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Environmental Microbiology Reports (2015) 7(1), 2–3
doi:10.1111/1758-2229.12236
Nutrition-based evolution of intracellular pathogens
Yousef Abu Kwaik, Department of Microbiology and Immunology and Center for Predictive Medicine, College of Medicine, University of Louisville, Louisville, Kentucky, USA. There has been a long-held presumption that the host cell cytosol has sufficient nutrients for any prokaryote, although many bacteria microinjected into eukaryotic cells fail to grow in the host cytosol. Microbial acquisition of nutrients in vivo is a fundamental aspect of host–microbe interaction and is a potential target for antimicrobial strategies in the environment and in the host. Part of the innate host defence against microbial invasion is nutritional restriction of access to sources of host nutrients (Abu Kwaik and Bumann, 2013). In addition, recent studies on few intra-vacuolar and cytosolic pathogens have shown that the levels of amino acids in the host cell cytosol are below the threshold sufficient to meet the tremendous demands for carbon, nitrogen and energy to power intracellular proliferation of these pathogens (Abu Kwaik and Bumann, 2013). It is most likely that there is a threshold level of amino acids in the host cell, but the needs of intracellular organisms for a major source of carbon and energy are not met by the threshold level of that major source. Therefore, many intracellular pathogens have evolved with efficient strategies to boost the levels of host amino acids to meet their demands for higher levels of carbon, nitrogen and energy sources (Abu Kwaik and Bumann, 2013). Interestingly, intracellular pathogens are auxotrophic for various amino acids that are also essential for the eukaryotic host, and this is highly unlikely to be a coincident in the evolution of pathogens. This may also trigger the question of whether many endosymbionts or obligate intracellular bacteria are restricted to their lifestyles due to their nutritional needs and their inability to evolve additional mechanisms for nutrient generation and acquisition within the host. The focus of this article is on how this microbe–host synchronization of amino acids auxotrophy has impacted the evolution of Legionella pneumophila to adapt to the intracellular life in vacuole within primitive unicellular eukaryotes as well as the mammalian host (Price et al., 2014). Upon transmission to humans, L. pneumophila proliferates in macrophages within a vacuole that is Endoplasmic Reticulum (ER)-derived and evades lysosomal fusion. However, L. pneumophila is an environmental aquatic organism that proliferates within many species of amoeba © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd
and ciliates, which impact bacterial ecology and pathogenicity. Within both evolutionarily distant host cells, the Dot/Icm type IV secretion system of L. pneumophila injects ∼ 300 protein effectors that govern the biogenesis of the pathogen-containing vacuole and modulate a myriad of highly conserved cellular processes to enable intra-vacuolar proliferation within evolutionarily distant hosts (Price et al., 2014). Legionella pneumophila utilizes amino acids as the main sources of carbon and energy, but the pathogen is auxotrophic for seven amino acids (Cys, Met, Arg, Thr, Val, Ile and Leu). Remarkably, there is a high level of synchronization in amino acids auxotrophy between L. pneumophila and its host cells, which has likely played a role in the nutritional evolution of L. pneumophila as an intra-vacuolar pathogen (Price et al., 2014). This high level of host–microbe synchronization of amino acids auxotrophy is also evident for other intracellular pathogens, such as Anaplasma and Francisella, both of which boost the cellular levels of amino acids through distinct mechanisms (Abu Kwaik and Bumann, 2013). The basal levels of host cellular amino acids are below the threshold sufficient for the robust intra-vacuolar proliferation of L. pneumophila. This is likely true for one or few amino acids that are metabolically favourable for the microbe, which utilize them as the major sources of carbon and energy to feed the TCA cycle. To boost that threshold to a level needed for microbial proliferation, L. pneumophila promotes host proteasomal degradation of polyubiquitinated proteins that decorate the pathogencontaining vacuole, which generates a surplus of all amino acids within both amoeba and human cells (Price et al., 2014). It is conceivable that many other intracellular pathogens manipulate other cellular processes to generate additional needed host nutrients for pathogen proliferation. Future studies should be directed at deciphering microbial nutrition and metabolism by endosymbionts and intracellular pathogens to determine its role in microbial evolution and adaptation to the intracellular microenvironment. In addition, future studies should unravel how host metabolites are imported across the pathogen-containing vacuolar membrane into the vacuolar lumen. The highly conserved eukaryotic solute carrier (SLC) family of membrane proteins are transporters of various compounds, including amino acids, TCA
Crystal ball intermediates, glucose, lipids and drugs. The SLCs are the most likely candidates to be involved in the import of various host compounds across the pathogen-containing vacuolar membrane, but microbial transporters are also possible to be integrated into the membrane of the pathogen-containing vacuole. It is likely that pathogen capacity to trigger the host to generate metabolically favourable sources of carbon and energy, and to import them across the pathogen-containing vacuolar membrane, are two powerful forces in the evolution and adaptation of intracellular pathogens. It is possible that part of the continuous relationship of endosymbionts within eukaryotic cells is determined by the nutrition of the endosymbiont that is not sufficient to allow proliferation and further parasitic exploitation of the host. As scientists continue to study the evolution of endosymbionts and intracellular pathogens, it is important to keep in mind the simple fact that generation of additional nutritional sources and their import to the microbe-containing
3
vacuole may be crucial and powerful factors in the nutrition-based evolution of obligate and facultative intracellular pathogens.
Acknowledgements YAK is supported by Public Health Service Awards R21AI107978 from NIAID and by the commonwealth of Kentucky Research Challenge Trust Fund.
References Abu Kwaik, Y., and Bumann, D. (2013) Microbial quest for food in vivo: ‘nutritional virulence’ as an emerging paradigm. Cell Microbiol 15: 882–890. Price, C.T., Richards, A.M., Von Dwingelo, J.E., Samara, H.A., and Abu Kwaik, Y. (2014) Amoeba host-Legionella synchronization of amino acid auxotrophy and its role in bacterial adaptation and pathogenic evolution. Environ Microbiol 16: 350–358.
© 2015 Society for Applied Microbiology and John Wiley & Sons Ltd, Environmental Microbiology Reports, 7, 2–3
Environmental Microbiology Reports (2015) 7(1), 2–3
doi:10.1111/1758-2229.12236
Nutrition-based evolution of intracellular pathogens
Yousef Abu Kwaik, Department of Microbiology and Immunology and Center for Predictive Medicine, College of Medicine, University of Louisville, Louisville, Kentucky, USA. There has been a long-held presumption that the host cell cytosol has sufficient nutrients for any prokaryote, although many bacteria microinjected into eukaryotic cells fail to grow in the host cytosol. Microbial acquisition of nutrients in vivo is a fundamental aspect of host–microbe interaction and is a potential target for antimicrobial strategies in the environment and in the host. Part of the innate host defence against microbial invasion is nutritional restriction of access to sources of host nutrients (Abu Kwaik and Bumann, 2013). In addition, recent studies on few intra-vacuolar and cytosolic pathogens have shown that the levels of amino acids in the host cell cytosol are below the threshold sufficient to meet the tremendous demands for carbon, nitrogen and energy to power intracellular proliferation of these pathogens (Abu Kwaik and Bumann, 2013). It is most likely that there is a threshold level of amino acids in the host cell, but the needs of intracellular organisms for a major source of carbon and energy are not met by the threshold level of that major source. Therefore, many intracellular pathogens have evolved with efficient strategies to boost the levels of host amino acids to meet their demands for higher levels of carbon, nitrogen and energy sources (Abu Kwaik and Bumann, 2013). Interestingly, intracellular pathogens are auxotrophic for various amino acids that are also essential for the eukaryotic host, and this is highly unlikely to be a coincident in the evolution of pathogens. This may also trigger the question of whether many endosymbionts or obligate intracellular bacteria are restricted to their lifestyles due to their nutritional needs and their inability to evolve additional mechanisms for nutrient generation and acquisition within the host. The focus of this article is on how this microbe–host synchronization of amino acids auxotrophy has impacted the evolution of Legionella pneumophila to adapt to the intracellular life in vacuole within primitive unicellular eukaryotes as well as the mammalian host (Price et al., 2014). Upon transmission to humans, L. pneumophila proliferates in macrophages within a vacuole that is Endoplasmic Reticulum (ER)-derived and evades lysosomal fusion. However, L. pneumophila is an environmental aquatic organism that proliferates within many species of amoeba © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd
and ciliates, which impact bacterial ecology and pathogenicity. Within both evolutionarily distant host cells, the Dot/Icm type IV secretion system of L. pneumophila injects ∼ 300 protein effectors that govern the biogenesis of the pathogen-containing vacuole and modulate a myriad of highly conserved cellular processes to enable intra-vacuolar proliferation within evolutionarily distant hosts (Price et al., 2014). Legionella pneumophila utilizes amino acids as the main sources of carbon and energy, but the pathogen is auxotrophic for seven amino acids (Cys, Met, Arg, Thr, Val, Ile and Leu). Remarkably, there is a high level of synchronization in amino acids auxotrophy between L. pneumophila and its host cells, which has likely played a role in the nutritional evolution of L. pneumophila as an intra-vacuolar pathogen (Price et al., 2014). This high level of host–microbe synchronization of amino acids auxotrophy is also evident for other intracellular pathogens, such as Anaplasma and Francisella, both of which boost the cellular levels of amino acids through distinct mechanisms (Abu Kwaik and Bumann, 2013). The basal levels of host cellular amino acids are below the threshold sufficient for the robust intra-vacuolar proliferation of L. pneumophila. This is likely true for one or few amino acids that are metabolically favourable for the microbe, which utilize them as the major sources of carbon and energy to feed the TCA cycle. To boost that threshold to a level needed for microbial proliferation, L. pneumophila promotes host proteasomal degradation of polyubiquitinated proteins that decorate the pathogencontaining vacuole, which generates a surplus of all amino acids within both amoeba and human cells (Price et al., 2014). It is conceivable that many other intracellular pathogens manipulate other cellular processes to generate additional needed host nutrients for pathogen proliferation. Future studies should be directed at deciphering microbial nutrition and metabolism by endosymbionts and intracellular pathogens to determine its role in microbial evolution and adaptation to the intracellular microenvironment. In addition, future studies should unravel how host metabolites are imported across the pathogen-containing vacuolar membrane into the vacuolar lumen. The highly conserved eukaryotic solute carrier (SLC) family of membrane proteins are transporters of various compounds, including amino acids, TCA
Crystal ball intermediates, glucose, lipids and drugs. The SLCs are the most likely candidates to be involved in the import of various host compounds across the pathogen-containing vacuolar membrane, but microbial transporters are also possible to be integrated into the membrane of the pathogen-containing vacuole. It is likely that pathogen capacity to trigger the host to generate metabolically favourable sources of carbon and energy, and to import them across the pathogen-containing vacuolar membrane, are two powerful forces in the evolution and adaptation of intracellular pathogens. It is possible that part of the continuous relationship of endosymbionts within eukaryotic cells is determined by the nutrition of the endosymbiont that is not sufficient to allow proliferation and further parasitic exploitation of the host. As scientists continue to study the evolution of endosymbionts and intracellular pathogens, it is important to keep in mind the simple fact that generation of additional nutritional sources and their import to the microbe-containing
3
vacuole may be crucial and powerful factors in the nutrition-based evolution of obligate and facultative intracellular pathogens.
Acknowledgements YAK is supported by Public Health Service Awards R21AI107978 from NIAID and by the commonwealth of Kentucky Research Challenge Trust Fund.
References Abu Kwaik, Y., and Bumann, D. (2013) Microbial quest for food in vivo: ‘nutritional virulence’ as an emerging paradigm. Cell Microbiol 15: 882–890. Price, C.T., Richards, A.M., Von Dwingelo, J.E., Samara, H.A., and Abu Kwaik, Y. (2014) Amoeba host-Legionella synchronization of amino acid auxotrophy and its role in bacterial adaptation and pathogenic evolution. Environ Microbiol 16: 350–358.
© 2015 Society for Applied Microbiology and John Wiley & Sons Ltd, Environmental Microbiology Reports, 7, 2–3
