Metabolic Host Response to Intracellular Infections

  • Catarina M. Ferreira
  • Ana Margarida Barbosa
  • Inês M. Pereira
  • Egídio Torrado
Part of the Experientia Supplementum book series (EXS, volume 109)


The interaction between intracellular bacterial pathogens with the host immune response can result in multiple outcomes that range from asymptomatic clearance to the establishment of infection. At its core, these interactions result in multiple metabolic adaptations of both the pathogen and its host cell. There is growing evidence that the host metabolic response plays a key role in the development of immune responses against the invading pathogen. However, successful intracellular pathogens have developed multiple mechanisms to circumvent the host response to thrive in the intracellular compartment. Here, we provide a brief overview on the crucial role of fundamental metabolic host responses in the generation of protective immunity to intracellular bacterial pathogens and discuss some of the mechanisms used by these pathogens to exploit the host metabolic response to their own advantage. This understanding will further our knowledge in host-pathogen interactions and may provide new insights for the development of novel therapies.


Host-pathogen interactions Intracellular bacteria Infection Immunity Metabolism 



Our work is funded by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and the Fundação para a Ciência e Tecnologia (FCT) through the FCT investigator grant IF/01390/2014 to E.T. and the PhD fellowship SFRH/BD/120371/2016 to A.M.B.


  1. Adams LB, Dinauer MC, Morgenstern DE, Krahenbuhl JL (1997) Comparison of the roles of reactive oxygen and nitrogen intermediates in the host response to Mycobacterium tuberculosis using transgenic mice. Tuber Lung Dis 78(5–6):237–246. Scholar
  2. Alfano M, Graziano F, Genovese L, Poli G (2013) Macrophage polarization at the crossroad between HIV-1 infection and cancer development. Arterioscler Thromb Vasc Biol 33(6):1145–1152. Scholar
  3. Allegra S, Leclerc L, Massard PA, Girardot F, Riffard S, Pourchez J (2016) Characterization of aerosols containing Legionella generated upon nebulization. Sci Rep 6:33998. Scholar
  4. Anderson CJ, Kendall MM (2017) Salmonella enterica Serovar Typhimurium strategies for host adaptation. Front Microbiol 8:1983. Scholar
  5. Antunes LC, Arena ET, Menendez A, Han J, Ferreira RB, Buckner MM, Lolic P, Madilao LL, Bohlmann J, Borchers CH, Finlay BB (2011) Impact of salmonella infection on host hormone metabolism revealed by metabolomics. Infect Immun 79(4):1759–1769. Scholar
  6. Ao TT, Feasey NA, Gordon MA, Keddy KH, Angulo FJ, Crump JA (2015) Global burden of invasive nontyphoidal Salmonella disease, 2010(1). Emerg Infect Dis 21(6):941. Scholar
  7. Armstrong JA, Hart PD (1971) Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med 134(3 Pt 1):713–740. Scholar
  8. Asrat S, Dugan AS, Isberg RR (2014) The frustrated host response to Legionella pneumophila is bypassed by MyD88-dependent translation of pro-inflammatory cytokines. PLoS Pathog 10(7):e1004229. Scholar
  9. Azad AK, Sadee W, Schlesinger LS (2012) Innate immune gene polymorphisms in tuberculosis. Infect Immun 80(10):3343–3359. Scholar
  10. Bachmann NL, Polkinghorne A, Timms P (2014) Chlamydia genomics: providing novel insights into chlamydial biology. Trends Microbiol 22(8):464–472. Scholar
  11. Bai X, Feldman NE, Chmura K, Ovrutsky AR, Su WL, Griffin L, Pyeon D, McGibney MT, Strand MJ, Numata M, Murakami S, Gaido L, Honda JR, Kinney WH, Oberley-Deegan RE, Voelker DR, Ordway DJ, Chan ED (2013) Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages. PLoS One 8(4):e61925. Scholar
  12. Baker RG, Hayden MS, Ghosh S (2011) NF-kappaB, inflammation, and metabolic disease. Cell Metab 13(1):11–22. Scholar
  13. Barry KC, Fontana MF, Portman JL, Dugan AS, Vance RE (2013) IL-1alpha signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo. J Immunol 190(12):6329–6339. Scholar
  14. Blumenthal A, Nagalingam G, Huch JH, Walker L, Guillemin GJ, Smythe GA, Ehrt S, Britton WJ, Saunders BM (2012) M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection. PLoS One 7(5):e37314. Scholar
  15. Boman J, Hammerschlag MR (2002) Chlamydia pneumoniae and atherosclerosis: critical assessment of diagnostic methods and relevance to treatment studies. Clin Microbiol Rev 15(1):1–20PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bowman CC, Bost KL (2004) Cyclooxygenase-2-mediated prostaglandin E2 production in mesenteric lymph nodes and in cultured macrophages and dendritic cells after infection with Salmonella. J Immunol 172(4):2469–2475PubMedCrossRefGoogle Scholar
  17. Bresciani G, da Cruz IB, Gonzalez-Gallego J (2015) Manganese superoxide dismutase and oxidative stress modulation. Adv Clin Chem 68:87–130. Scholar
  18. Brothwell JA, Muramatsu MK, Toh E, Rockey DD, Putman TE, Barta ML, Hefty PS, Suchland RJ, Nelson DE (2016) Interrogating genes that mediate Chlamydia trachomatis survival in cell culture using conditional mutants and recombination. J Bacteriol 198(15):2131–2139. Scholar
  19. Buck MD, O’Sullivan D, Pearce EL (2015) T cell metabolism drives immunity. J Exp Med 212(9):1345–1360. Scholar
  20. Byrne B, Swanson MS (1998) Expression of Legionella pneumophila virulence traits in response to growth conditions. Infect Immun 66(7):3029–3034PubMedPubMedCentralGoogle Scholar
  21. Byrne GI (2010) Chlamydia trachomatis strains and virulence: rethinking links to infection prevalence and disease severity. J Infect Dis 201(Suppl 2):S126–S133. Scholar
  22. Calder PC (2013) Feeding the immune system. Proc Nutr Soc 72(3):299–309. Scholar
  23. Carabeo RA, Mead DJ, Hackstadt T (2003) Golgi-dependent transport of cholesterol to the Chlamydia trachomatis inclusion. Proc Natl Acad Sci USA 100(11):6771–6776. Scholar
  24. Cardoso MS, Silva TM, Resende M, Appelberg R, Borges M (2015) Lack of the transcription factor Hypoxia-Inducible Factor 1alpha (HIF-1alpha) in macrophages accelerates the necrosis of Mycobacterium avium-induced granulomas. Infect Immun 83(9):3534–3544. Scholar
  25. Casanova JE (2017) Bacterial autophagy: offense and defense at the host-pathogen interface. Cell Mol Gastroenterol Hepatol 4(2):237–243. Scholar
  26. Cascales E (2017) Inside the chamber of secrets of the Type III secretion system. Cell 168(6):949–951. Scholar
  27. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S, Delgado-Vargas M, Timmins GS, Bhattacharya D, Yang H, Hutt J, Lyons CR, Dobos KM, Deretic V (2012) Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Natl Acad Sci USA 109(46):E3168–E3176. Scholar
  28. Chambers MC, Song KH, Schneider DS (2012) Listeria monocytogenes infection causes metabolic shifts in Drosophila melanogaster. PLoS One 7(12):e50679. Scholar
  29. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153(6):1239–1251. Scholar
  30. Chen AL, Johnson KA, Lee JK, Sutterlin C, Tan M (2012) CPAF: a Chlamydial protease in search of an authentic substrate. PLoS Pathog 8(8):e1002842. Scholar
  31. Cherayil BJ, McCormick BA, Bosley J (2000) Salmonella enterica serovar typhimurium-dependent regulation of inducible nitric oxide synthase expression in macrophages by invasins SipB, SipC, and SipD and effector SopE2. Infect Immun 68(10):5567–5574PubMedPubMedCentralCrossRefGoogle Scholar
  32. Chico-Calero I, Suarez M, Gonzalez-Zorn B, Scortti M, Slaghuis J, Goebel W, Vazquez-Boland JA, European Listeria Genome C (2002) Hpt, a bacterial homolog of the microsomal glucose- 6-phosphate translocase, mediates rapid intracellular proliferation in Listeria. Proc Natl Acad Sci USA 99(1):431–436. Scholar
  33. Choy A, Dancourt J, Mugo B, O’Connor TJ, Isberg RR, Melia TJ, Roy CR (2012) The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338(6110):1072–1076. Scholar
  34. Cianciotto NP (2001) Pathogenicity of Legionella pneumophila. Int J Med Microbiol 291(5):331–343. Scholar
  35. Cocchiaro JL, Kumar Y, Fischer ER, Hackstadt T, Valdivia RH (2008) Cytoplasmic lipid droplets are translocated into the lumen of the Chlamydia trachomatis parasitophorous vacuole. Proc Natl Acad Sci USA 105(27):9379–9384. Scholar
  36. Cooper AM, Magram J, Ferrante J, Orme IM (1997) Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J Exp Med 186(1):39–45. Scholar
  37. Czyz DM, Potluri LP, Jain-Gupta N, Riley SP, Martinez JJ, Steck TL, Crosson S, Shuman HA, Gabay JE (2014) Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens. MBio 5(4):e01534-01514. Scholar
  38. Dalebroux ZD, Edwards RL, Swanson MS (2009) SpoT governs Legionella pneumophila differentiation in host macrophages. Mol Microbiol 71(3):640–658. Scholar
  39. Dandekar T, Fieselmann A, Fischer E, Popp J, Hensel M, Noster J (2014) Salmonella-how a metabolic generalist adopts an intracellular lifestyle during infection. Front Cell Infect Microbiol 4:191. Scholar
  40. DeBerardinis RJ, Thompson CB (2012) Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148(6):1132–1144. Scholar
  41. Deretic V, Delgado M, Vergne I, Master S, De Haro S, Ponpuak M, Singh S (2009) Autophagy in immunity against Mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy. Curr Top Microbiol Immunol 335:169–188. Scholar
  42. Derre I, Swiss R, Agaisse H (2011) The lipid transfer protein CERT interacts with the Chlamydia inclusion protein IncD and participates to ER-Chlamydia inclusion membrane contact sites. PLoS Pathog 7(6):e1002092. Scholar
  43. Desai M, Fang R, Sun J (2015) The role of autophagy in microbial infection and immunity. Immunotargets Ther 4:13–26. Scholar
  44. Edwards RL, Dalebroux ZD, Swanson MS (2009) Legionella pneumophila couples fatty acid flux to microbial differentiation and virulence. Mol Microbiol 71(5):1190–1204. Scholar
  45. Ehrt S, Schnappinger D, Bekiranov S, Drenkow J, Shi S, Gingeras TR, Gaasterland T, Schoolnik G, Nathan C (2001) Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J Exp Med 194(8):1123–1140PubMedPubMedCentralCrossRefGoogle Scholar
  46. Eisenreich W, Heesemann J, Rudel T, Goebel W (2013) Metabolic host responses to infection by intracellular bacterial pathogens. Front Cell Infect Microbiol 3:24. Scholar
  47. Eisenreich W, Heesemann J, Rudel T, Goebel W (2015) Metabolic adaptations of intracellullar bacterial pathogens and their mammalian host cells during infection (“Pathometabolism”). Microbiol Spectr 3(3).
  48. Elks PM, Brizee S, van der Vaart M, Walmsley SR, van Eeden FJ, Renshaw SA, Meijer AH (2013) Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism. PLoS Pathog 9(12):e1003789. Scholar
  49. Elwell C, Mirrashidi K, Engel J (2016) Chlamydia cell biology and pathogenesis. Nat Rev Microbiol 14(6):385–400. Scholar
  50. Elwell CA, Jiang S, Kim JH, Lee A, Wittmann T, Hanada K, Melancon P, Engel JN (2011) Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development. PLoS Pathog 7(9):e1002198. Scholar
  51. Escoll P, Rolando M, Gomez-Valero L, Buchrieser C (2013) From amoeba to macrophages: exploring the molecular mechanisms of Legionella pneumophila infection in both hosts. Curr Top Microbiol Immunol 376:1–34. Scholar
  52. Escoll P, Song OR, Viana F, Steiner B, Lagache T, Olivo-Marin JC, Impens F, Brodin P, Hilbi H, Buchrieser C (2017) Legionella pneumophila modulates mitochondrial dynamics to trigger metabolic repurposing of infected macrophages. Cell Host Microbe 22(3):302–316. Scholar
  53. Feasey NA, Dougan G, Kingsley RA, Heyderman RS, Gordon MA (2012) Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet 379(9835):2489–2499. Scholar
  54. Fields BS, Benson RF, Besser RE (2002) Legionella and Legionnaires’ disease: 25 years of investigation. Clin Microbiol Rev 15(3):506–526PubMedPubMedCentralCrossRefGoogle Scholar
  55. Fonseca MV, Swanson MS (2014) Nutrient salvaging and metabolism by the intracellular pathogen Legionella pneumophila. Front Cell Infect Microbiol 4:12. Scholar
  56. Fraga AG, Barbosa AM, Ferreira CM, Fevereiro J, Pedrosa J, Torrado E (2017) Immune-evasion strategies of mycobacteria and their implications for the protective immune response. Curr Issues Mol Biol 25:169–198. Scholar
  57. Friedman H, Yamamoto Y, Klein TW (2002) Legionella pneumophila pathogenesis and immunity. Semin Pediatr Infect Dis 13(4):273–279. Scholar
  58. Gal-Mor O, Boyle EC, Grassl GA (2014) Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Front Microbiol 5:391. Scholar
  59. Gillmaier N, Gotz A, Schulz A, Eisenreich W, Goebel W (2012) Metabolic responses of primary and transformed cells to intracellular Listeria monocytogenes. PLoS One 7(12):e52378. Scholar
  60. Hackstadt T, Rockey DD, Heinzen RA, Scidmore MA (1996) Chlamydia trachomatis interrupts an exocytic pathway to acquire endogenously synthesized sphingomyelin in transit from the Golgi apparatus to the plasma membrane. EMBO J 15(5):964–977PubMedPubMedCentralGoogle Scholar
  61. Haferkamp I (2017) Crossing the border – solute entry into the chlamydial inclusion. Int J Med Microbiol.
  62. Ham H, Sreelatha A, Orth K (2011) Manipulation of host membranes by bacterial effectors. Nat Rev Microbiol 9(9):635–646. Scholar
  63. Harrison TG, Doshi N, Fry NK, Joseph CA (2007) Comparison of clinical and environmental isolates of Legionella pneumophila obtained in the UK over 19 years. Clin Microbiol Infect 13(1):78–85. Scholar
  64. Hatch TP (1975) Competition between Chlamydia psittaci and L cells for host isoleucine pools: a limiting factor in chlamydial multiplication. Infect Immun 12(1):211–220PubMedPubMedCentralGoogle Scholar
  65. Hatch TP, Allan I, Pearce JH (1984) Structural and polypeptide differences between envelopes of infective and reproductive life cycle forms of Chlamydia spp. J Bacteriol 157(1):13–20PubMedPubMedCentralGoogle Scholar
  66. Havell EA, Moldawer LL, Helfgott D, Kilian PL, Sehgal PB (1992) Type I IL-1 receptor blockade exacerbates murine listeriosis. J Immunol 148(5):1486–1492PubMedGoogle Scholar
  67. Hempstead AD, Isberg RR (2015) Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response. Proc Natl Acad Sci USA 112(49):E6790–E6797. Scholar
  68. Hill J, Samuel JE (2011) Coxiella burnetii acid phosphatase inhibits the release of reactive oxygen intermediates in polymorphonuclear leukocytes. Infect Immun 79(1):414–420. Scholar
  69. Hirsch E, Irikura VM, Paul SM, Hirsh D (1996) Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci USA 93(20):11008–11013PubMedPubMedCentralCrossRefGoogle Scholar
  70. Hovel-Miner G, Faucher SP, Charpentier X, Shuman HA (2010) ArgR-regulated genes are derepressed in the Legionella-containing vacuole. J Bacteriol 192(17):4504–4516. Scholar
  71. Howe D, Heinzen RA (2006) Coxiella burnetii inhabits a cholesterol-rich vacuole and influences cellular cholesterol metabolism. Cell Microbiol 8(3):496–507. Scholar
  72. Howe D, Mallavia LP (1999) Coxiella burnetii infection increases transferrin receptors on J774A. 1 cells. Infect Immun 67(7):3236–3241PubMedPubMedCentralGoogle Scholar
  73. Hubber A, Roy CR (2010) Modulation of host cell function by Legionella pneumophila type IV effectors. Annu Rev Cell Dev Biol 26:261–283. Scholar
  74. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R (2017) Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356(6337):513–519. Scholar
  75. Jennings E, Thurston TLM, Holden DW (2017) Salmonella SPI-2 Type III secretion system effectors: molecular mechanisms and physiological consequences. Cell Host Microbe 22(2):217–231. Scholar
  76. Jo EK, Yuk JM, Shin DM, Sasakawa C (2013) Roles of autophagy in elimination of intracellular bacterial pathogens. Front Immunol 4:97. Scholar
  77. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O’Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P (2004) LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119(2):299–309. Scholar
  78. Jouanguy E, Doffinger R, Dupuis S, Pallier A, Altare F, Casanova JL (1999) IL-12 and IFN-gamma in host defense against mycobacteria and salmonella in mice and men. Curr Opin Immunol 11(3):346–351PubMedCrossRefGoogle Scholar
  79. Kading N, Szaszak M, Rupp J (2014) Imaging of Chlamydia and host cell metabolism. Future Microbiol 9(4):509–521. Scholar
  80. Kalman S, Mitchell W, Marathe R, Lammel C, Fan J, Hyman RW, Olinger L, Grimwood J, Davis RW, Stephens RS (1999) Comparative genomes of Chlamydia pneumoniae and C. trachomatis. Nat Genet 21(4):385–389. Scholar
  81. Kand’ar R, Zakova P, Muzakova V (2006) Monitoring of antioxidant properties of uric acid in humans for a consideration measuring of levels of allantoin in plasma by liquid chromatography. Clin Chim Acta 365(1–2):249–256. Scholar
  82. Kelly B, O’Neill LA (2015) Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25(7):771–784. Scholar
  83. Kim MJ, Wainwright HC, Locketz M, Bekker LG, Walther GB, Dittrich C, Visser A, Wang W, Hsu FF, Wiehart U, Tsenova L, Kaplan G, Russell DG (2010) Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol Med 2(7):258–274. Scholar
  84. Kim YK, Shin JS, Nahm MH (2016) NOD-like receptors in infection, immunity, and diseases. Yonsei Med J 57(1):5–14. Scholar
  85. Kohler LJ, Roy CR (2015) Biogenesis of the lysosome-derived vacuole containing Coxiella burnetii. Microbes Infect 17(11–12):766–771. Scholar
  86. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ (2010) Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115(23):4742–4749. Scholar
  87. Kuehl CJ, Dragoi AM, Talman A, Agaisse H (2015) Bacterial spread from cell to cell: beyond actin-based motility. Trends Microbiol 23(9):558–566. Scholar
  88. Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30(1):16–34. Scholar
  89. Lecuit M, Sonnenburg JL, Cossart P, Gordon JI (2007) Functional genomic studies of the intestinal response to a foodborne enteropathogen in a humanized gnotobiotic mouse model. J Biol Chem 282(20):15065–15072. Scholar
  90. Leistikow RL, Morton RA, Bartek IL, Frimpong I, Wagner K, Voskuil MI (2010) The Mycobacterium tuberculosis DosR regulon assists in metabolic homeostasis and enables rapid recovery from nonrespiring dormancy. J Bacteriol 192(6):1662–1670. Scholar
  91. Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469(7330):323–335. Scholar
  92. Liao D, Fan Q, Bao L (2013) The role of superoxide dismutase in the survival of Mycobacterium tuberculosis in macrophages. Jpn J Infect Dis 66(6):480–488PubMedCrossRefGoogle Scholar
  93. Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41(3):211–218. Scholar
  94. Lin Z, Zhang YG, Xia Y, Xu X, Jiao X, Sun J (2016) Salmonella enteritidis effector AvrA stabilizes intestinal tight junctions via the JNK pathway. J Biol Chem 291(52):26837–26849. Scholar
  95. Liu X, Lu R, Xia Y, Sun J (2010) Global analysis of the eukaryotic pathways and networks regulated by Salmonella typhimurium in mouse intestinal infection in vivo. BMC Genomics 11:722. Scholar
  96. Lopez CA, Winter SE, Rivera-Chavez F, Xavier MN, Poon V, Nuccio SP, Tsolis RM, Baumler AJ (2012) Phage-mediated acquisition of a type III secreted effector protein boosts growth of salmonella by nitrate respiration. MBio 3(3).
  97. Lutay N, Hakansson G, Alaridah N, Hallgren O, Westergren-Thorsson G, Godaly G (2014) Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti-inflammatory IL-22 and IL-10 response. PLoS One 9(1):e86466. Scholar
  98. Macallan DC, McNurlan MA, Kurpad AV, de Souza G, Shetty PS, Calder AG, Griffin GE (1998) Whole body protein metabolism in human pulmonary tuberculosis and undernutrition: evidence for anabolic block in tuberculosis. Clin Sci (Lond) 94(3):321–331CrossRefGoogle Scholar
  99. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP, Rathmell JC (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20(1):61–72. Scholar
  100. Malhotra M, Sood S, Mukherjee A, Muralidhar S, Bala M (2013) Genital Chlamydia trachomatis: an update. Indian J Med Res 138(3):303–316PubMedPubMedCentralGoogle Scholar
  101. Manca C, Paul S, Barry CE 3rd, Freedman VH, Kaplan G (1999) Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro. Infect Immun 67(1):74–79PubMedPubMedCentralGoogle Scholar
  102. Mannonen L, Markkula E, Puolakkainen M (2011) Analysis of Chlamydia pneumoniae infection in mononuclear cells by reverse transcription-PCR targeted to chlamydial gene transcripts. Med Microbiol Immunol 200(3):143–154. Scholar
  103. Mansell A, Braun L, Cossart P, O’Neill LA (2000) A novel function of InIB from Listeria monocytogenes: activation of NF-kappaB in J774 macrophages. Cell Microbiol 2(2):127–136PubMedCrossRefGoogle Scholar
  104. Manske C, Hilbi H (2014) Metabolism of the vacuolar pathogen Legionella and implications for virulence. Front Cell Infect Microbiol 4:125. Scholar
  105. Mantegazza AR, Magalhaes JG, Amigorena S, Marks MS (2013) Presentation of phagocytosed antigens by MHC class I and II. Traffic 14(2):135–152. Scholar
  106. Marrero J, Rhee KY, Schnappinger D, Pethe K, Ehrt S (2010) Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci USA 107(21):9819–9824. Scholar
  107. Masoud GN, Li W (2015) HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5(5):378–389. Scholar
  108. Matsunaga K, Klein TW, Newton C, Friedman H, Yamamoto Y (2001) Legionella pneumophila suppresses interleukin-12 production by macrophages. Infect Immun 69(3):1929–1933. Scholar
  109. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442(7098):39–44. Scholar
  110. Michalek RD, Rathmell JC (2010) The metabolic life and times of a T-cell. Immunol Rev 236:190–202. Scholar
  111. Minton K (2017) Immune regulation: IL-10 targets macrophage metabolism. Nat Rev Immunol 17(6):345. Scholar
  112. Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, Sassetti CM (2013) Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta. Nat Immunol 14(1):52–60. Scholar
  113. Mishra BB, Lovewell RR, Olive AJ, Zhang G, Wang W, Eugenin E, Smith CM, Phuah JY, Long JE, Dubuke ML, Palace SG, Goguen JD, Baker RE, Nambi S, Mishra R, Booty MG, Baer CE, Shaffer SA, Dartois V, McCormick BA, Chen X, Sassetti CM (2017) Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat Microbiol 2:17072. Scholar
  114. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132. Scholar
  115. Moffatt JH, Newton P, Newton HJ (2015) Coxiella burnetii: turning hostility into a home. Cell Microbiol 17(5):621–631. Scholar
  116. Mulye M, Samanta D, Winfree S, Heinzen RA, Gilk SD (2017) Elevated cholesterol in the Coxiella burnetii intracellular niche is bacteriolytic. MBio 8(1).
  117. Munn DH, Mellor AL (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34(3):137–143. Scholar
  118. Munoz-Elias EJ, McKinney JD (2006) Carbon metabolism of intracellular bacteria. Cell Microbiol 8(1):10–22. Scholar
  119. Nathan C, Shiloh MU (2000) Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA 97(16):8841–8848PubMedPubMedCentralCrossRefGoogle Scholar
  120. Natividad A, Freeman TC, Jeffries D, Burton MJ, Mabey DC, Bailey RL, Holland MJ (2010) Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection. Infect Immun 78(11):4895–4911. Scholar
  121. Ng VH, Cox JS, Sousa AO, MacMicking JD, McKinney JD (2004) Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol 52(5):1291–1302. Scholar
  122. Nguyen GT, Green ER, Mecsas J (2017) Neutrophils to the ROScue: mechanisms of NADPH oxidase activation and bacterial resistance. Front Cell Infect Microbiol 7:373. Scholar
  123. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336(6086):1262–1267. Scholar
  124. Ninio S, Roy CR (2007) Effector proteins translocated by Legionella pneumophila: strength in numbers. Trends Microbiol 15(8):372–380. Scholar
  125. O’Neill LA (2015) A broken krebs cycle in macrophages. Immunity 42(3):393–394. Scholar
  126. O’Neill LA, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16(9):553–565. Scholar
  127. Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275–297. Scholar
  128. Olive AJ, Sassetti CM (2016) Metabolic crosstalk between host and pathogen: sensing, adapting and competing. Nat Rev Microbiol 14(4):221–234. Scholar
  129. Omsland A, Sager J, Nair V, Sturdevant DE, Hackstadt T (2012) Developmental stage-specific metabolic and transcriptional activity of Chlamydia trachomatis in an axenic medium. Proc Natl Acad Sci USA 109(48):19781–19785. Scholar
  130. Ouellette SP, Dorsey FC, Moshiach S, Cleveland JL, Carabeo RA (2011) Chlamydia species-dependent differences in the growth requirement for lysosomes. PLoS One 6(3):e16783. Scholar
  131. Pareja ME, Colombo MI (2013) Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms. Front Cell Infect Microbiol 3:54. Scholar
  132. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38(4):633–643. Scholar
  133. Pearce EL, Poffenberger MC, Chang CH, Jones RG (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342(6155):1242454. Scholar
  134. Peleg AY, Tampakakis E, Fuchs BB, Eliopoulos GM, Moellering RC Jr, Mylonakis E (2008) Prokaryote-eukaryote interactions identified by using Caenorhabditis elegans. Proc Natl Acad Sci USA 105(38):14585–14590. Scholar
  135. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO (2016) Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354(6311):481–484. Scholar
  136. Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, Daffe M, Emile JF, Marchou B, Cardona PJ, de Chastellier C, Altare F (2008) Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 4(11):e1000204. Scholar
  137. Pikuleva IA (2006) Cytochrome P450s and cholesterol homeostasis. Pharmacol Ther 112(3):761–773. Scholar
  138. Plain KM, de Silva K, Earl J, Begg DJ, Purdie AC, Whittington RJ (2011) Indoleamine 2,3-dioxygenase, tryptophan catabolism, and Mycobacterium avium subsp. paratuberculosis: a model for chronic mycobacterial infections. Infect Immun 79(9):3821–3832. Scholar
  139. Portnoy DA, Auerbuch V, Glomski IJ (2002) The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity. J Cell Biol 158(3):409–414. Scholar
  140. Price CT, Al-Quadan T, Santic M, Rosenshine I, Abu Kwaik Y (2011) Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science 334(6062):1553–1557. Scholar
  141. Price JD, Simpfendorfer KR, Mantena RR, Holden J, Heath WR, van Rooijen N, Strugnell RA, Wijburg OL (2007) Gamma interferon-independent effects of interleukin-12 on immunity to Salmonella enterica serovar Typhimurium. Infect Immun 75(12):5753–5762. Scholar
  142. Ragno S, Romano M, Howell S, Pappin DJ, Jenner PJ, Colston MJ (2001) Changes in gene expression in macrophages infected with Mycobacterium tuberculosis: a combined transcriptomic and proteomic approach. Immunology 104(1):99–108PubMedPubMedCentralCrossRefGoogle Scholar
  143. Ramirez-Alejo N, Santos-Argumedo L (2014) Innate defects of the IL-12/IFN-gamma axis in susceptibility to infections by mycobacteria and salmonella. J Interferon Cytokine Res 34(5):307–317. Scholar
  144. Rao PK, Li Q (2009) Protein turnover in mycobacterial proteomics. Molecules 14(9):3237–3258. Scholar
  145. Ren Q, Robertson SJ, Howe D, Barrows LF, Heinzen RA (2003) Comparative DNA microarray analysis of host cell transcriptional responses to infection by Coxiella burnetii or Chlamydia trachomatis. Ann N Y Acad Sci 990:701–713PubMedCrossRefGoogle Scholar
  146. Ribet D, Cossart P (2015) How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect 17(3):173–183. Scholar
  147. Robertson DK, Gu L, Rowe RK, Beatty WL (2009) Inclusion biogenesis and reactivation of persistent Chlamydia trachomatis requires host cell sphingolipid biosynthesis. PLoS Pathog 5(11):e1000664. Scholar
  148. Rosklint T, Ohlsson BG, Wiklund O, Noren K, Hulten LM (2002) Oxysterols induce interleukin-1beta production in human macrophages. Eur J Clin Invest 32(1):35–42PubMedCrossRefGoogle Scholar
  149. Santos RL, Raffatellu M, Bevins CL, Adams LG, Tukel C, Tsolis RM, Baumler AJ (2009) Life in the inflamed intestine, Salmonella style. Trends Microbiol 17(11):498–506. Scholar
  150. Scanu T, Spaapen RM, Bakker JM, Pratap CB, Wu LE, Hofland I, Broeks A, Shukla VK, Kumar M, Janssen H, Song JY, Neefjes-Borst EA, te Riele H, Holden DW, Nath G, Neefjes J (2015) Salmonella manipulation of host signaling pathways provokes cellular transformation associated with Gallbladder carcinoma. Cell Host Microbe 17(6):763–774. Scholar
  151. Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64(7):2627–2633PubMedCrossRefGoogle Scholar
  152. Scidmore MA, Fischer ER, Hackstadt T (1996) Sphingolipids and glycoproteins are differentially trafficked to the Chlamydia trachomatis inclusion. J Cell Biol 134(2):363–374PubMedCrossRefGoogle Scholar
  153. Shi L, Jung YJ, Tyagi S, Gennaro ML, North RJ (2003) Expression of Th1-mediated immunity in mouse lungs induces a Mycobacterium tuberculosis transcription pattern characteristic of nonreplicating persistence. Proc Natl Acad Sci USA 100(1):241–246. Scholar
  154. Shi L, Salamon H, Eugenin EA, Pine R, Cooper A, Gennaro ML (2015) Infection with Mycobacterium tuberculosis induces the Warburg effect in mouse lungs. Sci Rep 5:18176. Scholar
  155. Shiloh MU, Manzanillo P, Cox JS (2008) Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection. Cell Host Microbe 3(5):323–330. Scholar
  156. Shin JH, Yang JY, Jeon BY, Yoon YJ, Cho SN, Kang YH, Ryu DH, Hwang GS (2011) (1)H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J Proteome Res 10(5):2238–2247. Scholar
  157. Siegl C, Prusty BK, Karunakaran K, Wischhusen J, Rudel T (2014) Tumor suppressor p53 alters host cell metabolism to limit Chlamydia trachomatis infection. Cell Rep 9(3):918–929. Scholar
  158. Siemsen DW, Kirpotina LN, Jutila MA, Quinn MT (2009) Inhibition of the human neutrophil NADPH oxidase by Coxiella burnetii. Microbes Infect 11(6-7):671–679. Scholar
  159. Singh V, Jamwal S, Jain R, Verma P, Gokhale R, Rao KV (2012) Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype. Cell Host Microbe 12(5):669–681. Scholar
  160. Singh V, Kaur C, Chaudhary VK, Rao KV, Chatterjee S (2015) M. tuberculosis secretory protein ESAT-6 induces metabolic flux perturbations to drive foamy macrophage differentiation. Sci Rep 5:12906. Scholar
  161. Sinnis P, Ernst JD (2008) CO-opting the host HO-1 pathway in tuberculosis and malaria. Cell Host Microbe 3(5):277–279. Scholar
  162. Somashekar BS, Amin AG, Rithner CD, Troudt J, Basaraba R, Izzo A, Crick DC, Chatterjee D (2011) Metabolic profiling of lung granuloma in Mycobacterium tuberculosis infected guinea pigs: ex vivo 1H magic angle spinning NMR studies. J Proteome Res 10(9):4186–4195. Scholar
  163. Stratton CW, Sriram S (2003) Association of Chlamydia pneumoniae with central nervous system disease. Microbes Infect 5(13):1249–1253PubMedCrossRefGoogle Scholar
  164. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O'Neill LA (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496(7444):238–242. Scholar
  165. Tas SW, Vervoordeldonk MJ, Hajji N, Schuitemaker JH, van der Sluijs KF, May MJ, Ghosh S, Kapsenberg ML, Tak PP, de Jong EC (2007) Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 110(5):1540–1549. Scholar
  166. Thiennimitr P, Winter SE, Winter MG, Xavier MN, Tolstikov V, Huseby DL, Sterzenbach T, Tsolis RM, Roth JR, Baumler AJ (2011) Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota. Proc Natl Acad Sci USA 108(42):17480–17485. Scholar
  167. Tipples G, McClarty G (1993) The obligate intracellular bacterium Chlamydia trachomatis is auxotrophic for three of the four ribonucleoside triphosphates. Mol Microbiol 8(6):1105–1114PubMedCrossRefGoogle Scholar
  168. Uchiya K, Nikai T (2004) Salmonella enterica serovar Typhimurium infection induces cyclooxygenase 2 expression in macrophages: involvement of Salmonella pathogenicity island 2. Infect Immun 72(12):6860–6869. Scholar
  169. van der Windt GJ, Pearce EL (2012) Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249(1):27–42. Scholar
  170. van Ooij C, Kalman L, van I, Nishijima M, Hanada K, Mostov K, Engel JN (2000) Host cell-derived sphingolipids are required for the intracellular growth of Chlamydia trachomatis. Cell Microbiol 2(6):627–637PubMedCrossRefGoogle Scholar
  171. van Schaik EJ, Chen C, Mertens K, Weber MM, Samuel JE (2013) Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. Nat Rev Microbiol 11(8):561–573. Scholar
  172. Vazquez-Boland JA, Kuhn M, Berche P, Chakraborty T, Dominguez-Bernal G, Goebel W, Gonzalez-Zorn B, Wehland J, Kreft J (2001) Listeria pathogenesis and molecular virulence determinants. Clin Microbiol Rev 14(3):584–640. Scholar
  173. Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R, Ottenhoff TH (2004) Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA 101(13):4560–4565. Scholar
  174. Vonaesch P, Sellin ME, Cardini S, Singh V, Barthel M, Hardt WD (2014) The Salmonella Typhimurium effector protein SopE transiently localizes to the early SCV and contributes to intracellular replication. Cell Microbiol 16(12):1723–1735. Scholar
  175. Vromman F, Laverriere M, Perrinet S, Dufour A, Subtil A (2014) Quantitative monitoring of the Chlamydia trachomatis developmental cycle using GFP-expressing bacteria, microscopy and flow cytometry. PLoS One 9(6):e99197. Scholar
  176. Wagner RD, Steinberg H, Brown JF, Czuprynski CJ (1994) Recombinant interleukin-12 enhances resistance of mice to Listeria monocytogenes infection. Microb Pathog 17(3):175–186PubMedCrossRefGoogle Scholar
  177. Wahl DR, Byersdorfer CA, Ferrara JL, Opipari AW Jr, Glick GD (2012) Distinct metabolic programs in activated T cells: opportunities for selective immunomodulation. Immunol Rev 249(1):104–115. Scholar
  178. Way SS, Havenar-Daughton C, Kolumam GA, Orgun NN, Murali-Krishna K (2007) IL-12 and type-I IFN synergize for IFN-gamma production by CD4 T cells, whereas neither are required for IFN-gamma production by CD8 T cells after Listeria monocytogenes infection. J Immunol 178(7):4498–4505PubMedPubMedCentralCrossRefGoogle Scholar
  179. Wieland H, Ullrich S, Lang F, Neumeister B (2005) Intracellular multiplication of Legionella pneumophila depends on host cell amino acid transporter SLC1A5. Mol Microbiol 55(5):1528–1537. Scholar
  180. Wylie JL, Hatch GM, McClarty G (1997) Host cell phospholipids are trafficked to and then modified by Chlamydia trachomatis. J Bacteriol 179(23):7233–7242PubMedPubMedCentralCrossRefGoogle Scholar
  181. Yamada H, Mizuno S, Reza-Gholizadeh M, Sugawara I (2001) Relative importance of NF-kappaB p50 in mycobacterial infection. Infect Immun 69(11):7100–7105. Scholar
  182. Zaika AI, Wei J, Noto JM, Peek RM (2015) Microbial regulation of p53 tumor suppressor. PLoS Pathog 11(9):e1005099. Scholar
  183. Zhang YJ, Reddy MC, Ioerger TR, Rothchild AC, Dartois V, Schuster BM, Trauner A, Wallis D, Galaviz S, Huttenhower C, Sacchettini JC, Behar SM, Rubin EJ (2013) Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 155(6):1296–1308. Scholar
  184. Zou T, Garifulin O, Berland R, Boyartchuk VL (2011) Listeria monocytogenes infection induces prosurvival metabolic signaling in macrophages. Infect Immun 79(4):1526–1535. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Catarina M. Ferreira
    • 1
    • 2
  • Ana Margarida Barbosa
    • 1
    • 2
  • Inês M. Pereira
    • 1
    • 2
  • Egídio Torrado
    • 1
    • 2
  1. 1.Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryUniversity of MinhoBragaPortugal

Personalised recommendations