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Bacterial Persistence: Finding the “Sweet Spot”

2013; Cell Press; Volume: 14; Issue: 2 Linguagem: Inglês

10.1016/j.chom.2013.07.016

1934-6069

R. Martin Roop, Clayton C. Caswell,

Brucella: diagnosis, epidemiology, treatment

Studies described by Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar in this issue of Cell Host & Microbe show that the bacterial pathogens Salmonella and Brucella exploit the increased levels of glucose present in alternatively activated macrophages to sustain chronic infections in experimentally infected mice. Studies described by Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar in this issue of Cell Host & Microbe show that the bacterial pathogens Salmonella and Brucella exploit the increased levels of glucose present in alternatively activated macrophages to sustain chronic infections in experimentally infected mice. Anyone who has ever played tennis, golf, or baseball has an appreciation for the phrase "finding the sweet spot." When the ball makes contact with the racket, club, or bat in just the "right" place, the ball goes where you want it to go, and you get the maximum benefit from this interaction. Experimental evidence presented in this issue of Cell Host & Microbe indicates that the bacterial pathogens Salmonella and Brucella have found a "sweet spot" in alternatively activated macrophages and exploit this niche to sustain chronic infections in their mammalian hosts. Salmonella and Brucella strains are important pathogens in human and veterinary medicine. Although the diseases they produce in their natural and incidental hosts are generally quite different, both of these bacteria have the capacity to survive and replicate for prolonged periods in macrophages, which allows them to establish and maintain chronic infections (Monack et al., 2004Monack D.M. Bouley D.M. Falkow S. J. Exp. Med. 2004; 199: 231-241Crossref PubMed Scopus (314) Google Scholar, Roop et al., 2009Roop 2nd, R.M. Gaines J.M. Anderson E.S. Caswell C.C. Martin D.W. Med. Microbiol. Immunol. (Berl.). 2009; 198: 221-238Crossref PubMed Scopus (160) Google Scholar). During progression of the host inflammatory response to infection, macrophages can develop into two types depending upon the cytokines they encounter (Biswas and Mantovani, 2012Biswas S.K. Mantovani A. Cell Metab. 2012; 15: 432-437Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). Stimulation by IFN-γ leads to the development of classically activated macrophages (CAMs), which attain enhanced microbicidal activity and secrete proinflammatory cytokines. These phagocytes play an important role in the Th1 arm of the acquired immune response. In contrast, stimulation by IL-4 and IL-13 leads to the development of alternatively activated macrophages (AAMs), which have reduced microbicidal activity and secrete anti-inflammatory cytokines. AAMs play critical roles in resolution of the inflammatory response and wound healing. One consequence of the polarization of macrophages to the CAM- or AAM-type is a shift in their cellular metabolism. CAMs, for instance, rely on glycolysis for their energy and consume significant levels of glucose. AAMs, on the other hand, degrade fatty acids via the β-oxidation pathway as their source of carbon and energy. Employing mouse models of chronic Salmonella and Brucella infections, respectively, Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar have found that AAMs become the predominant form of macrophages inhabited by both of these bacteria during chronic infections. In both cases, these investigators showed that (1) intracellular glucose levels were higher in the AAMs than in the CAMs; (2) the bacteria were able to survive and replicate more efficiently in AAMs than in CAMs in culture and in experimentally infected animals; and (3) in order to be able to effectively replicate in the AAMs, these bacteria had to be able to transport (and presumably metabolize) glucose. In neither study, however, did the investigators find evidence that the reduced microbicidal activities of the AAMs were responsible for the enhanced intracellular replication of the Salmonella and Brucella strains in these phagocytes. These findings are important because they indicate that it is the increased availability of glucose as a carbon and energy source that makes AAMs a permissive site for intracellular replication of the salmonellae and brucellae during chronic infections rather than the fact that AAMs have reduced bactericidal activities compared to CAMs. In other words, these bacteria have literally found a "sweet spot" in AAMs where they can derive the maximum benefit from their interactions with host macrophages and sustain chronic infections in their hosts (Figure 1). Despite the commonalities in the interactions of the Salmonella and Brucella strains with AAMs, the individual studies described by Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar also found some important differences. Signal transduction through the nuclear peroxisome proliferator-activated receptors PPARγ and PPARδ orchestrates the patterns of gene expression required for the development of AAMs (Odegaard and Chawla, 2011Odegaard J.I. Chawla A. Annu. Rev. Pathol. 2011; 6: 275-297Crossref PubMed Scopus (439) Google Scholar). Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar found that infection of cultured macrophages with Salmonella induces expression of the gene encoding PPARδ, but not PPARγ. Moreover, they showed that modulation of PPARγ levels in AAMs had a significant impact on the capacity of Salmonella to replicate in these phagocytes, but did not influence the intracellular replication of Mycobacterium, Francisella, or Listeria strains within these host cells. These experimental findings lead the authors to hypothesize that the effect on PPARδ is unique to Salmonella and that this bacterium plays an active role in driving the polarization of macrophages toward the AAM phenotype. In contrast, while Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar found that PPARγ is responsible for the shift in metabolism that allows Brucella strains to gain access to glucose and replicate efficiently within AAMs, they could find no evidence that infection with Brucella strains had an impact on the development of macrophages into either the CAM or AAM phenotype. Clearly the differential roles of PPARγ and PPARδ in driving the development of AAMs during the course of Salmonella and Brucella infections merits further study, as does determining the extent to which these bacteria actively participate in this process. But given the fact that Salmonella strains induce a much stronger inflammatory response than Brucella strains (Barquero-Calvo et al., 2007Barquero-Calvo E. Chaves-Olarte E. Weiss D.S. Guzmán-Verri C. Chacón-Díaz C. Rucavado A. Moriyón I. Moreno E. PLoS ONE. 2007; 2: e631Crossref PubMed Scopus (236) Google Scholar), it would not be surprising to find that Salmonella strains require an active mechanism for enhancing the availability of AAMs in order establish and maintain a chronic infection, while Brucella strains do not. In addition to improving our basic understanding of the mechanisms employed by Salmonella and Brucella strains to produce disease in their hosts, and the different roles that CAMs and AAMs play in protective immunity and host-pathogen interactions, the results of the studies of Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar may also have important implications for the treatment of Salmonella and Brucella infections in humans. Although naturally occurring antibiotic resistance in Brucella strains is rare, brucellosis in humans is notoriously difficult to treat, requiring a combination of antibiotics administered for at least six weeks (Ariza et al., 2007Ariza J. Bosilkovski M. Cascio A. Colmenero J.D. Corbel M.J. Falagas M.E. Memish Z.A. Roushan M.R.H. Rubinstein E. Sipsas N.V. et al.International Society of ChemotherapyInstitute of Continuing Medical Education of IoanninaPLoS Med. 2007; 4: e317Crossref PubMed Scopus (299) Google Scholar). Antibiotic resistance and the existence of a chronic carrier state also complicate the effective treatment of Salmonella infections in humans (Pegues et al., 2005Pegues D.A. Ohl M.E. Miller S.I. Salmonella species, including Salmonella typhi.in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett"s Principles and Practice of Infectious Diseases. Sixth Edition. Elsevier, Philadelphia2005: 2636-2654Google Scholar). Drugs that target PPAR activity have been proposed for use in treating a variety of diseases including diabetes, cardiac disease, and inflammatory bowel disease (Mandard and Patsouris, 2013Mandard S. Patsouris D. PPAR Res. 2013; 2013: 613864Crossref PubMed Scopus (69) Google Scholar). Consequently, the findings presented by Eisele et al., 2013Eisele N.A. Ruby T. Jacobson A. Manzanillo P.S. Cox J.S. Lam L. Mukundan L. Chawla A. Monack D.M. Cell Host Microbe. 2013; 14 (this issue): 171-182Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and Xavier et al., 2013Xavier M.N. Winter W.G. Spees A.M. den Hartigh A.B. Nguyen K. Roux C.M. Silva T.M.A. Atluri V.L. Kerrinnes T. Keestra A.M. et al.Cell Host Microbe. 2013; 14 (this issue): 159-170Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar raise the possibility that these drugs may also be useful alone or in combination with antibiotics for the treatment of two bacterial diseases that have considerable public health importance on a global scale. Salmonella Require the Fatty Acid Regulator PPARδ for the Establishment of a Metabolic Environment Essential for Long-Term PersistenceEisele et al.Cell Host & MicrobeAugust 14, 2013In BriefHost-adapted Salmonella strains are responsible for a number of disease manifestations in mammals, including an asymptomatic chronic infection in which bacteria survive within macrophages located in systemic sites. However, the host cell physiology and metabolic requirements supporting bacterial persistence are poorly understood. In a mouse model of long-term infection, we found that S. typhimurium preferentially associates with anti-inflammatory/M2 macrophages at later stages of infection. Further, PPARδ, a eukaryotic transcription factor involved in sustaining fatty acid metabolism, is upregulated in Salmonella-infected macrophages. Full-Text PDF Open ArchivePPARγ-Mediated Increase in Glucose Availability Sustains Chronic Brucella abortus Infection in Alternatively Activated MacrophagesXavier et al.Cell Host & MicrobeAugust 14, 2013In BriefEradication of persistent intracellular bacterial pathogens with antibiotic therapy is often slow or incomplete. However, strategies to augment antibiotics are hampered by our poor understanding of the nutritional environment that sustains chronic infection. Here we show that the intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAMs), which are more abundant during chronic infection. A metabolic shift induced by peroxisome proliferator-activated receptor γ (PPARγ), which increases intracellular glucose availability, is identified as a causal mechanism promoting enhanced bacterial survival in AAMs. Full-Text PDF Open Archive