A mechanism for the inhibition of fever by a virus.

Abstract

Poxviruses encode proteins that block the activity of cytokines. Here we show that the study of such virulence factors can contribute to our understanding of not only virus pathogenesis but also the physiological role of cytokines. Fever is a nonspecific response to infection that contributes to host defense. Several cytokines induce an elevation of body temperature when injected into animals, but in naturally occurring fever it has been difficult to show that any cytokine has a critical role. We describe the first example of the suppression of fever by a virus and the molecular mechanism leading to it. Several vaccinia virus strains including smallpox vaccines express soluble interleukin 1 (IL-1) receptors, which bind IL-1p but not IL-la. These viruses prevent the febrile response in infected mice, whereas strains that naturally or through genetic engineering lack the receptor induce fever. Repair of the defective IL-18 inhibitor in the smallpox vaccine Copenhagen, a more virulent virus than the widely used vaccine strains Wyeth and Lister, suppresses fever and attenuates the disease. The vaccinia-induced fever was inhibited with antibodies to IL-lp. These findings provide strong evidence that IL-118, and not other cytokines, is the major endogenous pyrogen in a poxvirus infection. cies of postvaccinial complications, but the reasons are unknown (6).Poxviruses encode many proteins that interfere with host immune functions (7,8), such as soluble cytokine receptors that blockade cytokines and modulate virus virulence (9). The VV IL-1,B receptor (vIL-103R) is encoded by gene B15R in the Western Reserve (WR) strain (10), and binds IL-1l3 with high affinity, but not IL-la or IL-1 receptor antagonist (11). Inactivation of the B15R gene from VV WR decreases virus virulence in mice after intracranial injection (12) but enhances virus virulence when administered intranasally (11). These contradictory results might be explained by either deletion mutant virus having additional mutations affecting virus virulence or, alternatively, may reflect the properties of IL-ll3, a cytokine that induces beneficial effects but is detrimental when produced in large amounts (13). Since a natural route of poxvirus infections is the respiratory tract (4), the vIL-lf3R may function to prevent the adverse effects of excessive IL-1,B.Here we report that the WR vIL-lf3R prevents the febrile response in intranasally infected mice. In this model, smallpox vaccine strains lacking the vIL-lf3R induced fever, and repair of the nonfunctional vIL-l,BR in strain Copenhagen prevented fever and attenuated virus virulence.Fever is an ancient nonspecific systemic response to infection, which is conserved in both invertebrates and vertebrates (1). Temperature elevation during fever constitutes a component of host defense that increases host survival and enhances different arms of the inflammatory and immune responses, such as T-cell proliferation and differentiation, secretion of interferons (IFNs), neutrophil migration, and the neutralizing capa...

TLR3 Increases Disease Morbidity and Mortality from Vaccinia Infection

“…Both genotypes of mice were hypothermic on days 5 and 6 postinfection (Fig. 1D), consistent with previous studies showing that mice lose body temperature after infection with vaccinia (22). Notably, TLR3…”

Soluble receptors in human disease

“…Several vaccinia strains express soluble IL-1 receptors that bind to IL-1␤ but not to IL-1␣. When the gene encoding the viral soluble IL-1 receptor is disrupted, infected mice develop fever [139]. A viral strain of human smallpox vaccine that normally causes fever was found to have a mutation in the viral soluble IL-1 receptor.…”

“…The soluble receptors also appear to be important in viral pathogenesis. When the genes encoding either the soluble IL-1 receptor or the soluble IFN receptor are disrupted in vaccinia virus, the virus is attenuated [136,139]. Several vaccinia strains express soluble IL-1 receptors that bind to IL-1␤ but not to IL-1␣.…”

Deletion of Specific Immune-Modulatory Genes from Modified Vaccinia Virus Ankara-Based HIV Vaccines Engenders Improved Immunogenicity in Rhesus Macaques

“…We therefore targeted for deletion those genes encoding a secreted interleukin-18 (IL-18) binding protein (MVA008L) (75,80), a soluble IL-1␤ receptor (MVA184R) (3,76), a CC-chemokine binding protein (MVA153L) (7,62), and a dominant negative Toll/IL-1 signaling adapter (MVA159R) (13,77). The biological activities of these factors can be inferred by the fact that deletions of their orthologs from replication-competent strains of vaccinia virus result in altered pathogenic phenotypes in murine models (2,62,74,77,80). Additionally, the observation that MVA recombinants lacking MVA184R and/or MVA153L may elicit modestly augmented CD8 T cell responses in mice indicates that the deletion of immune-modulatory genes from MVA-based vaccines is a relevant approach toward improving vaccine immunogenicity (18,21,32,78).…”