A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense
Thais P. Salazar-Mather, Thomas A. Hamilton, Christine A. Biron
Thais P. Salazar-Mather, Thomas A. Hamilton, Christine A. Biron
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A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense

Abstract

Macrophage inflammatory protein 1α (MIP-1α) promotes natural killer (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) infections, and NK cell–produced interferon γ (IFN-γ) contributes to defense against MCMV infections. A specific role for local NK cell IFN-γ production, however, has not been established. The importance of MIP-1α and NK cell–produced IFN-γ in shaping endogenous immune responses and defense in different compartments was examined. MIP-1α deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-γ production in liver. MIP-1α–independent IFN-γ responses were observed in serum and spleen, and infection-induced elevations in blood NK cell populations occurred in absence of the factor, but peak liver expression of another chemokine, the monokine induced by IFN-γ (Mig), depended upon presence of MIP-1α, NK cells, and IFN-γ. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-1α is critical for NK cell migration and IFN-γ delivery to mediate protection; and Mig induction in tissues is a downstream protective response resulting from the process. These results define a critical chemokine-to-cytokine-to-chemokine cascade required for defense during a viral infection establishing itself in tissues.

Authors

Thais P. Salazar-Mather, Thomas A. Hamilton, Christine A. Biron

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Induction of Mig protein expression. Livers were harvested from uninfect...
Induction of Mig protein expression. Livers were harvested from uninfected or 36 and 48-hour MCMV-infected MIP-1α+ and MIP-1α– mice, or 48-hour MCMV-infected C57BL/6-SCID mice. Tissue sections were prepared and immunohistochemically stained as described in Methods. The Mig protein is identified by dark blue precipitates. Tissues are counterstained with methyl green. Results shown are from (a) MIP-1α+ mice after 36 hours of MCMV infection, (b) MIP-1α– mice after 36 hours of MCMV infection, (c and e) MIP-1α+ mice after 48 hours of MCMV infection, (d and f) MIP-1α– mice after 48 hours of MCMV infection, (g) uninfected MIP-1α+, and (h) C57BL/6-SCID mice after 48 hours of MCMV infection. Photographs were taken at magnifications of ×31.25 (a–d, g, h) or ×125 (e, f).