Recent studies indicate that respiratory syncytial virus (RSV), like influenza, causes significant morbidity and mortality among elderly persons. There are currently no animal models to study the effects of aging on RSV disease and immunity. This manuscript provides an initial description of such a model. Aged and young BALB/c mice (22-24 and 2-4 months, respectively) were infected with 104 TCID50 of RSV A2. RSV was detected by culture in lung and nose wash specimens obtained 4-6 days following infection at a slightly higher titer in old mice in comparison with young mice. RT-PCR assay detected RSV in the lungs and nose washes of all mice on 4, 8, and 21 days postinoculation, with only a slightly less frequency in young mice. Splenic lymphocytes from old mice exhibited significantly lower RSV-specif ic MHC class I-restricted CD8+ CTL responses (P < 0.01-0001), and reduced IFN-production (P < 0.03) than young mice. Conversely, IL-4 production was somewhat elevated in old mice. These results demonstrate diminished RSV virus-specific CD8+ CTL responses and IFN-γ production in old mice in comparison with young. It is speculated that the deficient RSV-specific CTL responses may account for the Increased morbidity and mortality from RSV Infections in elderly persons. Although detailed hlstopathological, virological, and immunological analyses are incomplete at present, the old BALB/c RSV infection model described provides an opportunity to evaluate the role of CD8+ CTL and cytokines in RSV disease in aging.
FalseyAR, WalshEE. Relationship of serum antibody to risk of respiratory syncytial virus infection in elderly adults. J Infect Dis177: 463–466, 1998.
4.
FalseyAR, CunninghamCK, BarkerWH, KouidesRW, YuenJB, MenegusM, WeinerLB, BonvilleCA, BettsRF. Respiratory syncytial virus and influenza A infections in the hospitalized elderly. J Infect Dis172: 389–394, 1995.
5.
DrinkaPJ, GravensteinS, KrauseP, LangerEH, BarthelsL, DissingM, ShultP, SchillingM. Non-influenza respiratory viruses may overlap and obscure influenza activity. J Am Geriatr Soc47: 1087–1093, 1999.
6.
DrinkaPJ, GravensteinS, LangerE, KrauseP, ShultP. Mortality following isolation of various respiratory viruses in nursing home residents. Infect Control Hosp Epidemiol20: 812–815, 1999.
7.
GlezenWP, ParedesA, AllisonJE, TaberLH, FrankAL. Risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level. J Pediatr98: 708–715, 1981.
8.
FalseyAR, WalshEE. Humoral immunity to respiratory syncytial virus infection in the elderly. J Med Viral36: 39–43, 1992.
9.
FishautM, TubergenD, McintoshK. Cellular response to respiratory viruses with particular reference to children with disorders of cell-mediated immunity. J Pediatr96: 179–186, 1980.
WhimbeyE, ChamplinRE, EnglundJA, MirzaNQ, PiedraPA, GoodrichJM, PrzepiorkaD, LunaMA, MoriceRC, NeumannJL, . Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant16: 393–399, 1995.
12.
CouchRB, EnglundJA, WhimbeyE. Respiratory viral infections in immunocompetent and immunocompromised persons. Am J Med102:2–9; discussion 25–26, 1997.
13.
WongDT, OgraPL. Viral infections in immunocompromised patients. Med Clin North Am67: 1075–1092, 1983.
14.
CannonMJ, StottEJ, TaylorG, AskonasBA. Clearance of persistent respiratory syncytial virus infections in immunodeficient mice following transfer of primed T cells. Immunology62: 133–138, 1987.
15.
CannonMJ, OpenshawPJ, AskonasBA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med168: 1163–1168, 1988.
16.
WongDT, RosenbandM, HoveyK, OgraPL. Respiratory syncytial virus infection in immunosuppressed animals: implications in human infection. J Med Virol17: 359–370, 1985.
17.
AndersonLJ, TsouC, PotterC, KeyserlingHL, SmithTF, AnanabaG, BanghamCR. Cytokine response to respiratory syncytial virus stimulation of human peripheral blood mononuclear cells. J Infect Dis170: 1201–1208, 1994.
18.
RomanM, CalhounWJ, HintonKL, AvendanoLF, SimonV, EscobarAM, GaggeroA, DiazPV. Respiratory syncytial virus infection in infants is associated with predominant Th-2-like response. Am J Respir Crit Care Med156: 190–195, 1997.
19.
ThurauAM, StreckertHJ, RiegerCH, SchauerU. Increased number of T cells committed to IL-5 production after respiratory syncytial virus (RSV) infection of human mononuclear cells in vitro. Clin Exp Immunol113: 450–455, 1998.
20.
SheeranP, JafriH, CarubelliC, SaavedraJ, JohnsonC, KrisherK, SanchezPJ, RamiloO. Elevated cytokine concentrations in the nasopharyngeal and tracheal secretions of children with respiratory syncytial virus disease. Pediatr Infect Dis J18: 115–122, 1999.
21.
MbawuikeIN, LangeAR, CouchRB. Diminished influenza A virus-specific MHC class I-restricted cytotoxic T lymphocyte activity among elderly persons. Viral Immunol6: 55–64, 1993.
22.
MbawuikeIN, AcunaCL, WalzKC, AtmarRL, GreenbergSB, CouchRB. Cytokines and impaired CD8+ CTL activity among elderly persons and the enhancing effect of IL-12. Mech Aging Dev94: 25–39, 1997.
23.
PowersDC, BelsheRB. Effect of age on cytotoxic T lymphocyte memory as well as serum and local antibody responses elicited by inactivated influenza virus vaccine. J Infect Dis167: 584–592, 1993.
24.
PowersDC. Influenza A virus-specific cytotoxic T lymphocyte activity declines with advancing age. J Am Geriatr Soc41: 1–5, 1993.
25.
MbawuikeIN, AcunaC, CaballeroD, Pham-NguyenK, GilbertB, PetribonP, HarmonM. Reversal of age-related deficient influenza virus-specific CTL responses and IFN-γ production by monophosphoryl lipid A. Cell Immunol173: 64–78, 1996.
26.
MbawuikeIN, WydePR, AndersonPM. Enhancement of the protective efficacy of inactivated influenza A virus vaccine in aged mice by IL-2 liposomes. Vaccine8: 347–352, 1990.
27.
ZhangY, AcunaCL, SwitzerKC, SongL, SayersR, MbawuikeIN. Corrective effects of interleukin-12 on age-related deficiencies in IFN-γ production and IL-12 Rbeta2 expression in virus-specific CD8+ T cells. J Interferon Cytokine Res20: 235–245, 2000.
28.
GrahamBS, PerkinsMD, WrightPF, KarzonDT. Primary respiratory syncytial virus infection in mice. J Med Virol26: 153–162, 1988.
29.
GrahamBS, BuntonLA, WrightPF, KarzonDT. Reinfection of mice with respiratory syncytial virus. J Med Virol34: 7–13, 1991.
30.
MbawuikeIN, WellsJ, ByrdR, CronSG, GlezenWP, PiedraPA. HLA-Restricted CD8+ cytotoxic T lymphocyte, interferon-γ, and interleukin-4 responses to respiratory syncytial virus infection in infants and children. J Infect Dis183: 687–696, 2001.
31.
PiedraPA, GlezenWP, KaselJA, WelliverRC, JewelAM, RayfordY, HogermanDA, HildrethSW, ParadisoPR. Safety and immunogenicity of the PFP vaccine against respiratory syncytial virus (RSV): the western blot assay aids in distinguishing immune responses of the PFP vaccine from RSV infection. Vaccine13: 1095–1101, 1995.
32.
KadoG. Relative sensitivity of three cell substrates to the Sabin poliovirus strains. Dev Biol Stand37: 261–264, 1976.
33.
PatonAW, PatonJC, LawrenceAJ, GoldwaterPN, HarrisRJ. Rapid detection of respiratory syncytial virus in nasopharyngeal aspirates by reverse transcription and polymerase chain reaction amplification. J Clin Microbiol30: 901–904, 1992.
34.
HenkelJH, AberleSW, KundiM, Popow-KrauppT. Improved detection of respiratory syncytial virus in nasal aspirates by seminested RT-PCR. J Med Virol53: 366–371, 1997.
35.
StocktonJ, EllisJS, SavilleM, ClewleyJP, ZambonMC. Multiplex PCR for typing and subtyping influenza and respiratory syncytial viruses. J Clin Microbiol36: 2990–2995, 1998.
36.
IsaacsD, TaylorCJ, TingA, McMichaelAJ. HLA class I antigens in severe RSV bronchiolitis. Tissue Antigens34: 210–212, 1989.
37.
BanghamCR, OpenshawPJ, BallLA, KingAM, WertzGW, AskonasBA. Human and murine cytotoxic T cells specific to respiratory syncytial virus recognize the viral nucleoprotein (N), but not the major glycoprotein (G), expressed by vaccinia virus recombinants. J Immunol137: 3973–3977, 1986.
GrahamBS, BuntonLA, WrightPF, KarzonDT. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest88: 1026–1033, 1991.
41.
SrikiatkhachornA, BracialeTJ. Virus-specific CD8+ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. J Exp Med186: 421–432, 1997.
42.
KulkarniAB, ConnorsM, FirestoneCY, MorseHCd, MurphyBR. The cytolytic activity of pulmonary CD8+ lymphocytes, induced by infection with a vaccinia virus recombinant expressing the M2 protein of respiratory syncytial virus (RSV), correlates with resistance to RSV infection in mice. J Virol67: 1044–1049, 1993.
43.
ConnorsM, KulkarniAB, FirestoneCY, HolmesKL, MorseHCIII, SotnikovAV, MurphyBR. Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells. J Virol66: 7444–7451, 1992.
TangYW, GrahamBS. Anti-IL-4 treatment at immunization modulates cytokine expression, reduces illness, and increases cytotoxic T lymphocyte activity in mice challenged with respiratory syncytial virus. J Clin Invest94: 1953–1958, 1994.
46.
FischerJE, JohnsonJE, Kuli-ZadeRK, JohnsonTR, AungS, ParkerRA, GrahamBS. Overexpression of interleukin-4 delays virus clearance in mice infected with respiratory syncytial virus. J Virol71: 8672–8677, 1997.
47.
Plotnicky-GilquinH, RobertA, ChevaletL, HaeuwJF, BeckA, BonnefoyJY, BrandtC, SiegristCA, NguyenTN, PowerUF. CD4+ T-cell-mediated antiviral protection of the upper respiratory tract in BALB/c mice following parenteral immunization with a recombinant respiratory syncytial virus G protein fragment. J Virol74: 3455–3463, 2000.
48.
AlwanWH, RecordFM, OpenshawPJ. CD4+ cells clear virus but augment disease in mice infected with respiratory syncytial virus: comparison with the effects of CD8+ T cells. Clin Exp Immunol88: 527–536, 1992.
