Abstract
Aging results in a general waning of immunity and enhanced susceptibility to many intracellular pathogens. However, in some instances, aging is accompanied by alternative immune responses that can be equal to, or even more effective, than those of young adults. Brucella spp. are intracellular bacteria and important human and animal pathogens, but there are no data regarding the effect of age on host defense in brucellosis. Young or old adult mice (DBA/2 or BALB/c) were infected with either an attenuated B. abortus strain that over-expressed the Brucella superoxide dismutase (strain RB51-SOD) or a fully virulent strain (strain 2308). Survival, organism burden in the spleen, and immune responses were assessed. All young adult and aged mice survived infection with RB51-SOD (up to 6 × 108 cfu) or strain 2308 (up to 8 × 108 cfu). Old mice had a lower organism burden in the spleen than young adult mice five or more weeks after infection. Antibody and cytokine responses were Th1-focused in young adult mice, but Th-mixed in older mice, including evidence of the newly defined Th17 subtype immune response. Immunization with the RB51-SOD strain provided protection vs. strain 2308 challenge in young and aged BALB/c, but only young adult DBA/2 mice. Thus, clinical outcomes of Brucella infection in aged mice are equal or superior to those of young adult mice; immune responses in older mice are less-Th1 specific suggesting alternate pathways may contribute to host defense vs. Brucella in aged mice.
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Al-Mariri A, Tibor A, Mertens P, De Bolle X, Michel P, Godefroid J, Walravens K, Letesson J-J (2001) Protection of BALB/c mice against Brucella abortus 544 challenge by vaccination with bacterioferritin or P39 recombinant proteins with CpG oligodeoxynucleotides as adjuvant. Infect Immun 69:4816–4822
Argentati K, Re F, Sonnin A, Tucci MG, Franceschi C, Bartozzi B, Bernardini G, Provinciali M (2002) Numerical and functional alterations of circulating γδ T lymphocytes in aged people and centenarians. J Leuk Biol 72:65–71
Baldwin CL, Parent M (2002) Fundamentals of host immune response against Brucella abortus: what the mouse model has revealed about control of infection. Vet Microbiol 90:367–382
Bradley SF, Kauffman CA (1990) Aging and response to Salmonella infection. Exp Gerontol 25:75–80
Cannat A, Serre A (1981) Genetic factors involved in murine susceptibility to experimental brucellosis. Ann Immunol 132D:15–24
Castle SC (2002) Clinical relevance of age-related immune dysfunction. Clin Infect Dis 31:578–585
Celli J, de Chastellier C, Franchini DM, Pizarro-Cerda J, Moreno E, Gorvel JP (2003) Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J Exp Med 198:545–556
Chiu CH, Lin TY, Ou JT (2000) Age-related differences of nontyphoid Salmonella bacteremia in clinical presentation and outcome: association with specific serovars but not necessarily with the virulence plasmids. Clin Infect Dis 30:239–241
Colmenero JD, Reguera JM, Cabrera JP, Cisneros JM, Orjuela DL, Fernandez-Crehuet J (1990) Serology, clinical manifestations and treatment of Brucellosis in different age groups. Infection 18:152–156
Colmenero JD, Reguera JM, Martos F, Sanchez-De-Mora D, Delgado M, Causse M, Martin-Farfan A, Juarez C (1996) Complications associated with Brucella melitensis infection: a study of 530 cases. Medicine 75:195–211
Connoy AC, Trader M, High KP (2006) Age related changes in cell surface and senescence markers in the spleen of DBA/2 mice: a flow cytometric analysis. Exp Gerontol 41:225–229
Cooper AM, Callahan JE, Griffin JP, Roberts AD, Orme IM (1995) Old mice are able to control low-dose aerogenic infections with Mycobacterium tuberculosis. Infect Immun 63:3259–3265
Dornand J, Gross A, Lafont V, Liautard J, Oliaro J, Liautard JP (2002) The innate immune response against Brucella in humans. Vet Microbiol 90:383–394
Ehrchen J, Sindrilaru A, Grabbe S, Schonlau F, Schlesiger C, Sorg C, Scharffetter-Kochanek K, Sunderkotter C (2004) Senescent BALB/c mice are able to develop resistance to Leishmania major infection, Infect Immun 72:5106–5114
Emmerling P, Hof H, Finger H (1979) Age-related defense against infection with intracellular pathogens. Gerontology 25:327–336
Gavazzi G, Herrmann F, Krause KH (2004) Aging and infectious diseases in the developing world. Clin Infect Dis 39:83–91
Golding B, Scott DE, Scharf O, Huang LY, Zaitseva M, Lapham C, Eller N, Golding H (2001) Immunity and protection against Brucella abortus. Microb Infect 3:43–48
Goronzy JJ, Weyand CM (2005) T cell development and receptor diversity during aging. Curr Opinion Immunol 17:469–475
Gorvel JP, Moren E (2002) Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 90:281–297
Gur A, Geyik MF, Dikici B, Nas K, Cevik R, Sarac J, Hosoglu S (2003) Complications of Brucellosis in different age groups: a study of 283 cases in southeastern Anatolia of Turkey. Yonsei Med J 44:33–44
He Y, Vemulapalli R, Zeytun A, Schurig GG (2001) Induction of specific cytotoxic lymphocytes in mice vaccinated with Brucella abortus RB51. Infect Immun 69:5502–5508
He Y, Vemulapalli R, Schurig GG (2002) Recombinant Ochrobactrum anthropi expressing Brucella abortus Cu,Zn superoxide dismutase protects mice against B. abortus infection only after switching of immune responses to Th1 type. Infect Immun 70:2535–2543
High KP (2003) Why should the infectious diseases community focus on aging and care of the older adult? Clin Inf Dis 37:196–200
High KP (2006) Murine models of infectious diseases in the aged. In: Conn PM (ed) Handbook of models for human aging. Elsevier Academic Press, pp 651–660
High KP, Loeb M (2003) Infection in the elderly. In: Hazard WR, Blass JP, Halter JB, Ouslander JG, Tinetti ME (eds) Principles of geriatric medicine and gerontology, 5th edn. McGraw-Hill, pp 1071–1081
Hirokawa K, Utsuyama M (2002). Animal models and possible human application of immunological restoration in the elderly. Mech Ageing Dev 123:1055–1063
Huang W, Na L, Fidel PL, Schwarzenberger P (2004) Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190:624–631
Humphreys NE, Grencis RK (2002). Effects of ageing on the immunoregulation of parasitic infection. Infect Immun 70:5148–5157
Kinsella K, Velkoff V (2001) An aging world. U.S. Census Bureau, Series P95/01-1
Kleinman R, Lewis JA (1983) Bacteria-immune system interactions. XII. Effects of aging on Balb/c mice responsiveness to Salmonella typhimurium. Dev Comp Immunol 7:555–562
Maggio M, Guralnik JM, Longo DL, Ferruci L (2006) Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci 61:575–584
Maletto B, Rópolo A, Morón V, Pistoresi-Palencia MC (2002) CpG-DNA stimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice. J Leuk Biol 72:447–454
Manning BM, Enioutina EY, Visic DM, Knudson AD, Daynes RA (2001) CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice, Exp Gerontol 37:107–126
Miller R (1999) Aging and immunity. In: Paul WE (ed) Fundamental immunology, 4th edn. Lippincott-Raven, pp 947–966
Miyamoto M, Emoto M, Emoto Y et al (2003) Neutrophilia in LFA-1-deficient mice confers resistance to listeriosis: possible contribution of granulocyte-colony-stimulating factor and IL-17. J Immunol 170:5228–5234
Murphy EA, Parent M, Sathiyaseelan J, Jiang X, Baldwin CL (2001a) Immune control of Brucella abortus 2308 infections in BALB/c mice. MEMS Immunol Med Microbiol 32:85–88
Murphy EA, Sathiyaseelan J, Parent MA, Zou B, Baldwin CL (2001b) Interferon-γ is crucial for surviving a Brucella abortus infection in both resistant C57BL/6 and susceptible BALB/c mice, Immunology 103:511–518
Ogawa T, Kitagawa M, Hirokawa K (2000) Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mech Ageing Dev 117:57–68
Oliaro J, Dudal S, Liautard J, Andrault J-B, Liautard J-P, Lafon V (2005) Vγ9Vδ2 T cells use a combination of mechanisms to limit the spread of the pathogenic bacteria Brucella. J Leuk Biol 77:652–660
Ońate AA, Vemulapalli R, Andrews E, Schurig GG, Boyle S, Folch H (1999) Vaccination with live Escherichia coli expressing Brucella abortus Cu/Zn superoxide dismutase protects mice against virulent B. abortus. Infect Immun 67:986–988
Orme IM (1987) Age and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J Immunol 138:4414–4418
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
Ottones F, Dornand J, Naroenia A, Liautard J-P, Favero J (2000) Vγ9Vδ2 T cells impair intracellular multiplication of Brucella suis in autologous monocytes through soluble factor release and contact-dependent cytotoxic effect. J Immunol 165:7133–7139
Pawelec G, Solana R, Remarque E, Marian E (1998) Impact of aging on immunity. J Leuk Biol 64:703–712
Sakata-Keneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T (2000) Altered Th1/Th2 commitment in human CD4+ T cells with ageing, Clin Exp Immunol 120:267–273
Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R (2001). Toll-like receptors control activation of adaptive immune responses, Nature Immunol 2:947–950
Shearer GM (1997) Th1/Th2 changes in ageing, Mech Ageing Dev 94:1–5
Shimoni Z, Pitlik S, Leibovici L et al (1999) Nontyphoid Salmonella bacteremia: age-related differences in clinical presentation, bacteriology, and outcome. Clin Infect Dis 28:822–827
Tasat DR, Mancuso R, Evelson P, Polo JM, Llesuy S, Molinari B (2002) Radiation effects on oxidative metabolism in young and aged rat alveolar macrophages. Cell Mol Biol (Noisy-le-grand) 48:529–535
Turner J, Frank AA, Orme IM (2002) Old mice express a transiently early resistance to pulmonary tuberculosis that is mediated by CD8 T cells. Infect Immun 70:4628–4637
Vannier E, Borggraefe I, Tellford III SR, Menon S, Brauns T, Spielman A, Gelfand JA, Wortis HH (2004) Age-associated decline in resistance to Babesia microti is genetically determined. J Infect Dis 189:1721–1728
Vemulapalli R, He Y, Boyle SM, Sriranganathan N, Schurig GG (2000a) Brucella abortus strain RB51 as a vector for heterologous protein expression and induction of specific Th1 type immune responses. Infect Immun 68:3290–3296
Vemulapalli R, He Y, Cravero S, Sriranganathan N, Boyle SM, Schurig GG (2000b) Overexpression of protective antigen as a novel approach to enhance vaccine efficacy of Brucella abortus strain RB51. Infect Immun 68:3286–3289
Vemulapalli R, He Y, Sriranganathan N, Boyle SM, Schurig GG (2002) Brucella abortus RB51: enhancing vaccine efficacy and developing multivalent vaccines. Vet Microbiol 90:521–532
Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688
Ye P, Garvey PB, Zhang P et al (2001) Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol 25:335–340
Acknowledgements
The authors wish to thank Melissa Trader, Sherry Poff and Catherine B. Carlson for technical assistance. Financial Support: This work was supported by NIAID grant AI057952.
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High, K.P., Prasad, R., Marion, C.R. et al. Outcome and immune responses after Brucella abortus infection in young adult and aged mice. Biogerontology 8, 583–593 (2007). https://doi.org/10.1007/s10522-007-9106-6
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DOI: https://doi.org/10.1007/s10522-007-9106-6