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Macrophages from elders are more permissive to intracellular multiplication of Mycobacterium tuberculosis

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Abstract

The elderly account for a disproportionate share of all tuberculosis cases, and the population ageing may not fully explain this phenomenon. We have performed in vitro infection experiments to investigate whether there is an immunological basis for the apparent susceptibility of elders to tuberculosis. In our infection model, Mycobacterium tuberculosis induces a higher production of interleukin (IL)-6 and reactive oxygen species in macrophages from elders than from younger adults. This response did not prevent, however, an increased multiplication of M. tuberculosis in macrophages from elders as compared with the growth observed within cells from adults. By performing a factorial experiment, we have found that IFN-γ, but not IL-1β, IL-6 or TNF-α, stimulate the macrophages to restrict the multiplication of the bacterium in macrophages from elders. Although monocytes from elders seem to be in a higher level of activation, we present evidences that protein tyrosine phosphorylation response induced by M. tuberculosis is stronger in monocytes from adults than from elders. Using a protein array that detects 71 tyrosine phosphorylated kinases, we identified Pyk2 as the only kinase that displayed a difference of intensity larger than 50 % in adults than in elders. Furthermore, monocytes from elders that were incubated in the presence of tyrosine kinase inhibitors (genistein and PP2) allowed a higher level of bacterial multiplication. These observations may help to explain the susceptibility of elders to tuberculosis. An unexpected result was that both genistein and its negative control, daidzein, abundant soy isoflavones, promoted intracellular mycobacterial growth.

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References

  • Álvarez E, Santa María C (1996) Influence of the age and sex on respiratory burst of human monocytes. Mech Ageing Dev 90:157–161

    Article  PubMed  Google Scholar 

  • Beharka AA, Meydani M, Wu D, Leka LS, Meydani A, Meydani SN (2001) Interleukin-6 production does not increase with age. J Gerontol A Biol Sci Med Sci 56:B81–B88

    Article  PubMed  CAS  Google Scholar 

  • Bermudez LE, Wu M, Petrofsky M, Young LS (1992) Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in macrophages. Infect Immun 60:4245–4252

    PubMed  CAS  Google Scholar 

  • Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004) Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75:342–349

    Article  PubMed  CAS  Google Scholar 

  • Cabre M (2009) Pneumonia in the elderly. Curr Opin Pulm Med 15:223–229

    Article  PubMed  Google Scholar 

  • Cardona PJ (2009) A dynamic reinfection hypothesis of latent tuberculosis infection. Infection 37:80–86

    Article  PubMed  Google Scholar 

  • Chatta GS, Dale DC (1996) Aging and haemopoiesis. Implications for treatment with haemopoietic growth factors. Drugs Aging 9:37–47

    Article  PubMed  CAS  Google Scholar 

  • DelaRosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R (2006) Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 7:471–481

    Article  PubMed  CAS  Google Scholar 

  • Delpedro AD, Barjavel MJ, Mamdouh Z, Faure S, Bakouche O (1998) Signal transduction in LPS-activated aged and young monocytes. J Interferon Cytokine Res 18:429–437

    Article  PubMed  CAS  Google Scholar 

  • Ernst JD (1998) Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 66:1277–1281

    PubMed  CAS  Google Scholar 

  • Fazal N, Bartlett R, Lammas DA, Kumararatne DS (1992) A comparison of the different methods available for determining BCG–macrophage interactions in vitro, including a new method of colony counting in broth. FEMS Microbiol Immunol 5:355–362

    Article  PubMed  CAS  Google Scholar 

  • Fietta A, Merlini C, De Bernardi PM, Gandola L, Piccioni PD, Grassi C (1993) Non specific immunity in aged healthy subjects and in patients with chronic bronchitis. Aging (Milano) 5:357–361

    CAS  Google Scholar 

  • Fietta A, Merlini C, Dos Santos C, Rovida S, Grassi C (1994) Influence of aging on some specific and nonspecific mechanisms of the host defense system in 146 healthy subjects. Gerontology 40:237–245

    Article  PubMed  CAS  Google Scholar 

  • Fortin CF, Larbi A, Lesur O, Douziech N, Fülöp T Jr (2006) Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukoc Biol 79:1061–1072

    Article  PubMed  CAS  Google Scholar 

  • Fortin CF, Larbi A, Dupuis G, Lesur O, Fülöp T Jr (2007) GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals. Biogerontology 8:173–187

    Article  PubMed  CAS  Google Scholar 

  • Franceschi C, Bonafè M, Valensin S, Olivieri F, De LM, Ottaviani E, Giovanna DB (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    Article  PubMed  CAS  Google Scholar 

  • Fülöp T Jr, Varga Z, Jacob MP, Robert L (1997) Effect of lithium on superoxide production and intracellular free calcium mobilization in elastin peptide (kappa-elastin) and FMLP stimulated human PMNS. Effect of age. Life Sci 60:PL325–PL332

    Article  Google Scholar 

  • Gomez CR, Nomellini V, Faunce DE, Kovacs EJ (2008) Innate immunity and aging. Exp Gerontol 43:718–728

    Article  PubMed  CAS  Google Scholar 

  • Gon Y, Hashimoto S, Hayashi S, Koura T, Matsumoto K, Horie T (1996) Lower serum concentrations of cytokines in elderly patients with pneumonia and the impaired production of cytokines by peripheral blood monocytes in the elderly. Clin Exp Immunol 106:120–126

    PubMed  CAS  Google Scholar 

  • Howard NS, Gomez JE, Ko C, Bishai WR (1995) Color selection with a hygromycin-resistance-based Escherichia coli-mycobacterial shuttle vector. Gene 166:181–182

    Article  PubMed  CAS  Google Scholar 

  • Huang R, Singh M, Dillon GH (2010) Genistein directly inhibits native and recombinant NMDA receptors. Neuropharmacology 58:1246–1251

    Article  PubMed  CAS  Google Scholar 

  • Jacobs WR Jr, Kalpana GV, Cirillo JD, Pascopella L, Snapper SB, Udani RA, Jones W, Barletta RG, Bloom BR (1991) Genetic systems for mycobacteria. Methods Enzymol 204:537–555

    Article  PubMed  CAS  Google Scholar 

  • Kamen LA, Schlessinger J, Lowell CA (2011) Pyk2 is required for neutrophil degranulation and host defense responses to bacterial infection. J Immunol 186:1656–1665

    Article  PubMed  CAS  Google Scholar 

  • Karim AF, Chandra P, Chopra A, Siddiqui Z, Bhaskar A, Singh A, Kumar D (2011) Express path analysis identifies a tyrosine kinase Src-centric network regulating divergent host responses to Mycobacterium tuberculosis infection. J Biol Chem 286:40307–40319

    Article  PubMed  CAS  Google Scholar 

  • Kim HJ, Ahn HS, Choi BH, Hahn SJ (2011) Inhibition of Kv4.3 by genistein via a tyrosine phosphorylation-independent mechanism. Am J Physiol Cell Physiol 300:C567–C575

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Kornfeld H (2010) Interferon-γ regulates the death of M. tuberculosis-infected macrophages. J Cell Death 3:1–11

    PubMed  CAS  Google Scholar 

  • Lee J, Hartman M, Kornfeld H (2009) Macrophage apoptosis in tuberculosis. Yonsei Med J 50:1–11

    Article  PubMed  Google Scholar 

  • Liang S, Domon H, Hosur KB, Wang M, Hajishengallis G (2009) Age-related alterations in innate immune receptor expression and ability of macrophages to respond to pathogen challenge in vitro. Mech Ageing Dev 130:538–546

    Article  PubMed  CAS  Google Scholar 

  • McLachlan JA, Serkin CD, Morrey KM, Bakouche O (1995) Antitumoral properties of aged human monocytes. J Immunol 154:832–843

    PubMed  CAS  Google Scholar 

  • Meyer KC (2005) Aging. Proc Am Thorac Soc 2:433–439

    Article  PubMed  CAS  Google Scholar 

  • Montgomery Douglas C (2001) Design and analysis of experiments, 5th edn. Wiley, New York

    Google Scholar 

  • Mori T, Leung CC (2010) Tuberculosis in the global aging population. Infect Dis Clin North Am 24:751–768

    Article  PubMed  Google Scholar 

  • Nagabhushanam V, Solache A, Ting LM, Escaron CJ, Zhang JY, Ernst JD (2003) Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-γ. J Immunol 171:4750–4757

    PubMed  CAS  Google Scholar 

  • O'Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K (1998) Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol 113:213–219

    Article  PubMed  Google Scholar 

  • Orme IM (1987) Aging and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J Immunol 138:4414–4418

    PubMed  CAS  Google Scholar 

  • Orme IM, Griffin JP, Roberts AD, Ernst DN (1993) Evidence for a defective accumulation of protective T cells in old mice infected with Mycobacterium tuberculosis. Cell Immunol 147:222–229

    Article  PubMed  CAS  Google Scholar 

  • Ottenhoff TH, Verreck FA, Hoeve MA, van de Vosse E (2005) Control of human host immunity to mycobacteria. Tuberculosis (Edinb) 85:53–64

    Article  CAS  Google Scholar 

  • Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  PubMed  CAS  Google Scholar 

  • Rajagopalan S, Yoshikawa TT (2000) Tuberculosis in the elderly. Z Gerontol Geriatr 33:374–380

    Article  PubMed  CAS  Google Scholar 

  • Reyes-Ruvalcaba D, González-Cortés C, Rivero-Lezcano OM (2008) Human phagocytes lack the ability to kill Mycobacterium gordonae, a non-pathogenic mycobacteria. Immunol Lett 116:72–78

    Article  PubMed  CAS  Google Scholar 

  • Rhoades ER, Orme IM (1998) Similar responses by macrophages from young and old mice infected with Mycobacterium tuberculosis. Mech Ageing Dev 106:145–153

    Article  PubMed  CAS  Google Scholar 

  • Rottinghaus EK, Vesosky B, Turner J (2010) TLR-2 independent recognition of Mycobacterium tuberculosis by CD11c+ pulmonary cells from old mice. Mech Ageing Dev 131:405–414

    Article  PubMed  CAS  Google Scholar 

  • Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA (1998) Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 53:M20–M26

    Article  PubMed  CAS  Google Scholar 

  • Rudd AG, Banerjee DK (1989) Interleukin-1 production by human monocytes in ageing and disease. Age Ageing 18:43–46

    Article  PubMed  CAS  Google Scholar 

  • Sadeghi HM, Schnelle JF, Thoma JK, Nishanian P, Fahey JL (1999) Phenotypic and functional characteristics of circulating monocytes of elderly persons. Exp Gerontol 34:959–970

    Article  PubMed  CAS  Google Scholar 

  • Sakai T, Kogiso M (2008) Soy isoflavones and immunity. J Med Invest 55:167–173

    Article  PubMed  Google Scholar 

  • Schaaf HS, Collins A, Bekker A, Davies PDO (2010) Tuberculosis at extremes of age. Respirology 15:747–763

    Article  PubMed  Google Scholar 

  • Sörensen M, Lippuner C, Kaiser T, Miβlitz A, Aebischer T, Bumann D (2003) Rapidly maturing red fluorescent protein variants with strongly enhanced brightness in bacteria. FEBS Lett 552:110–114

    Article  PubMed  Google Scholar 

  • Turner J, Frank AA, Orme IM (2002) Old mice express a transient early resistance to pulmonary tuberculosis that is mediated by CD8 T cells. Infect Immun 70:4628–4637

    Article  PubMed  CAS  Google Scholar 

  • van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, Allore HG, Medzhitov R, Shaw AC (2007) Age-associated defect in human TLR-1/2 function. J Immunol 178:970–975

    PubMed  Google Scholar 

  • Vesosky B, Turner J (2005) The influence of age on immunity to infection with Mycobacterium tuberculosis. Immunol Rev 205:229–243

    Article  PubMed  CAS  Google Scholar 

  • Vesosky B, Flaherty DK, Turner J (2006) Th1 cytokines facilitate CD8-T-cell-mediated early resistance to infection with Mycobacterium tuberculosis in old mice. Infect Immun 74:3314–3324

    Article  PubMed  CAS  Google Scholar 

  • Warwick-Davies J, Dhillon J, O'Brien L, Andrew PW, Lowrie DB (1994) Apparent killing of Mycobacterium tuberculosis by cytokine-activated human monocytes can be an artefact of a cytotoxic effect on the monocytes. Clin Exp Immunol 96:214–217

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa TT (1981) Important infections in elderly persons. West J Med 135:441–445

    PubMed  CAS  Google Scholar 

  • Zaffran Y, Zhang L, Ellner JJ (1998) Role of CR4 in Mycobacterium tuberculosis-human macrophages binding and signal transduction in the absence of serum. Infect Immun 66:4541–4544

    PubMed  CAS  Google Scholar 

  • Zevallos M, Justman JE (2003) Tuberculosis in the elderly. Clin Geriatr Med 19:121–138

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the nurses who helped us with the blood collection and Ignacio Rodríguez-Barbosa for the flow cytometry technical assistance. This study was supported by grants from the Consejería de Sanidad de la Junta de Castilla y León (2010 and 2011) and Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III [PI05/1288]. Dr. Rivero-Lezcano is a member of the Fundación Instituto Ciencias de la Salud de Castilla y León and participates in the SACYL research program. González Cortés was supported by the Instituto de Salud Carlos III program for national health system research support.

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Authors and Affiliations

  1. Servicio de Medicina Interna, Hospital de León, Altos de Nava s/n, 24008, León, Spain

    José M. Guerra-Laso

  2. Unidad de Investigación, Hospital de León, Edif. S. Antonio Abad, Altos de Nava s/n, 24008, León, Spain

    Sandra González-García, Carolina González-Cortés & Octavio M. Rivero-Lezcano

  3. Servicio de Anatomía Patológica, Hospital de León, Altos de Nava s/n, 24008, León, Spain

    Cristina Diez-Tascón

  4. Servicio de Microbiología, Hospital Comarcal del Bierzo, Médicos sin Fronteras, 7, 24411, Fuentesnuevas, Spain

    Ramiro López-Medrano

  5. Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León, Parque de Santa Clara s/n, 42002, Soria, Spain

    Octavio M. Rivero-Lezcano

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  1. José M. Guerra-Laso
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  2. Sandra González-García
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  3. Carolina González-Cortés
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  4. Cristina Diez-Tascón
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  5. Ramiro López-Medrano
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  6. Octavio M. Rivero-Lezcano
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Correspondence to Octavio M. Rivero-Lezcano.

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Guerra-Laso, J.M., González-García, S., González-Cortés, C. et al. Macrophages from elders are more permissive to intracellular multiplication of Mycobacterium tuberculosis . AGE 35, 1235–1250 (2013). https://doi.org/10.1007/s11357-012-9451-5

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  • DOI: https://doi.org/10.1007/s11357-012-9451-5

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