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Host Cell Modulation By Human, Animal and Plant Pathogens

Posted on: Thursday, 17 June 2004, 06:00 CDT

Abstract

Members of the [alpha]-proteobacteria display a broad range of interactions with higher eukaryotes. Some are pathogens of humans, such as Rickettsia and Bartonella that are associated with diseases like epidemic typhus, trench fever, cat scratch disease and bacillary angiomatosis. Others like the Brucella cause abortions in pregnant animals. Yet other species have evolved elaborate interactions with plants; in this group we find both plant symbionts and parasites. Despite radically different host preferences, extreme genome size variations and the absence of toxin genes, similarities in survival strategies and host cell interactions can be recognized among members of the [alpha]-proteobacteria. Here, we review some of these similarities, with a focus on strategies for modulation of the host target cell.

Key words: Rickettsia - Bartonella - Brucella - Agrobacterium tumefaciens - Sinorhizobium meliloti - host cell modulation - evolution

Introduction

Comparative genomics enables the identification of the genetic basis for phenotypic characteristics of bacteria mediating infectious diseases. As yet, we do not fully understand why even closely related species with few genetic differences often differ widely in host-range sizes, and why some are pathogenic to humans while others are not. To understand the processes whereby bacteria cause disease it is necessary to compare the genomes of microbes with defined lifestyle characteristics and host-cell interaction profiles. Many of the mechanisms underlying disease phenotypes are similar for plant and animal pathogens, yet these similarities are seldom characterized and explored in terms of pathogenicity and survival strategies in the different growth niches. The recent characterization of genome sequence data from both plant and animal pathogens provides a basis for such trans-kingdom comparisons.

The [alpha]-proteobacterial subdivision offers an excellent model system for comparative studies of bacteria that have descended from a common ancestor and yet have evolved many different types of interactions with their eukaryotic host cells. Many members are of interest from medical, veterinary and agricultural perspectives. For example, in this subdivision we find intracellular parasites that cause disease in humans and domestic animals, such as Rickettsia, Ehrlicbia, Bartonella and Brucella. The latter two genera are closely related to the rhizobacteria that otherwise mostly consists of plant-associated bacteria, several of which are important for nitrogen fixation in plants. The most well known representative species from this group is Sinorhizobium meliloti, which lives in a complex nitrogen-fixing symbiosis with leguminous host plants (Savka and Farrand, 1997; Wells and Long, 2002). Even within single genera, there are differences in host cell interaction preferences. For example, some species of Rickettsia and Bartonella cause disease, whereas others are commensals or mutualists causing no observable harm to their hosts.

The genome sizes within the [alpha]-proteobacteria range from circa 1 Mb in Rickettsia to 9 Mb in Bradyrhizobium japonicum (Andersson et al., 1998; Galibert et al., 2001; Goodner et al., 2001; Kaneko et al., 2002; Ogata et al., 2001; Wood et al., 2001; DelVecchio et al., 2002; Paulsen et al, 2002). Species with small genomes typically grow in intracellular environments that are enriched for nutrients, whereas species with large genomes are normally associated with nutritionally poor and unstable growth niches. The intracellular growth characteristics of Rickettsia have hampered the identification of potential pathogenicity factors since attempts to perform genetic manipulations are strongly restricted for bacteria that are only cultivatable in the presence of viable host cells.

Broad comparisons of [alpha]-proteobacerial genomes across the different genera have revealed a remarkable conservation of gene order structures. For example, comparisons of the Brucella suis genomes with the main chromosomes of the plant symbiont Mesorhizobium loti reveal extensive gene synteny over a large genomic region (Paulsen et al., 2002). Shorter stretches of gene order synteny were also identified with the main chromosomes of B. suis, S. meliloti and Agrobacterium tumefaciens (Paulsen et al., 2002). In addition, there are many similarities between the small megareplicon of Brucella and the auxiliary chromosomes of the plant- associated species. The shared segments contain for example genes coding for transport and metabolic capabilities required for the utilization of plant-derived compounds from the soil. Below, we discuss some of the conserved strategies used by these bacteria concerning the interactions with their host cells.

The intracellular parasites: Rickettsia, Brucella and Bartonella

The first genome to be sequenced within the [alpha]- proteobacteria was that of the typhus pathogen, Rickettsia prowazekii (Andersson et al., 1998), a member of the Typhus Group Rickettsia (TG). This is an obligate intracellular parasite with no natural animal reservoir other than humans. It is transmitted among humans by the human body lice and all attempts to define in vitro culture conditions have so far failed. The genome sequence is also available for Rickettsia conorii, a member of the Spotted Fever Group Rickettsia (SFG) and the causative agent of Mediterranean spotted fever (Ogata et al., 2001). Ticks are the natural host for this species, with dogs and humans serving as vectors for transmission among ticks.

The two genomes are very small, only 1.1 Mb for R. prowazekti and 1.3 Mb for R. conorii. Both genomes seem to be deteriorating, as indicated by high fractions of pseudogenes and coding contents of less than 80% (Andersson et al., 1998; Ogata et al., 2001). A close comparison of the two genomes show that R. conorii have circa 500 genes not present in R. prowazekii, whereas only very few genes are uniquely present in the typhus agent (Ogata et al., 2001). As many as 400 of the R. conorii-specific genes are orphans and have no homologs outside of the Rickettsia. A comparative analysis of a selected set of orphan genes across a variety of species in the SFG suggests that many are deteriorating gene fragments that have already been eliminated from the TG (Amiri et al., 2003). This suggests that the same set of genes is being targeted for elimination, although the rate of deterioration is variable across strains and species (Amiri et al., 2003).

The genus Bartonella was established already 70 years ago, but at the time it contained only a single species, Bartonella bacilliformis, the agent of Carrion's disease. The acute phase of the disease is called Oroya fever, which if untreated has one of the highest mortality rates of all infectious diseases (40 - 85%). B. bacilliformis parasitizes on up to all erythrocytes during the first phase of the disease, leading to hemolysis and anaemia, and possible multi-organ failure. Fatalities occur directly by suffocation through lack of functional erythrocytes, or through secondary infections. During a later phase of the disease, called verruga peruana, vascular endothelial cells start proliferating and form angiogenic skin lesions. These occur in numerous forms, bleed easily and disappear normally over a period of a few months. Bartonellosis is almost entirely limited to the inter-Andean valleys of Peru, Ecuador and Columbia, in an area that matches that of Lutzomyia verrucarum, the sand fly, although other vectors may also exist. Humans are the only known reservoir for the disease and up to 10% of all individuals that live in endemic regions have asymptomatic infections (reviewed in (Birtles and Raoult, 1998)).

Currently, the genus Bartonella encompasses 18 or more species and these are able to infect a wide variety of animals, such as cats, rats, rabbits, mice, squirrels, and deers (Breitschwerdt and Kordick, 2000). In addition to B. bacilliformis, four species have been associated with human disease: B. quintana, B. henselae, B. washoensis and B. elizabethae. B. henselae is the causative agent of cat-scratch disease, a lymphadenitis upon a Bartonella infection, typically occurring on head or neck. In immunosuppressed patients this species is also associated with diseases called "bacillary angiomatosis" or "peliosis hepatis". The remarkable capability of Bartonella spp. to make host cells proliferating is unique for human pathogenic bacteria (Regnery et al., 1992; Koehler, 1996; Anderson and Neuman, 1997). Less frequently, B. henselae causes endocarditis and other infections, e.g. encephalitis (Glaser et al., 2003). Cats serve as the natural reservoir for this disease. Approximately, 30- 60% of all cats in the US are carriers of the bacterium, which is transmitted to humans by a cat-scratch or a cat-bite.

B. quintana, also capable of inducing bacillary angiomatosis, is the causative agent of trench fever, a common disease among soldiers during the first world war (Anderson and Neuman, 1997). B. quintana is transmitted by the human body louse, as is also Rickettsia prowazekii, the causative agent of epidemic typhus. Trench fever and epidemic typhus are two of only a few vector-borne diseases for which no animal reservoirs are known so far. The genomes of Bartonella are in the 1.5 to 2 Mb range, i.e. about twice as largeas those of Rickettsia. The difference reflects in part the facultative versus obligate intracellular lifestyles; Bartonella spp. have for example a set of genes for glycolysis (Canback et al., 2002) whereas Rickettsia spp. parasitizes on the pyruvate available in the cytoplasm of the host cell (Andersson et al., 1998; Ogata et al., 2001). Bartonella also contains a broader set of biosynthetic genes for amino acids and nucleotides making them more metabolically versatile than Rickettsia (unpublished).

The genus Brucella contains six recognized species that are intracellular parasites of domestic animals. Infection of pregnant animals leads to abortion. Each species has a distinct host range; Brucella melitensis infects sheep and goats, Brucella abortus is associated with cattle, Brucella canis with dogs and Brucella neotomae with desert wood rats. Human infections are zoonoses and occur by direct contact with infected animals or by contaminated food. Brucella spp. are facultative intracellular parasites that invade macrophages and replicate within the endoplasmic reticulum without restricting basic cellular functions (Gorvel and Moreno, 2002).

Brucella species have genomes in the 3 Mb range (DelVecchio et al., 2002; Paulsen et al., 2002). Genomic comparisons of B. suis and B. melitensis has shown that host preferences is governed by a limited set of genes; only 32 and 42 genes are uniquely present in B. melitensis and B. suis, respectively (Paulsen et al., 2002). These genes are located on islands that have been acquired by phage- mediated integration events. A few of the unique genes putatively code for amino acid ABC binding and transport proteins, although most encode hypothetical proteins, approximately half of which are predicted to be surface exposed (Paulsen et al., 2002). No classical virulence factors such as exotoxins, exoenzymes, cytolysins or fimbrae have been identified. Instead, the virulence features of Brucella reside in their ability to invade (Guzman-Verri et al., 2001), resist intracellular killing (Moreno and Moriyon, 2002) and replicate within phagocytes (Kohler et al., 2002). Thus, intracellular survival is a key factor for the successful spread of Brucella species.

Inhibition of cell suicide

Interactions between an infectious agent and the host normally result in induction or prevention of apoptosis (Fig. 1). Cell death by apoptosis is a common response of mammalian cells to a wide variety of bacterial infections (reviewed in (Zychlinsky and Sansonetti, 1997)). Apoptosis might be induced by "classical toxins" like Clostridium difficile toxin A and B (Mahida et al., 1996; QuaDan et al., 2002) or by bacterial effector molecules with the function of toxins, although not always named as such (e.g., YopP/J of Yersinia spp. inducing apoptosis via inhibition of NF-[kappa]B (Ruckdeschel et al., 1998)). Remarkably, neither toxins nor cytotoxic effector molecules have been described in the [alpha]- proteobacteria. However a gene with similarity to yopJ has been identified in B. quintana (unpublished) and anti-apoptotic properties are well known from several bacterial representatives of this subdivision, such as B. suis (Gross et al., 2000), Rickettsia rickettsii (Clifton et al., 1998) and Ehrlichia spp. (Yoshiie et al., 2000).

The induction of cell death by apoptosis is a particular danger for obligate intracellular bacteria like Rickettsia, Ehrlichia and Chlamydia. Perhaps not surprisingly, these bacteria have evolved mechanisms to modulate the cell death machinery (reviewed in (Hacker and Fischer, 2002)). Rickettsia species can infect a wide range of cell types, including endothelial and epithelial cells, human fibroblasts, macrophages and macrophage-like cells (Winkler, 1990). Cell death in the case of infections by R. prowazekii occurs by physical disruption of the host cell due to the accumulation of hundreds or thousands of parasite cells following rapid intracytoplasmic multiplication. In contrast, members of the SFG, such as Rickettsia rickettsii, escape from the host cell into the surrounding medium without observable cell injury. R. rickettsii has been demonstrated to use an anti-apoptotic strategy mediated by NF- [kappa]B activation, presumably to preserve the host cell environment for a prolonged period (Clifton et al., 1998). Likewise, Ehrlichia shows anti-apoptotic activities in human neutrophils (Yoshiie et al., 2000). A proteinaceous nature of the anti- apoptotic compound was suggested, and in addition, ehrlichial internalization is required for apoptosis inhibition. However, the nature of the anti-apoptotic compounds is not known in either species.

Since B. henselae is associated with a facultative intracellular lifestyle (Broqui and Raoult, 1996; Kempf et al., 2000) it is perhaps not surprising that this species inhibits apoptosis of endothelial cells, which are assumed to represent one of its growth habitats. B. henselae prevents cell death by suppressing caspase activation and DNA fragmentation (Kirby et al., 2002). Direct contact is not essential for the anti-apoptotic effect of B. henselae, suggesting that the effect may be mediated by a soluble factor. Likewise, Brucella has been shown to inhibit programmed cell death in phagocytes, and neighbouring cells that are not infected by Brucella are nevertheless protected from apoptosis, arguing for the involvement of a secreted compound also in this species (Gross et al., 2000).

Most likely, a battery of molecules interacts to promote host cell survival and prevent cell death, thereby expanding the longevity of the intracellular growth environments in which these species multiply. A potential bacterial candidate gene cluster involved in inhibition of apoptosis is the operon coding for the type IV secretion apparatus, which is highly conserved among members of the [alpha]-proteobacteria. This system has been shown to be required for intracellular survival of Brucella (Kohler et al., 2002; Kim et al., 2003) and for colonization of the still unknown primary growth niche of B. tribocorum prior to the establishment of intraerythrocytic bacteraemia in a rat infection model of trench fever (Schulein and Dehio, 2002).

Induction of cell proliferation

One of the most remarkable features of Bartonella spp. is the association with vasculoproliferative disorders in immunocompromised patients. B. henselae and B. quintana have been associated with bacillary angiomatosis, cystic forms in the liver and spleen are referred to as bacillary peliosis. These angioproliferative lesions contain proliferating endothelial cells, bacteria and mixed infiltrates of macrophages and polymorphomiclear neutrophils (PMNs) (Kostianovsky and Greco, 1994; Manders, 1996).

The induction of endothelial cell proliferation by Bartonella is crucial for the development of these diseases. As there is no animal model for "bacillary angiomatosis", most of Bartonella-knowledge is based on cell culture assays. From these observations, the hypothetical model for Bartonella-triggered angioproliferation might be suggested: initially, Bartonella infects endothelial cells leading to a proinflammatory response that is regulated by the nuclear transcription factor NF-[kappa]B and results in the attraction of circulating PMNs and macrophages (Fuhrmann et al., 2001; Maeno et al., 2002) which are subsequently infected by B. henselae (Musso etal., 2001). Bartonella-mfected macrophages, although their role in bacillary angiomatosis is not yet clear, could trigger a two-step program for angioproliferation in which Bartonella infected host cells secrete vascular endothelial growth factor (VEGF) (Kempf et al., 2001; Resto-Ruiz et al., 2002). This results in a paracrine angiogenic loop, where the release of VEGF stimulates the proliferation of endothelial cells, which sustain the infection, and provide a growth niche for Bartonella (Kempf et al., 2001); induction of endothelial cell proliferation by a proteinaceous factor detectable in the insoluble cell wall fraction of the bacterium possibly represented by GroEL (Conley et al., 1994; Maeno et al. 1999; Minnick et al. 2003) and inhibition of endothelial cell apoptosis might additionally contribute to this phenomenon (Kirby and Nekorchuk, 2002). The proposed role of VEGF as the major angioproliferative substance is directly supported by immunohistological detection of VEGF in patient's specimen of bacillary angiomatosis (Kempf et al., 2001) and indirectly by studies demonstrating that mice develop a syndrome resembling bacillary peliosis when implanted with VEGF-secreting melanoma cells (Wong et al., 2001).

The resulting cell proliferation, which is clinically manifested as a vascularized tumor, might be understood as bacterial pathogen- triggered promotion of the Bartonella-habitat as the bacteria replicate in endothelial cells (Kempf et al., 2000; Broqui and Raoult, 1996). In this respect, B. henselae resembles A. tumefadens, an inducer of vascularized tumours in plants. The similarity between the stimulation of host cell proliferation by Bartonella spp. and the plant pathogen A. tumefaciens is intriguing (Kempf et al., 2002). In the latter species, the proliferative process is initiated by the generation of wounds in plants that stimulate the production of acetosyringones. These compounds activate the expression of the type IV secretion system in A. tumefaciens that mediates the transfer of the T-DNA into the plant cells, where it becomes chromosomally integrated. Gene expression from the T-DNA induces plant cell production of cytokines and auxins. These plant hormones trigger the formation of tumour growth (crown gall) and production of tumour-specific compounds (opines) that are used as a source of carbon and nitrogen by A. tumefaciens.

Likewise, plant infection of S. meliloti is followed by bacterial and host cell multiplication, which in this case results in the formation of root nodules. The nitroge\n-fixing symbiosis with leguminous host plants enables the plants to use atmospheric nitrogen. Upon infection, "rhizopines" (analogous to A. tumefaciens opines) are produced in alfalfa (Medicago saliva] nodules, which in turn, can be used by S. meliloti as a selective growth substrate. Thus, it has been suggested that proliferation of the bacterial growth habitat is a general strategy used by B. henselae, A. tumefaciens and S. meliloti, possibly mediated by genes present already in their common ancestors (Kempf et al., 2002). In any case, it is clear that an elaborate series of regulatory loops and interactive events is required to prevent the host cell from committing suicide and instead activate its proliferation to the benefit of the bacterium.

The genomes of Rickettsia and Brucella spp. contain no genes coding for toxic compounds, as inferred from sequence homology searches (Andersson et al., 1998; Ogata et al., 2001; Paulsen et al., 2002). This means that the classical bacterial pathogenicity factors "toxins" may not be involved in ocproteobacterial infections, although a yopJ homolog has been identified in the B. quintana genome (unpublished). Instead, [alpha]-proteobacteria infections tend to preserve host cell functions for best ecological benefit. The observation that both bacterial pathogens and symbionts of higher eukaryotes inhibit host cell death and/or induce host cell proliferation blurs the traditional borders between mutualism and pathogenicity and might lead to new insights of the "cross-talk" between pathogens and their host cells.

Conclusions

A surprising feature of a-proteobacterial pathogens has been the absence of genes for many of the classical toxins and virulence factors. This may partly be explained by their dependence on host cells for multiplication in their natural growth environment. To sustain growth these bacteria have evolved intriguing communication processes with their respective hosts, including mechanisms for inhibition of cell death and promotion of proliferative loops (Fig. 1). In such close interactions between bacteria and hosts, the borders between symbiosis and pathogenicity become less distinct. Rather than having acquired novel virulence factors, particularly virulent strains may result from the loss of some of the control mechanisms that have evolved during the past hundreds of millions of years to ensure the coexistence and interaction of [alpha]- proteobacteria with their eukaryotic hosts to the benefit of one or both partners.

Fig. 1. Bacteria manipulate the machinery for host cell growth and death to their own benefit. a. Bacterial pathogens like Clostridium difficile and Yersinia spp. produce toxins or compounds that induce host cell death. b. Intracellular and host-associated bacteria like Rickettsia spp., Bartoneila spp., Brucella spp., and Agrobacterium tumefaciens have evolved mechanisms to alter host cell responses to infection. By preventing cell suicide and stimulating cell proliferation (e.g. Bartoneila spp.), these bacteria maintain and expand their own growth environment for own ecological benefit.

Acknowledgements. The work of Siv Andersson is supported by the Swedish Research Council (VR), the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), the Swedish Foundation for Strategic Research (SSF), the Knut and Alice Wellenberg Foundation (KAW) and the European Union (EU). The work of Volkhard Kempf is supported by the Deutsche Forschungsgemeinschaft and the Fortuene program of the University of Tubingen, Germany.

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Siv G. E. Andersson(a), Volkhard A. J. Kempf(b)

a Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Uppsala, Sweden

b Institut fur Medizinische Mikrobiologie und Krankenhaushygiene, Tubingen, Germany

Corresponding author: Siv Andersson, Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University, Norbyvagen 18C, 752 36 Uppsala, Sweden. E-mail: Siv.Andersson@ebc.uu.se

Copyright Urban & Fischer Verlag Apr 2004

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