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*
Children’s Research Institute, Children’s Hospital, Columbus, OH 43205;
Division of Pediatric Pathology, Department of Pediatrics, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210;
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892
Formalin-inactivated respiratory syncytial virus (RSV) vaccine
preparations have been shown to cause enhanced disease in naive hosts
following natural infection. In this study we demonstrate a similar
pattern of enhanced disease severity following primary RSV infection of
IFN-nonresponsive STAT1-/- mice. STAT1-/-
mice showed markedly increased illness compared with wild-type BALB/c
animals following RSV inoculation despite similar lung virus titers and
rates of virus clearance. Histologically, STAT1-/-
animals had eosinophilic and neutrophilic pulmonary infiltrates not
present in wild-type or IFN-
-/--infected mice. In
cytokine analyses of infected lung tissue, IFN- was induced in both
STAT1-/- and wild-type mice, with preferential IL-4,
IL-5, and IL-13 induction only in the STAT1-/- animals.
Eotaxin was detected in the lungs of both wild-type and
STAT1-/- mice following infection, with a 1.7-fold
increase over wild-type in the STAT1-/- mice. Using a
peptide epitope newly identified in the RSV fusion protein, we were
able to demonstrate that wild-type memory CD4+ T cells
stimulated by this peptide produce primarily IFN-, while
STAT1-/-CD4+ cells produce primarily IL-13.
These findings suggest that STAT1 activation by both type I (
)
and type II () IFNs plays an important role in establishing a
protective, Th1 Ag-specific immune response to RSV
infection.
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