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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Chronic spinal cord injury attenuates influenza virus-specific antiviral immunity

Authors: Valerie Bracchi-Ricard, Ji Zha, Annalise Smith, Darlah M. Lopez-Rodriguez, John R. Bethea, Samita Andreansky

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Individuals suffering from spinal cord injury (SCI) are at higher risk for respiratory-related viral infections such as influenza. In a previous study (Zha et al., J Neuroinflammation 11:65, 2014), we demonstrated that chronic spinal cord injury caused impairment in CD8+T cell function with increased expression of the immunosuppressive protein, programmed cell death 1 (PD-1). The present study was undertaken to establish whether chronic SCI-induced immune deficits would affect antiviral immunity directed against primary and secondary infections.

Methods

Six to seven weeks following a SCI contusion at thoracic level T9, mice were infected intranasally with influenza virus. Virus-specific immunity was analyzed at various time points post-infection and compared to uninjured controls.

Results

We report that chronic thoracic SCI impairs the ability of the animals to mount an adequate antiviral immune response. While all uninjured control mice cleared the virus from their lungs by day 10 post-infection, a significant number (approximately 70 %) of chronic SCI mice did not clear the virus and succumbed to infection-induced mortality. This was attributed to severe deficits in both virus-specific antibody production and CD8+ T cell response in injured mice after primary infection. We also determined that previously acquired humoral immunity was maintained after spinal cord injury as vaccination against influenza A prior to injury-protected mice from a homologous viral challenge. In contrast, prior immunization did not protect mice from a heterotypic challenge with a different strain of influenza virus.

Conclusions

Taken together, our data demonstrate that chronic SCI attenuates virus-specific humoral and cellular immunity during the establishment of primary response and impairs the development of memory CD8+ T cells. In contrast, B cell memory acquired through vaccination prior to SCI is preserved after injury which demonstrates that antigen-specific memory cells are refractory following injury. Our study defines important parameters of the deficits of chronic SCI-induced immune depression during a viral respiratory infection. Our objective is to better understand the mechanisms of spinal cord injury-induced immune depression with the goal of developing more effective therapies and reduce mortality due to complications from influenza and other infections.
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Literature
1.
Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005;6(10):775–86.CrossRefPubMed
2.
Failli V, Kopp MA, Gericke C, Martus P, Klingbeil S, Brommer B, Laginha I, Chen Y, DeVivo MJ, Dirnagl U, et al. Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain. 2012;135(Pt 11):3238–50.CrossRefPubMed
3.
Soden RJ, Walsh J, Middleton JW, Craven ML, Rutkowski SB, Yeo JD. Causes of death after spinal cord injury. Spinal Cord. 2000;38(10):604–10.CrossRefPubMed
4.
Held KS, Steward O, Blanc C, Lane TE. Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection. Exp Neurol. 2010;226(1):242–53.CrossRefPubMed
5.
Nash MS. Known and plausible modulators of depressed immune functions following spinal cord injuries. J Spinal Cord Med. 2000;23(2):111–20.PubMed
6.
Lucin KM, Sanders VM, Jones TB, Malarkey WB, Popovich PG. Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp Neurol. 2007;207(1):75–84.CrossRefPubMedPubMedCentral
7.
8.
Riegger T, Conrad S, Liu K, Schluesener HJ, Adibzahdeh M, Schwab JM. Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur J Neurosci. 2007;25(6):1743–7.CrossRefPubMed
9.
Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S, Huang K, Weil Z, Bratasz A, Wells J, Powell ND, et al. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J Neurosci. 2013;33(32):12970–81.CrossRefPubMedPubMedCentral
10.
Oropallo MA, Held KS, Goenka R, Ahmad SA, O’Neill PJ, Steward O, Lane TE, Cancro MP. Chronic spinal cord injury impairs primary antibody responses but spares existing humoral immunity in mice. J Immunol. 2012;188(11):5257–66.CrossRefPubMedPubMedCentral
11.
Zha J, Smith A, Andreansky S, Bracchi-Ricard V, Bethea JR. Chronic thoracic spinal cord injury impairs CD8+ T-cell function by up-regulating programmed cell death-1 expression. J Neuroinflammation. 2014;11:65.CrossRefPubMedPubMedCentral
12.
Brommer B, Engel O, Kopp MA, Watzlawick R, Muller S, Pruss H, Chen Y, DeVivo MJ, Finkenstaedt FW, Dirnagl U, et al. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain. 2016;139:692.CrossRefPubMed
13.
DeVivo MJ, Black KJ, Stover SL. Causes of death during the first 12 years after spinal cord injury. Arch Phys Med Rehabil. 1993;74(3):248–54.PubMed
14.
DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and causes of death among persons with spinal cord injury. Arch Phys Med Rehabil. 1999;80(11):1411–9.CrossRefPubMed
15.
Osterthun R, Post MW, van Asbeck FW, van Leeuwen CM, van Koppenhagen CF. Causes of death following spinal cord injury during inpatient rehabilitation and the first five years after discharge. A Dutch cohort study. Spinal Cord. 2014;52(6):483–8.CrossRefPubMed
16.
Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, Vugia D, Harriman K, Matyas B, Glaser CA, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA. 2009;302(17):1896–902.CrossRefPubMed
17.
Kreijtz JH, Fouchier RA, Rimmelzwaan GF. Immune responses to influenza virus infection. Virus Res. 2011;162(1–2):19–30.CrossRefPubMed
18.
19.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412.CrossRefPubMedPubMedCentral
20.
Kilbourne ED. Future influenza vaccines and the use of genetic recombinants. Bull World Health Organ. 1969;41(3):643–5.PubMedPubMedCentral
21.
Flano E, Jewell NA, Durbin RK, Durbin JE. Methods used to study respiratory virus infection. Curr Protoc Cell Biol. 2009;Chapter 26:Unit 26 23.
22.
Hall JD, Woolard MD, Gunn BM, Craven RR, Taft-Benz S, Frelinger JA, Kawula TH. Infected-host-cell repertoire and cellular response in the lung following inhalation of Francisella tularensis Schu S4, LVS, or U112. Infect Immun. 2008;76(12):5843–52.CrossRefPubMedPubMedCentral
23.
Webby RJ, Andreansky S, Stambas J, Rehg JE, Webster RG, Doherty PC, Turner SJ. Protection and compensation in the influenza virus-specific CD8+ T cell response. Proc Natl Acad Sci U S A. 2003;100(12):7235–40.CrossRefPubMedPubMedCentral
24.
Andreansky SS, Stambas J, Thomas PG, Xie W, Webby RJ, Doherty PC. Consequences of immunodominant epitope deletion for minor influenza virus-specific CD8 + -T-cell responses. J Virol. 2005;79(7):4329–39.CrossRefPubMedPubMedCentral
25.
Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996;274(5284):94–6.CrossRefPubMed
26.
Townsend AR, Rothbard J, Gotch FM, Bahadur G, Wraith D, McMichael AJ. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986;44(6):959–68.CrossRefPubMed
27.
Belz GT, Xie W, Altman JD, Doherty PC. A previously unrecognized H-2D(b)-restricted peptide prominent in the primary influenza A virus-specific CD8(+) T-cell response is much less apparent following secondary challenge. J Virol. 2000;74(8):3486–93.CrossRefPubMedPubMedCentral
28.
Allan W, Tabi Z, Cleary A, Doherty PC. Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J Immunol. 1990;144(10):3980–6.PubMed
29.
Swain SL, Dutton RW, Woodland DL. T cell responses to influenza virus infection: effector and memory cells. Viral Immunol. 2004;17(2):197–209.CrossRefPubMed
30.
31.
Allen IC, Scull MA, Moore CB, Holl EK, McElvania-TeKippe E, Taxman DJ, Guthrie EH, Pickles RJ, Ting JP. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30(4):556–65.CrossRefPubMedPubMedCentral
32.
33.
Maines TR, Szretter KJ, Perrone L, Belser JA, Bright RA, Zeng H, Tumpey TM, Katz JM. Pathogenesis of emerging avian influenza viruses in mammals and the host innate immune response. Immunol Rev. 2008;225:68–84.CrossRefPubMed
34.
Coro ES, Chang WL, Baumgarth N. Type I IFN receptor signals directly stimulate local B cells early following influenza virus infection. J Immunol. 2006;176(7):4343–51.CrossRefPubMed
35.
Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14(3):167–82.CrossRefPubMed
36.
37.
Topham DJ, Tripp RA, Doherty PC. CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J Immunol. 1997;159(11):5197–200.PubMed
38.
La Gruta NL, Kedzierska K, Stambas J, Doherty PC. A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol. 2007;85(2):85–92.CrossRefPubMed
39.
Goldstein B, Weaver FM, Hammond MC. New CDC recommendations: annual influenza vaccination recommended for individuals with spinal cord injuries. J Spinal Cord Med. 2005;28(5):383–4.PubMedPubMedCentral
40.
Kirchenbaum GA, Ross TM. Eliciting broadly protective antibody responses against influenza. Curr Opin Immunol. 2014;28:71–6.CrossRefPubMed
41.
42.
Rimmelzwaan GF, Fouchier RA, Osterhaus AD. Influenza virus-specific cytotoxic T lymphocytes: a correlate of protection and a basis for vaccine development. Curr Opin Biotechnol. 2007;18(6):529–36.CrossRefPubMed
43.
Doherty PC, Turner SJ, Webby RG, Thomas PG. Influenza and the challenge for immunology. Nat Immunol. 2006;7(5):449–55.CrossRefPubMed
44.
Lorton D, Bellinger DL. Molecular mechanisms underlying beta-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015;16(3):5635–65.CrossRefPubMedPubMedCentral
45.
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52(4):595–638.PubMed
46.
Allison DJ, Ditor DS. Immune dysfunction and chronic inflammation following spinal cord injury. Spinal Cord. 2015;53(1):14–8.CrossRefPubMed
47.
Inskip JA, Ramer LM, Ramer MS, Krassioukov AV. Autonomic assessment of animals with spinal cord injury: tools, techniques and translation. Spinal Cord. 2009;47(1):2–35.CrossRefPubMed
48.
Gerhard W. The role of the antibody response in influenza virus infection. Curr Top Microbiol Immunol. 2001;260:171–90.PubMed
49.
Ito R, Ozaki YA, Yoshikawa T, Hasegawa H, Sato Y, Suzuki Y, Inoue R, Morishima T, Kondo N, Sata T, et al. Roles of anti-hemagglutinin IgA and IgG antibodies in different sites of the respiratory tract of vaccinated mice in preventing lethal influenza pneumonia. Vaccine. 2003;21(19-20):2362–71.CrossRefPubMed
50.
Tamura S, Tanimoto T, Kurata T. Mechanisms of broad cross-protection provided by influenza virus infection and their application to vaccines. Jpn J Infect Dis. 2005;58(4):195–207.PubMed
51.
Justewicz DM, Doherty PC, Webster RG. The B-cell response in lymphoid tissue of mice immunized with various antigenic forms of the influenza virus hemagglutinin. J Virol. 1995;69(9):5414–21.PubMedPubMedCentral
52.
Belz GT, Wodarz D, Diaz G, Nowak MA, Doherty PC. Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice. J Virol. 2002;76(23):12388–93.CrossRefPubMedPubMedCentral
53.
Turner DL, Bickham KL, Farber DL, Lefrancois L. Splenic priming of virus-specific CD8 T cells following influenza virus infection. J Virol. 2013;87(8):4496–506.CrossRefPubMedPubMedCentral
54.
Moskophidis D, Kioussis D. Contribution of virus-specific CD8+ cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model. J Exp Med. 1998;188(2):223–32.CrossRefPubMedPubMedCentral
55.
Altenburg AF, Rimmelzwaan GF, de Vries RD. Virus-specific T cells as correlate of (cross-)protective immunity against influenza. Vaccine. 2015;33(4):500–6.CrossRefPubMed
56.
Gotch F, McMichael A, Smith G, Moss B. Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes. J Exp Med. 1987;165(2):408–16.CrossRefPubMed
57.
58.
Kopp MA, Druschel C, Meisel C, Liebscher T, Prilipp E, Watzlawick R, Cinelli P, Niedeggen A, Schaser KD, Wanner GA, et al. The SCIentinel study—prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS)—study protocol and interim feasibility data. BMC Neurol. 2013;13:168.CrossRefPubMedPubMedCentral
Metadata
Title
Chronic spinal cord injury attenuates influenza virus-specific antiviral immunity
Authors
Valerie Bracchi-Ricard
Ji Zha
Annalise Smith
Darlah M. Lopez-Rodriguez
John R. Bethea
Samita Andreansky
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0574-y

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