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in Virus Infection-Induced Sensitization to Endotoxin1
Departments of
*
Pediatrics and
Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912; and
Division of Pediatric Pathology, Department of Pediatrics, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
Underlying viral infections can heighten sensitivity and worsen
cytokine-mediated disease following secondary inflammatory challenges.
Mechanisms for this are poorly understood. The impact of the innate
response to lymphocytic choriomeningitis virus (LCMV) infection on
sensitivity to endotoxin (LPS) was investigated. Compared with
uninfected mice, infection with LCMV for 2-days-sensitized mice to LPS
by 
2-fold for lethality and by 2- to 6-fold for serum TNF-
levels. Priming for LPS-induced TNF- was also seen with splenic and
peritoneal leukocytes isolated from infected mice and challenged with
LPS ex vivo. The effect on TNF- production was present in the
absence of IFN-
, its major producers NK and T cells, and the major
pathways for its induction through IL-12 and the signal transducer and
activator of transcription 4 (STAT4), and therefore was IFN-
independent. Early LCMV infection induces high concentrations of the
type 1 IFNs, IFN-
. Administration of recombinant IFN- alone
heightened the TNF- response to LPS. Innate IFN- and IFN-
responses to LCMV exist in a delicate balance. To reduce priming for
LPS-induced TNF- during LCMV, deficiencies in both the IFN-
and IFN- receptors or STAT1, a transcription factor downstream to
both IFNs, were required. These data demonstrate that early viral
infection can enhance sensitivity to bacterial products, and that this
sensitization can occur in part as a result of endogenously expressed
IFN-. This work also raises issues about potential complications
associated with IFN- therapies.
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