Molecular Mechanisms in Legionella Pathogenesis: 376 (Current Topics in Microbiology and Immunology)

Adaptive immunity Waltenbaugh, C. Animal models of burkitt's lymphoma Vrazo, A. Springer New York , p. Culturing, media, and handling of legionella Chatfield, C. Epstein-barr virus Longnecker, R. Elsevier Inc , p. Legionnaires' disease Cianciotto, N. Springer-Verlag Berlin Heidelberg , p. Legionnaires' Disease Cianciotto, N. Rous sarcoma virus retropepsin and avian myeloblastosis virus retropepsin Ridky, T. Targeting Th17 cells for therapy of multiple sclerosis Martin, A. Role in Inflammation and Autoimmunity.

Birkhauser Verlag , p. Type II secretion and legionella virulence Cianciotto, N. Viral transformation of epithelial cells Regan, J. A Tribute to Bernard Roizman. World Scientific Publishing Co. Current theories for multiple sclerosis pathogenesis and treatment Muller, M. InTech Press , p. Helper T-cell subsets and control of the inflammatory response Eagar, T.

McGraw Hill Research output: Mouse models of multiple sclerosis: Experimental autoimmune encephalomyelitis and theiler's virus-induced demyelinating disease McCarthy, D. Chemokines and cytotoxic effector molecules in rejection Krensky, A. Lippincott, Williams and Wilkins Research output: Elsevier, Churchill Livingstone , p. Prospects for antigen-specific tolerance based therapies for the treatment of multiple sclerosis Turley, D.

Results and Problems in Cell Differentiation; vol. Role in Inflammation and Autoimmune Disease. Viruses, autoimmunity and cancer Getts, MT. ASM Press , p. Several human pathogenic microorganisms also contain members of a protein family called Microbial Surface Components Recognizing Adhesive Matrix Molecules or MSCRAMMs , which interact in a ligand-receptor fashion with common host surface molecules including collagen, fibronectin, vitronectin, cytokeratin and others Kreikemeyer et al.

General blueprint of a microbial infection. After attachment of a pathogenic microorganism, pathogens may enter host tissues a through active penetration processes, or b through wounds or natural openings. Subsequently, pathogenic microorganisms colonize host tissues. This colonization occurs either c intercellularly or d extracellularly. In a next stage, progeny of the pathogen is released and dispersed after which new infections can take place. After attachment, the pathogenic microorganism may physically penetrate or enter the host.

Mammalian pathogens can infect either intracellularly, as occurs with Salmonella , Mycoplasma, Mycobacterium spp. Intracellular bacterial pathogens enter the host cells by an active invasion process that is often facilitated by surface-exposed proteins Isberg et al. Some vertebrate pathogens thrive within the host after being taken up by macrophages. Plant-pathogenic bacteria are predominantly extracellular microorganisms that multiply in the intercellular spaces between host cells. They enter host tissues either through wounds or through natural openings such as stomata, microscopic pores in the leaf epidermis essential for gas exchange.

Although most mammalian fungal pathogens are extracellular, some invade the host cytoplasm, a process that is poorly understood Tsarfaty et al. The unicellular phase of Candida albicans , for example, has been shown to induce phagocytosis in host cells through the induction of polymerization of host microfilaments and microtubules Filler et al. Although fungal plant pathogens may be specialized to detect stomata or wounds and to enter plant tissues through these openings, many highly specialized fungal plant pathogens forcibly enter the host by piercing the leaf with an infection peg that arises from a so-called appressorium that facilitates the exertion of pressure Bechinger et al.

In the next stage, microorganisms need to colonize the host in order to feed and replicate. Based on their interaction with the host, plant-pathogenic microorganisms are often divided into biotrophs and necrotrophs, although many intermediate forms exist Thomma et al. Biotrophic pathogens feed on living plant cells, often by means of specialized feeding structures termed haustoria. In contrast, necrotrophic pathogens secrete toxins and lytic enzymes and absorb nutrients from necrotic tissues. The mode of infection of such pathogenic microorganisms is somewhat unsophisticated, as they apparently do not avoid triggering the host defence system and tend to be adapted to kill host cells as quickly as possible.

This situation actually resembles human and animal infections by microbial pathogens. These infections are classified either as chronic, where a persisting pathogen causes a long-term infection, or as acute, where the pathogen quickly grows and spreads within the host. It has been suggested that the difference between chronic and acute infections is correlated with the mode of microbial growth, with acute infections associated with planktonic growth and chronic infections caused by microorganisms that form a biofilm Furukawa et al.

Biofilms are structurally complex, multicellular communities produced through the production of an extracellular matrix by extracellularly growing microorganisms that adhere to abiotic as well as to living surfaces Lam et al. This slimy matrix can be very diverse in composition, but generally consists of macromolecules that include polysaccharides and proteins. Biofilms offer their member cells protection from adverse environmental conditions, including host defence components and externally administered antimicrobial agents.

Their formation is initiated by the interaction of cells with a surface, as well as by the interaction with each other quorum sensing; Abraham et al. Foreign bodies implanted into human hosts form an excellent attachment matrix for the development of biofilms. Such biofilms incur costs for the medical system replacing any catheter is expensive and risky and predispose patients to the development of more serious infectious syndromes because biofilms can act as reservoirs for recurrent infections Jones, When nutrient conditions become limiting, cells are released from the biofilm and enter a free-living, planktonic phase.

These cells can spread, colonize new habitats, and form new biofilms Costerton et al. It was recently discovered for uropathogenic Escherichia coli that biofilm-like structures can even occur intracellularly, embedding bacteria in a matrix shell in the host cell cytoplasm, which may facilitate resistance to host defence responses Anderson et al.

Even today, a set of five postulates formulated by Koch, and later adapted to fit viral infections, is the gold standard to prove that a specific microorganism is the cause of a specific disease Koch, ; Rivers Essentially, it has been stated in these postulates that the microbial pathogen must be found in all diseased individuals and not in healthy ones. Even in Koch's time it was noted that certain elements of the postulates may be problematic in specific cases.

For instance, some microorganisms cannot be grown in a cell-free culture outside the host, reinoculation with a strictly human-pathogenic microorganism is often considered unethical and therefore impossible, and pathogens may have a carrier state in which they do not necessarily cause disease in all individuals that harbour them. Nevertheless, such criteria are important in defining diseased state and pathogenicity from the perspectives of the host and pathogen.

Whether or not a particular microorganism infects a particular target organism depends on multiple conditions. First of all, an infection can only occur if both partners are compatible. Compatibility depends on the genetic constitution of the microbial pathogen as well as on that of the target organism. In addition, environmental circumstances influence the interaction. The most important requirements for establishing a pathogenic relationship will be discussed below. Compatible interactions between a pathogen and a host will only result in disease when environmental conditions are also fulfilled.

The interactions not fulfilling all requirements will not result in disease. It is self-evident that the possibility of a microorganism developing a relationship with an organism will increase the more the two organisms meet. The actual circumstances entailed by this word can be very diverse, as it ranges from mutualistic symbiosis both species benefit through commensalism one organism benefits and the other is not significantly harmed or helped , to parasitism one species benefits at the expense of the other. The distinction between these relationships is not always clear-cut.

Moreover, especially in mutualistic and commensalistic relationships, a fine balance is maintained between the host and the microorganism, and a small disturbance can lead to a change in the relationship whereby mutualists or commensals can become pathogenic Tanaka et al.

This has been well documented, for example, for Candida albicans , a commensal yeast of human gastrointestinal and genital mucosa that can become pathogenic and infect many body sites if the person hosting it becomes immunocompromised Hube, Another clear example of opportunistic pathogenicity is provided by the bacterial species Staphylococcus aureus. These bacteria can be encountered in the nasal cavity of c. Such nasal colonization, however, predisposes the carrier to opportunistic bacterial infection in times of waning immunity Wertheim et al. Furthermore, the primary host may bring a pathogenic microorganism into contact with a potential new host, with which it may go on to develop a novel pathogenic relationship.

In this way, normally mutualistic or commensal plant endophyte bacteria and fungi, which may build upon their capacity to enter hosts in which they do not cause disease, may develop into pathogens on or in other hosts. Bacterial species such as Pseudomonas aeruginosa, Staphylococcus aureus and Burkholderia cepacia are known as beneficials, occurring as endophytes on some plant hosts, while functioning as pathogens on others Berg et al. In order for a pathogenic microorganism to become stabilized and to persist in time, the host should be able to provide all required conditions for the microorganism to complete its life cycle.

Each host presents different nutritional conditions that nonetheless must be relied upon to provide essential cellular requirements such as water, amino acids, micronutrients and energy. Auxotrophy for nearly any amino acid or fatty acid will diminish or abolish microbial pathogenicity, and therefore quorum-sensing of nutrient availability is essential for successful pathogenicity Guerinot et al. Iron is an important example of an essential host factor that can determine whether the interaction of a microorganism with a possible future host will be successful. It is essential for many cellular processes in all microorganisms except, possibly, lactobacilli Archibald et al.

Microorganisms living in or on plants have developed specialized mechanisms for acquiring iron from the host Expert, Animals, on the other hand, have levels of available iron between 20 and times lower than those found in plants Lux et al. At the same time, animals are generally characterized by high extracellular iron content in iron complexes transported in the blood stream. Intracellular iron is complexed in heme, iron-sulphur proteins, and ferritin, as well as in other proteins, whereas extracellular iron is bound to transferrin and lactoferrin proteins Weinberg, ; Payne et al.

Invasive microbial pathogens that multiply in the extracellular spaces of the host need to employ different strategies for iron acquisition from those used by microorganisms that grow within host cells. After iron has been chelated outside the microbial cell, the iron-siderophore complex is transported back into the cell, where the iron is removed and utilized. An alternative strategy for iron acquisition is the direct use of host iron compounds, including heme, hemoglobin, transferrin, and lactoferrin.

In a few cases, such as for the plant pathogen Erwinia chrysanthemi , siderophores have been shown to serve as pathogenicity factors Enard et al.

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On the other hand, microbial pathogenicity mechanisms may be influenced by changes in iron availability in the environment Guerinot, Furthermore, synthesis of a hemolysin toxin by Vibrio cholerae , a bacterium well known as a human gastrointestinal pathogen, is regulated by iron Masclaux et al. For Cryptococcus neoformans , a facultative pathogen and causal agent of meningitis and pneumonia, it was recently shown that the iron-responsive transcription factor Cir1 controls regulation of genes involved in iron acquisition, and in addition controls various other important virulence characteristics Jung et al.

It is obviously the case that availability of iron and metals in general will be low in the acid stomach niche, and various methods for iron acquisition have been developed Pflock et al. Interestingly, nickel signalling is coregulated with urease production. The latter involves a mechanism useful for modulating environmental conditions, especially the pH, implicating a link between iron sequestration and pH modulation Van Vliet, Because iron sequestration is crucial for pathogenic microorganisms, vertebrate hosts have developed iron-withholding defence mechanisms.

One such mechanism is the complexing of iron with ferritins as soon as microbial invasion is sensed; the result is rapidly reduced levels of serum iron Weinberg, Interestingly, a similar mechanism involving ferritins seems to be employed by plants in response to pathogen attack Neema et al. In general, there seems to be a correlation between the capacity to acquire iron from diverse environments and cross-kingdom pathogenicity.

These microorganisms are pathogenic to hosts from more than one kingdom see Table 1. Species are indicated and belong to the kingdom Fungi unless otherwise indicated in brackets: C kingdom Chromista, E kingdom Eubacteria. All living pathogenic microorganisms produce molecular components that, upon secretion within the host or upon injection into host tissue, play a role in the establishment of an infection.

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These components may play a role in the release or uptake of nutrients or in the evasion or suppression of the host immune system. Early in the evolution of pathogenic relationships, successful factors will tend to become fixed in populations through positive selection Read, Molecules that target specific components of a specialized cell type are far less likely to facilitate cross-kingdom host jumps than molecules that target a generally conserved host component, and therefore microorganisms displaying a capacity for cross-kingdom host jumps are likely to express factors that act upon a wide range of organisms.

Indeed, an examination of microorganisms that possess cross-kingdom pathogenicity Table 1 appears to support this scenario. An overview of broadly effective factors conferring the capacity for pathogenicity towards hosts from different kingdoms is shown in Table 2. Examples of such factors are the subtilisin-like proteases produced by several Aspergillus species Kolattukudy et al. These compounds all show activity against plant, insect and human tissues see Table 2.

Furthermore, secondary metabolites low-molecular-weight molecules that are not directly necessary for growth but instead are a by-product of regular metabolism can have targets in hosts belonging to different kingdoms. These compounds function in microbial defence and in antibiosis Wicklow, For instance, helvolic acid produced by some Aspergillus fumigatus isolates can suppress the respiratory oxidative burst that is essential to the innate immune response in both plants and animals Rementeria et al.

The infection-promoting factors produced by microbial cross-kingdom pathogens tend to be toxins that directly target cellular membranes, which are among the most conserved cellular components. The direct mode of toxin action, the induction of necrosis, is to be expected from pathogens that benefit from inducing cellular lysis and then taking up cellular components as nutrient source after preprocessing them with extracellular enzymes.

In order to develop stable pathogenicity as opposed to occasional chance infection, the future pathogen must be able to suppress or avoid host immune responses. Invertebrate animals and plants rely completely on innate immunity for their self-defence Thomma et al. Plants have a more or less rigid vascular system that transports dissolved compounds in an aqueous solution throughout the plant, although they lack a system with circulating cells that can swiftly carry host defence components to distal parts of the organism.

In addition to containing antimicrobial proteins and peptides, the hemolymph contains circulating cells known as hemocytes. This category of cell includes plasmatocytes and granulocytes, which are capable of phagocytosis and encapsulation of invading microorganisms. In contrast to the open hemolymph system of invertebrates, vertebrate animals have a closed circulatory system in which blood is contained within vessels. One unique feature of vertebrate self-defence is a very efficient adaptive immune system.

This system utilizes T- and B-cells, outfitted with a diversity of antigen-specific receptors, which travel in the blood stream and detect and combat components recognized as potential pathogens. The antigen-specific receptors are quickly generated through somatic recombination, which gives the immune system an extensive capacity to mount large numbers of different but specific defence reactions.

Despite the absence of an adaptive immune system in invertebrates and plants, the innate immune system in these organisms still possesses some degree of specificity, as specialized defence mechanisms are activated in cases of attack by particular types of pathogens Lemaitre et al. In addition, as with the genes encoding mammalian antigen-specific receptors, plant genes involved in the recognition of specific pathogen types have been found to occur in clusters on the genome. Despite the presence of an adaptive immune system, innate immunity still plays a central role in vertebrate host defence.

Apart from serving as a first line of defence against potential pathogens, especially at the body's natural openings, innate immunity is involved in the activation of adaptive immune responses Yang et al. Despite fundamental differences, the innate immune systems in different higher eukaryotic kingdoms share a number of common features Fig. These include molecular structures involved in microbial recognition, mitogen-associated protein kinase-based downstream signalling pathways, and the defensive use of reactive oxygen species respiratory burst and antimicrobial peptides and proteins.

However, clear differences can be observed as well. For instance, the vertebrate complement system does not seem to have a counterpart system in the other kingdoms. This complement cascade poses a barrier to infection, resulting in pathogen elimination, and, obviously, human pathogens have developed means of circumventing this.

Multifactorial complement resistance has been observed for Moraxella catarrhalis , a human pathogen causing otitis media Verduin et al. Even more indicative of adaptation, Staphylococcus aureus has developed sophisticated means of interference in the complement-mediated opsonization. An inhibitor of one of the convertases involved in complement activation has been acquired through a bacteriophage Foster, ; Rooijakkers et al. All of the above implies that pathogenic microorganisms are likely to meet similar molecular host defence components if they invade different hosts.

This all suggests that the molecular processes required for host defence have a high degree of fundamental similarity, and the ability to overcome a particular defence mechanism in one host could have implications for the ability to overcome similar mechanisms in other hosts. Apparently, the ability of a pathogen to infect multiple hosts might be very well reflected by homologies in their innate defence methodologies van Baarlen, Similarities in molecular components that play a role in the innate immune systems in different higher eukaryotic kingdoms.

Pathogens are detected through various pattern recognition receptors PRRs that perceive microbial-associated molecular patterns MAMPs or effector proteins that may be released either extracellularly or in the host cytoplasm. PRRs on the left-hand side occur in mammalian hosts, while PRRs on the right-hand side occur in plants. Upon microbial recognition, MAPK signalling generally leads to transcriptional responses and the activiation of host immunity.

Innate immunity is activated by the initial recognition processes of microbial invaders. This recognition can occur through so-called pathogen-associated molecular patterns PAMPs , which include molecules of various natures such as the lipopolysaccharides of Gram-negative bacteria and the peptidoglycans of Gram-positive bacteria, as well as bacterial flagellin, microbial DNA and fungal cell-wall constituents Girardin et al.

Although the term PAMP suggests that these molecules are unique to pathogenic microorganisms, they are in fact produced by both pathogenic and nonpathogenic microorganisms, and are therefore also frequently called microbial-associated molecular patterns MAMPs. In addition to MAMPs, microbial effector molecules are also detected by the host.

The actual microbial recognition is mediated by so-called pattern recognition receptors Fig. Whereas both types of proteins are anchored in the cell membrane, neither of them contains a cytoplasmic TIR domain. The RLPs are characterized by a short cytoplasmic tail lacking obvious signalling domains, while RLKs contain a cytoplasmic kinase domain. In addition to these extracellular receptors for MAMP recognition, intracellular pattern recognition receptors have been identified. Apart from the central nucleotide-binding domain they contain a C-terminal LRR region.

Remarkably, neither nematodes nor insects have homologues of the mammalian NLR or plant NBS-LRR proteins, suggesting independent evolutionary origins for those proteins in plants and mammals. The siglecs can adhere to surface-expressed complex microbial sugar molecules and initiate downstream activation of, for instance, B cell differentiation Crocker, Siglecs are also suggested to provide portals of entry for various viruses and bacteria. This siglec system is best studied in mammalian systems, but the first sialic acid-specific receptors were identified on plant cell surfaces Muthing et al.

This might render siglec activity as yet another cross-kingdom conserved feature involved in the signalling upon detection of microorganisms. However, this involvement has yet to be confirmed for the plant sialic acid-binding proteins. Once a pathogenic microorganism has been recognized, the host response often requires kinase activity that is mediated by a conserved family of serine-threonine kinases. Further downstream of these initial serine-threonine kinases, MAP kinase cascades are activated.

Although the general patterns of these immune responses in different hosts are highly similar, there is little conservation between the individual components of these signalling cascades. It is likely that pathogen recognition capabilities and the ensuing cascade of responses have evolved independently in diverse members of different kingdoms, even though the evolutionary process may have built upon general signalling cascades that originated very early in evolution. The origin of such ancient signalling systems is likely to predate even the occurrence of multicellularity, because homologous general signalling blueprints are found in unicellular yeast species that are unlikely to have had multicellular ancestors Ausubel et al.

Interestingly, it was recently shown that Arabidopsis plants respond similarly to inoculation with human and plant-pathogenic bacteria, with the induction of many genes that correspond to transcription factors, signalling components, and cell wall- or secretion-associated components Thilmony et al. A central aspect of innate immunity is the production of antimicrobial proteins, most of which are cationic, polar molecules with spatially separated, charged and hydrophobic regions Boman et al.

To date, hundreds of such proteins and peptides have been identified Brahmachary, They are organized in families that differ in size, sequence and structural motifs. Most of these peptides exert their antimicrobial activity by destabilizing negatively charged phospholipids in the plasma membranes of invading microorganisms, resulting in pore formation and membrane permeabilization Kagan et al.

Alternatively, cationic peptides may exert antimicrobial activity in part by affecting specific cytoplasmic targets. For these cases, the ability of cationic peptides to permeabilize cytoplasmic membranes might provide a means for inhibitory components to reach an intracellular target. One class of antimicrobial peptides that is found to be conserved across kingdom boundaries comprises the defensins Thomma et al.

Representatives of this peptide family isolated from plants, insects, invertebrates and vertebrates display remarkable structural homology Fig. Recently, the first defensin of fungal origin was identified and structurally characterized Mygind et al. In contrast to most other cationic peptides, it has been demonstrated that defensins, in at least some cases, do not undergo electrostatic binding to membrane phospholipids but interact specifically with membrane sphingolipid targets Thevissen et al.

Interestingly, in one case it was found that an identical target was shared by a plant defensin from radish seeds and an insect defensin from a moth Thevissen et al. Insensitivity of fungal mutants to the plant defensin renders them insensitive to the insect defensin as well. Three-dimensional structure of defensins of fungal, animal and plant origin from the saprotrophic fungus Pseudoplectania nigrella , flesh fly, tobacco budworm and garden pea as examples.

Structures were downloaded from the protein data bank http: Pictures were generated using Swiss-PDB viewer. Alpha-helices and beta-sheets are shown in yellow and red, respectively. It has recently been shown that the phenolic plant metabolite salicylic acid SA that mediates the expression of a number of genes encoding antimicrobial proteins acts against the virulence of Pseudomonas aeruginosa by repressing attachment, biofilm formation, and the production of virulence factors Prithiviraj et al.

Inside the gut of Caenorhabditis elegans nematodes, SA-treated bacteria accumulate to densities similar to those attained by untreated bacteria, but they are less capable than the untreated bacteria of killing the nematodes. This difference supports the hypothesis that SA directly influences virulence factors Prithiviraj et al. Similar results were obtained in SA trials in which Arabidopsis and Caenorhabditis elegans were used as infection models for Staphylococcus aureus Sifri et al.

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Interestingly, intravenous aspirin [acetylsalicylic acid ASA ] was shown to result in a reduction of Staphylococcus aureus densities on the endocardial surface in a rabbit model of invasive endocarditis. This effect could be attributed to the retention by ASA of the inhibitory properties of its precursor molecule, SA. Also in this interaction, pretreatment of bacteria with SA significantly reduced attachment to the cardiac epithelium Kupferwasser et al. If a pathogenic microorganism is sensitive to defence components released by the host, it has to find ways to evade or suppress them in order to cause infection.

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In several cases, similar strategies have been developed by different pathogens affecting hosts from different kingdoms. A first strategy to deal with host defence is self-protection. Pigments deposited in microbial cell walls, such as carotenoids and melanin, have been shown to be important for microbial survival and pathogenicity. Melanins may play direct as well as indirect roles in microbial virulence. They act in protection, often of propagative structures such as spores and resting structures. These specialized structures are shielded by melanin against adverse conditions and environmental stresses of various kinds, such as extreme temperatures, UV radiation and detrimental compounds, and thus attain extended survival times Frye et al.

In the human-pathogenic fungi Cryptococcus neoformans and Exophiala dermatitidis , melanin-deficient strains were shown to exhibit decreased virulence Dixon et al. The precise means by which melanin may contribute to virulence is only partially understood. Several studies have shown that melanin can act as a scavenger of reactive oxygen species that are produced during host defence reactions Fels et al.

Melanized cells are less sensitive to killing by reactive oxygen species than are unmelanized mutants or other unmelanized cells. Moreover, melanized cells are more resistant than unmelanized cells to lysis, and, unlike unmelanized equivalents, can prevent phagocytosis Wang et al. A second strategy to deal with host defence is suppression. Several microbial pathogens are known to produce metabolites that display immunosuppressive effects, of which gliotoxin is probably the best characterized. Gliotoxin is produced by several phylogenetically separated fungi including Aspergillus fumigatus , Trichoderma virens , Candida albicans and some Penicillium spp.

It belongs to the class of epipolythiodioxopiperazine ETP compounds, of which some members, such as sirodesmin, which is produced by the plant pathogen Leptosphaeria maculans Rouxel et al.

The putative gliotoxin biosynthetic gene cluster identified in the Aspergillus fumigatus genome Gardiner et al. Bacterial mutants that are incapable of injecting these effectors are nonpathogenic Lindgren et al. The type III secretion system is not restricted to pathogenic bacteria, as symbiotic plant and insect bacteria also use type III secretion systems to interact with their hosts Viprey et al.

For the plant pathogen Pseudomonas syringae it has been determined that, depending on the strain, about 20—30 effectors are injected into the host cells Chang et al.

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For plant pathogens in particular, the biological function of a growing number of bacterial effectors has been elucidated Nomura et al. The emerging view is that many plant pathogen effector molecules act to suppress the MAMP-triggered immune response Chisholm et al. For instance, the Pseudomonas syringae effectors AvrPto and AvrPtoB were found to intercept multiple mitogen-associated protein kinase MAPK signalling cascades that act in nonhost immune responses He et al. Bacterial virulence factors other than type III effectors may also play a role in the suppression of basal host defences.

Several Pseudomonas syringae pathovars produce the phytotoxin coronatine, which mimics the action of jasmonic acid JA , a plant compound involved in basal defence against pathogenic microorganisms Thomma et al. Coronatine activates the JA signalling pathway in tomato, thereby suppressing SA-dependent defence responses Zhao et al. Two newly discovered immune modulators from Staphylococcus aureus , namely staphylococcal complement inhibitor SCIN and chemotaxis inhibitory protein of Staphylococcus aureus CHIPS , are important virulence factors that protect Staphylococcus aureus from host innate immune responses.

While SCIN is a C3 convertase inhibitor that inhibits the ability of host neutrophils to phagocytose Staphylococcus aureus by blocking the formation of C3b on the surface of the bacterium, CHIPS specifically binds two chemokine receptors, resulting in the inhibition of neutrophil chemotaxis de Haas, ; Rooijakkers et al. Besides modulating basal defence responses, the programmed cell death PCD or apoptosis response may also be targetted as part of the modification of host defences.

In some such cases cell death is triggered, while in other cases it is suppressed. These modulating actions can be achieved by various effectors. YopJ is an effector protein produced by Yersinia spp. YopJ achieves its effect through its activity as a promiscuous deubiquitinating enzyme that negatively regulates signalling by removing ubiquitin moieties from critical signalling proteins Zhou et al. On the other hand, the effector molecule AvrPtoB that displays ubiquitin ligase activity and that is produced by diverse plant pathogens is found to inhibit PCD initiated by disease resistance proteins Janjusevic et al.

Remarkably, AvrPtoB is also able to suppress PCD induced by various triggers in the nonpathogenic baker's yeast Saccharomyces cerevisiae , indicating that AvrPtoB acts on PCD components apparently conserved across different kingdoms Abramovitch et al. Other ways to modulate PCD have also been reported. The pathogenicity factor tomatinase, produced by the tomato leaf spot fungus Septoria lycopersici during infection, was found to suppress host PCD by degrading preformed antimicrobial host saponins into PCD-suppressive degradation products Bouarab et al.

Most pathogenic microorganisms have a free-living life style too, or at least have free-living nonpathogenic sister species or genera. For instance, many Pseudomonas spp. Similarly, fungi belonging to the genus Penicillium are ubiquitous saprotrophs, but the species Penicillium marneffei can cause systemic opportunistic infection of people suffering from AIDS Kaufman, Survival upon entering a living organism is associated with an innate capacity for rapid modification of metabolic activity or adapting to and taking advantage of host metabolism.

A difference in the capacity for pathogenicity may be decided for at the transcriptional level Berg et al. As can be expected, the presence of virulence factors is an additional prerequisite Foster, ; Mendes-Giannini et al. For example, virulence factors can appear to be correlated with host preference Melles et al. The lifestyle and environmental niche are among a number of factors determined by fundamental requirements with respect to humidity, nutrients, pH and temperature optima of a species.

These basic growth conditions may be similar in both the pathogenic and the harmless members of clades containing pathogens Xu, ; Heurlier et al. When these pathogens enter mammals, this tolerance may enable them to persist at least temporarily. Such tolerance may have evolved in the environment: Many fungi occur mainly in the soil or on decaying plant materials, but some species or isolates can nonetheless infect various hosts upon contact.

Several species of the genus Aspergillus are good examples of this; for instance Aspergillus fumigatus and Aspergillus terreus are important pathogens of humans, whereas Aspergillus flavus has an even wider host range including plants. A shift from an environmental state into a clinical, pathogenic state inside a host requires adaptation to or tolerance of the new environment. Not all organisms are able to survive this shift. One decisive moment is when fungal spores enter a mammalian host and experience substantially increased temperature.

Furthermore, the iron-responsive Cryptococcus neoformans transcription factor Cir1 was determined to control the ability to grow at human body temperature Jung et al. It can also use over 80 organic compounds for growth, and has a good ability to survive under a variety of conditions including oligotrophic aquatic habitats and high-redox stress environments such as wounded or necrotic tissue Wick et al.

Especially for opportunistic and facultative pathogens, pathogenicity mechanisms may be selected for in alternative hosts or in the environment. Interactions between microorganisms may lead to the development of pathogenicity towards other organisms. Cryptococcus neoformans pathogenicity towards humans and the capacity to persist within mammalian macrophages may have arisen as a result of adaptations necessary for survival in interactions with soil protozoa or other soil organisms Steenbergen et al.

The primary niche for Cryptococcus neoformans is not well understood but includes microorganism-rich sites such as bird and bat guano and animal-inhabited tree holes Randhawa et al. Cryptococcus neoformans has been shown to be capable of surviving phagocytosis by amoebae and can even replicate within, and then escape from, these organisms Steenbergen et al.

Macrophages and amoebae share common properties that include the phagocytosis of particles into vacuoles where lytic enzymes are secreted for digestion. It is thought that pathogens escape killing in both cell types through mechanisms that are similar at the cellular level. A bacterial parallel to Cryptococcus neoformans is the pathogen Legionella pneumophila , which persists in both macrophages and amoebae Rowbotham et al.

The genes required for survival and replication in the two hosts have been shown to share a remarkable overlap Gao et al. There is a dynamic dimension to these interactions, as in an experimental slime mould model passage of Cryptococcus neoformans through the microorganism-digesting myxomycete not only failed to kill the yeast, but also increased its virulence on a mammalian host Steenbergen et al.

A similar increase in virulence was observed by passage of the bacterium Mycobacterium avium and the yeast Histoplasma capsulatum through amoebae Cirillo et al. All these finding support the idea that key aspects of pathogenesis in these microorganisms are derived from mechanisms employed for survival in the environment external to the host Steenbergen et al. This might represent a general mechanism: It has been shown that the yeast forms of the facultative mammalian pathogens Blastomyces dermatitidis , Sporothrix schenckii and Histoplasma capsulatum possess the capability to infect amoebae Steenbergen et al.

Amoeba-like protozoans were also suggested to be an ancestral host to Rickettsia spp. One species, Rickettsia bellii , was found to be able to survive in the vacuole of amoebae as well as to replicate in nuclei of eukaryotic cells. Interestingly, this species expresses sex pili-like appendages on its surface and contains genes enabling transfer of DNA. Ogata suggested that protozoans hosting Rickettsia spp. Such a genetic reservoir within protozoans may have contained factors enabling the survival, adaptation and reproduction of Rickettsia within the protozoans and eukaryotic cells Ogata et al.

In general, the survival of microorganisms in protozoans which often display a predatory-like behaviour towards bacteria may well have driven the evolution of bacterial virulence factors, some of which may eventually be employed in mammalian infection. Adaptation to a specific environment or host may lead to a decreased capacity to prosper in other environments or hosts. Radial growth was constant when Aspergillus flavus isolates were subcultured multiple times on culture media. After repeated passage of Aspergillus flavus through an insect host, increasing numbers of conidia were formed on cadavers after the infected insects had died.

Interestingly, continued propagation of Aspergillus flavus on wax moth larvae resulted in a strain that was affected in host range as well as conidia production in vitro , while pathogenicity and conidial production on the insect host was maintained. This seems to be an opportunistically driven adaptive process. This could similarly have occurred in Yersinia pestis , an obligate pathogen that causes plague.

The facultative pathogen Yersinia pseudotuberculosis is thought to be the ancestor of the obligate pathogen Y. This has been corroborated by estimating the evolutionary history and its timing for Y. Not all fungi show an evolution towards increasing pathogenicity after serial passage through insect hosts Hall, Understanding the differences between taxonomic groups in this capacity is important if we are to understand the evolution of pathogenicity. Adaptation is a very important feature of host—pathogen interaction, and bacteria have developed various mechanisms to adapt.

In simple molecular terms these mechanisms could all be traced back to genomic differences: A very interesting example is provided by variation in tandem repeat loci. In many bacteria, regions of repetitive DNA are likely to undergo changes during replication. The number of repeat units may vary locally, and when the repeat is within a coding region or gene promoter differential gene expression may be the consequence of the repeat variation van Belkum, This results in phase variation and is a widespread phenomenon in the bacterial kingdom.

Haemophilus influenzae , for instance, uses arbitrary repeat variation to introduce variability into its lipopolysaccharide Schweda et al. This may affect survival in given niches or the capacity to overcome host responses. Species such as the opportunistic pathogen Aspergillus fumigatus not only produce factors that induce necrosis and cell death in human tissue Rementeria et al. In contrast to virulence factors, fitness factors contribute to microbial survival, for instance through protection of the fungus from adverse conditions during growth inside the host, or outside in the environment.

For Aspergillus , these factors are generally found in nonpathogenic Aspergillus species as well as in the opportunistic aspergilli Nierman et al. Some widely distributed fitness factors may, however, predispose the fungi possessing them to develop true pathogenicity. Fitness factors and other factors fortuitously contributing to pathogenic success may circulate among the members of microbial communities, including the soil-borne communities that many microorganisms belong to during at least some phase of their life histories. The growth in soil or decaying vegetation of environmentally common opportunistic fungal pathogens such as Aspergillus fumigatus and Aspergillus flavus appears to have allowed genetic exchange and recombination among isolates, giving rise to a diverse gene pool that underlies the capacity of these organisms to tolerate an extremely wide range of environments.

These fungi, although apparently asexual, are characterized by high genetic diversity Debeaupuis et al. Indeed, the complete genetic machinery for sexual reproduction has been found in Aspergillus fumigatus and it must be there for a reason Debeaupuis et al. This highlights the fact that genome sequencing is an important tool for establishing microbial factors important not only for sexual reproduction but also for controlled and successful reproduction in the host environment.

Nevertheless, sexual reproduction has not yet been observed for Aspergillus fumigatus in nature. Similarly, a soil-borne phase as part of the life history is found in bacteria that show the capacity for cross-kingdom infection Berg et al. Reproduction of the pathogenic microorganism on the host or in its immediate environments is essential in the establishment of evolutionarily stable host—pathogen relationships as opposed to incidental or chance infection.

Many fungal pathogens reproduce both sexually and asexually. While sexual reproduction is important in the generation of variation by means of meiotic recombination, asexual reproduction can efficiently generate massive amounts of one specific, successful genotype. When the necessary fitness and pathogenicity factors are recombined in a single genetic background, a future pathogen may become able to infect an otherwise resistant, novel host. However, stable pathogenicity will depend on two major features: In other words, the microorganism needs to reproduce on the host or on host products faeces for instance.

Bacteria and yeasts generally only undergo typical dividing or budding of unicells in a host medium that in some way can be disseminated for example via aerosols, via surface contact, or via insect transmission. Filamentous fungi must undergo a relatively complex sporulation process, because hyphae themselves are harder to disseminate. Some fungi are also able to undergo a phase shift in their life cycle from a modular filamentous state to a particulate yeast or spherule state, known as dimorphism. The small and thus easily translocated yeast form is able to circulate in the bloodstream and, in susceptible hosts, cause disseminated disease.

Interestingly, many fungi with the capacity to form small air-borne conidia or to undergo dimorphism cluster together in a phylogenetic tree Fig. Recently, a hybrid histidine kinase was identified as a global regulator of dimorphism in several pathogenic fungi Nemecek et al. In addition to the transition from filamentous to yeast, this kinase also regulates the expression of virulence genes. Phylogenetic relationships between various cross-kingdom pathogens and a number of selected pathogenic as well as nonpathogenic np relatives. Efficient sporulation is determined not only by the pathogenic microorganism, but also by the host and the environment.

The extent to which tissue is colonized, yielding microbial biomass, influences the amount of potential sporulation generated, as does the extent to which tissue is necrotized in necrotrophic pathogens or tapped in biotrophic pathogens to provide nutrients. The final quantity of sporulation that can be produced is, however, also strongly influenced by the environment Rotem et al. Particular triggers such as optimal light and humidity conditions may be required for maximal sporulation to occur. Facultative pathogens that combine a saprotrophic and a pathogenic lifestyle require sporulation-promoting conditions while growing on their hosts in addition to having their basic nutritional requirements met Rotem et al.

Environmental triggers may only be necessary for a specific type of spore, for example those serving as survival structures. Such highly resistant spores frequently result from sexual processes. In some fungi, sexual sporulation may also depend on hormonal regulation by small molecules, such as terpenoids, or by peptides as the yeast alpha- and a -factor. Host factors and local C: N imbalance may directly stimulate sporulation of the pathogen Rotem et al.

Dry-spored fungi typically sporulate at the substrate-to-air interface. This implies that, in order to sporulate, these fungi must be able to form conidiophores outside colonized host substrate. An example of this is seen in the sporulation of Aspergillus fumigatus inside the lungs case studies listed at the Aspergillus website, The Fungal Research Trust, This fungus is not able to sporulate within colonized human tissue, but can sporulate in air pockets such as pulmonary cavities.

Some fungi form spore types that have more relaxed sporulation prerequisites, such as the macroconidia of Fusarium: For pathogenic bacteria, perpetuation of the genome depends on cell division, tissue destruction with lysis giving access to the immediate environment, and release of progeny into this environment.

Pathogenic bacteria are thus most effectively transferred between hosts when there is frequent contact between hosts, or when there is contact between a recently sacrificed host and future hosts, or when the pathogenic bacteria are able to produce resistant but still infectious structures that can survive for prolonged periods outside a sacrificed host before infecting a new host.

Spores of Clostridium difficile can survive for prolonged periods in inanimate environments and can even withstand the aggressive action of a variety of cleansing detergents Margosch et al. All bacteria that have made cross-kingdom jumps fulfil one or more of these requirements. For at least some bacteria, including Pseudomonas aeruginosa, Burkholderia cepacia, Pantoea and Enterobacter , dispersion across distances in the kilometre range can be achieved by biofilm-derived, aerosolized particles.

Several general aspects and requirements of microbial cross-kingdom pathogenicity have been discussed. Microorganisms that have been documented as pathogens on hosts belonging to different kingdoms are listed in Table 1. Some of these pathogen—host combinations are based only on laboratory experiments and have thus far not been encountered in nature.

However, the ease with which such partially artificial infections are induced is highly suggestive of the existence of natural infectious syndromes crossing kingdom borders. The following section of this review will highlight a number of cross-kingdom pathogens. Pseudomonas aeruginosa is a Gram-negative saprotrophic bacterial species that is ubiquitously present in the environment. This microorganism is notorious for causing sepsis in burned patients and in immunodeficient patients including neonates, and for being the major cause of mortality in humans afflicted with cystic fibrosis CF.

It rarely causes infections in immunocompetent patients and is generally considered as an opportunistic pathogen. Remarkably, in a study investigating the genomes of Pseudomonas aeruginosa isolates from various clinical and environmental sources, it was found that the total genome content, including known virulence genes, was strongly conserved in all isolates. This suggests that Pseudomonas aeruginosa isolates essentially possess the basic machinery to cause human infections regardless of the habitat from which they are isolated Wolfgang et al.

The increased virulence of pathogenic strains was found to be correlated with the presence of pathogenicity islands harbouring clusters of virulence genes that may have been acquired from other microorganisms or mobile genetic elements including bacteriophages through horizontal gene transfer He et al. One important feature of Pseudomonas aeruginosa isolates is their capacity to adapt to human hosts suffering from CF. They seemingly do so in direct competition with other microbial species, because they do appear to be conquering niches initially occupied by Haemophilus influenzae and Staphylococcus aureus.

Most isolates successfully adapted to the human CF lung show a so-called mucoid phenotype upon cultivation. In vivo mutation rates were found to be elevated such that isolates showed positive or diversifying selection across the whole genome, especially in those regions involved in pathogenicity Smith et al.

Interestingly, those virulence factors that are necessary for acute infection were found to be negatively selected against in isolates causing chronic infections. Isolates that were recovered from CF patients after a period of eight years were found to be genetically different from the initial, clonal Pseudomonas aeruginosa population, and were also different from natural wild-type isolates Smith et al. In vivo adaptation towards a susceptible host is an important feature of pathogens and may be stress-related, for example in reaction to inflammatory host responses Brown et al.

The observation that different Arabidopsis ecotypes display differential degrees of resistance to different Pseudomonas aeruginosa isolates has been interpreted to suggest that this microorganism may infect Arabidopsis under natural conditions Rahme et al. Many bacterial cell-associated and secreted factors that play a role in Pseudomonas aeruginosa virulence have been identified. These include flagella and type IV pili, type III secretion systems, lipopolysaccharides, proteases, endotoxins and exotoxins, and the mucous exopolysaccharide alginate.

The production of these virulence factors is regulated by environmental stimuli and by quorum-sensing cascades Rahme et al. Remarkably, several bacterial mutants have been identified that display reduced virulence in multiple cross-kingdom hosts. Bacterial mutants at the exotoxin A gene a protein synthesis inhibitor , the phospholipase C gene involved in phospholipid degradation and the gacA gene a transcriptional activator of effector genes were found to display pathogenicity reduced below wild-type levels in mice as well as in Arabidopsis Rahme et al.

Similar studies with these and additional mutants in other cross-kingdom hosts have shown that a number of virulence factors promote virulence on multiple hosts Rahme et al. Although the relative severity of the effects of particular mutations does not always correspond among the different hosts, at least a subset of the existing virulence factors is required for full pathogenicity in all hosts Rahme et al.

It is not only Pseudomonas aeruginosa that behaves as a cross-kingdom pathogen in various laboratory infection models. A similar situation is true for the vertebrate bacterial pathogens Staphylococcus aureus and Enterococcus faecalis. Both pathogens have been reported also to infect Arabidopsis and Caenorhabditis elegans Garsin et al. Although these pathogens can be regarded as cross-kingdom pathogens, they have rarely or never been reported to cause cross-kingdom infections in nature.

Interestingly, however, the same regulatory mechanisms that lead to attenuated virulence in humans seem to play key roles in diminishing the deleterious effect of plant infections van Baarlen, The following examples, however, concern pathogens that have been reported to cause natural cross-kingdom infections. Bacteria from the genus Burkholderia formerly classified as rRNA group II of Pseudomonas , of which Burkholderia cepacia is the type species, are Gram-negative rod-shaped bacteria that, like Pseudomonas spp.

Members of the Burkholderia complex were first classified as Pseudomonas species. The Burkholderia cepacia complex consists of ten closely related species, or genomovars, that have been identified as pathogens of hosts belonging to three kingdoms: Plantae, Animalia and Fungi. The species complex is especially predominant in the group of culturable bacteria that occur in the plant rhizosphere, not only on the outside of plant roots but also internalized in root tissues, where they can influence plant growth in many ways.

Some endophytic Burkholderia strains are even capable of fixing atmospheric nitrogen Gillis et al. Originally, Burkholderia cepacia was described as the causal agent of sour skin of onion, also known as onion rot. When a large collection of Burkholderia cepacia strains collected from soil, clinical sources and rotting onions was studied, clinical strains were not able to induce rot in onion slices.

For the other isolates, regardless of their origin, pathogenicity towards onion was found to correlate with pectinolytic activity Gonzalez et al. This activity is based on the production of an endopolygalacturonase that is essential for the maceration of onion tissue; Burkholderia cepacia isolates that are not pathogenic towards plants do not produce this enzyme Gonzalez et al.

Pathogenicity towards humans features the establishment of lung necrosis by endotoxin activity of bacterial lipopolysaccharide. Additional Burkholderia cepacia complex virulence factors contribute to pathogenic processes but are not essential for pathogenicity. These include factors inducing necrosis in lung tissue, including porins and N -acyl homoserine lactones usually abbreviated to AHL based on acyl-homoserine- l -lactone.

Also included are factors that promote survival and persistence during in vivo growth, for example amidase, a protein involved in amino acid metabolism Baldwin et al. AHL is involved in quorum sensing, the regulation of protease production, and endopolygalacturonase secretion Aguilar et al. Overall, there is no clear correlation between the origin of isolates and their pathogenicity towards animals or plants, and different strains of the same species may display different patterns of pathogenicity.

In an experimental model using the nematode Caenorhabditis elegans , the pathogenicity of Burkholderia cepacia strains isolated from different origins clinical, onion or environmental was found to be strain-dependent, but species- or genomovar- independent Cardona et al. Interestingly, plant-pathogenic isolates as well as environmental isolates recovered from wheat and maize rhizospheres were all found to belong to genomovar group III, in which the most virulent human-pathogenic isolates are also found Jones et al.

The extreme virulence of this group was found to be associated with the presence of so-called cable pili. The pili form dense structures surrounding the cells, which apparently generates a selective advantage and proliferative microbial expansion Sun et al. This possibility is supported by the ability of some strains to occur as endophytes. It was recently demonstrated that Burkholderia spp. This bacteria—fungus relationship may be seen as an extreme form of the horizontal transfer of metabolite-encoding genes, in which the fungus may also transfer or introduce bacteria into novel hosts or niches.

Clearly, symbiotic relationships of pathogenic bacteria and other organisms may have important implications for host ranges and may thereby modulate the clinical impact of these bacteria. In addition, because Alternaria spp. Although the fungus generally occurs as a soil-borne saprotroph, some species are plant pathogens that, collectively, cause various diseases in a wide range of host plants Thomma, They have, moreover, emerged as opportunistic pathogens of humans, particularly of immuno-compromised individuals Viviani et al.

Most isolates found as pathogens in humans belong to Alternaria alternata and Alternaria infectoria , with some cases also credibly attributed to Alternaria tenuissima and Alternaria dianthicola. These include alternariol, altertoxin, tenuazonic acid and AAL-toxin, some of which have been implicated in the development of cancers Shier et al.

Alternaria is also implicated in respiratory diseases.