can cause acute or chronic infections in cats, dogs and humans. On a comparative medical basis, different clinical manifestations, such as periods of intermittent fever, granulomatous inflammation involving the heart, liver, lymph nodes and other tissues, endocarditis, bacillary angiomatosis, peliosis hepatis, uveitis and vasoproliferative tumors have been reported in cats, dogs and humans. The purpose of this review is to provide an update and European perspective on Bartonella infections in cats and dogs, including clinical, diagnostic, epidemiological, pathological, treatment and zoonotic aspects.

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Bartonella infections in cats and dogs including zoonotic aspects

Bartonella rochalimae was first isolated from the blood of a human who traveled to Peru and was exposed to multiple insect bites. Foxes and dogs are likely natural reservoirs for this bacterium. We report the results of experimental inoculation of two dogs, five cats and six guinea pigs with the only human isolate of this new Bartonella species. Both dogs became bacteremic for 5-7 weeks, with a peak of 10 3 -10 4 colony forming units (CFU)/mL blood. Three cats had low bacteremia levels (< 200 CFU/mL) of 6-8 weeks' duration. One cat that remained seronegative had two bacterial colonies isolated at a single culture time point. A fifth cat never became bacteremic, but seroconverted. None of the guinea pigs became bacteremic, but five seroconverted. These results suggest that dogs could be a reservoir of this strain of B. rochalimae, in contrast to cats and guinea pigs. Bartonella rochalimae / dogs / cats / guinea pigs / zoonosis

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Dogs are more permissive than cats or guinea pigs to experimental infection with a human isolate of Bartonella rochalimae.

Recent emerging and re-emerging diseases in animals and humans show the vulnerability of humans, animals, and crops to disease outbreaks and the large potential impact on health, food security, and economies worldwide. A technology-enabled One Health (OH) surveillance program offers an opportunity for early detection and response as well as prevention of disease outbreaks in resource-limited settings. As an initial step toward developing the surveillance program, we aimed to identify at-risk groups of households for potential shared health challenges at the human-animal-environmental interface in a rural community of the Philippines.A cross-sectional household survey was conducted in the municipality of Los Baños in proximity (63 kilometers south) to Metro Manila by enumerators living in the same community. Twenty-four enumerators conducted household interviews asking a) household characteristics including ownership of animals and crops; b) awareness, beliefs and knowledge about OH; c) family-level health practices related to sanitation, hygiene, and food safety; and d) risk factors for potential OH issues. All data collection and transferring process were streamlined using a mobile application.Of 6,055 participating households, 68% reported having one or more of gardens, farms, and animals for various reasons. While only 2% of the households have heard about OH, 97% believed they can get disease from animals, plants or the environment. A latent class analysis with nine risk factors for potential OH issues suggested that 46% of the households were at moderate to high risk for exposure to zoonotic pathogens and environmental contaminants.Our findings indicate that there are unaddressed threats to human, animal, and plant health. Given the importance of the interconnections between the health of humans, animals, and plants, further evaluations of the at-risk households would be necessary to mitigate potential shared health threats in the community. Further, our study demonstrates that mHealth technology can provide an opportunity to systematically assess potential one health problems in the rural communities with limited internet connection. 

/pdf/a-community-based-survey-to-assess-risk-for-one-health-2wkc7dmv.pdf

Sophia Papageorgiou

Papers

Dogs are more permissive than cats or guinea pigs to experimental infection with a human isolate of Bartonella rochalimae.

A community-based survey to assess risk for one health challenges in rural Philippines using a mobile application