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Comparative Study
. 2009 Dec;22(6):457-62.
doi: 10.1089/vim.2009.0034.

Attenuated and lethal variants of Pichindé virus induce differential patterns of NF-kappaB activation suggesting a potential target for novel therapeutics

Gavin C Bowick  1 , Susan M Fennewald, Lihong Zhang, Xianbin Yang, Judith F Aronson, Robert E Shope, Bruce A Luxon, David G Gorenstein, Norbert K Herzog
Affiliations
Comparative Study

Attenuated and lethal variants of Pichindé virus induce differential patterns of NF-kappaB activation suggesting a potential target for novel therapeutics

Gavin C Bowick et al. Viral Immunol. 2009 Dec.

Abstract

Lassa virus pathogenesis is believed to involve dysregulation of cytokines. We have previously shown nuclear factor-kappaB (NF-kappaB) inhibition using a BSL-2 model for Lassa fever. Here we further define the potential mechanism for NF-kappaB inhibition as involving increased levels of repressive p50/p50 homodimers, and suggest a novel therapeutic strategy that acts via modulation of host signaling.

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Figures

FIG. 1.
FIG. 1.
DNA-binding activity of NF-κB family members. We used 5 μg of nuclear extracts from mock, P2, and P18 PICV-infected cells to assay DNA binding of NF-κB p65 and p50 to the κB consensus site in vitro. (A) The bar graphs show the results from three independent infections. Error bars show the standard error of the mean. Data are normalized to the DNA-binding activity of a triplicate set of nuclear extracts from time-point zero. Asterisks indicate significant differences (p <0.05 by Students T-test). (B) Line graph representations are used to illustrate the oscillatory nature of the responses. The y axis shows absorbance, and the x axis is hours post-infection.
FIG. 2.
FIG. 2.
PICV infection increases expression of NF-κB p50. Quadruplicate cultures of mock, P2, and P18 PICV-infected cells were harvested in SDS-PAGE loading buffer at 24 h post-infection, and total levels of p50 were detected by immunoblotting. (A) Levels of p50 in infected cells were calculated relative to levels in mock-infected cells by densitometry (n = 4). (B) A cell-based phospho-specific ELISA was used to investigate Src phosphorylation in vitro over the time-course of infection. Error bars show the standard error of the mean (n = 3). Statistically significant differences between P2 and P18 are shown by an asterisk (Student's t-test, p < 0.05). (C) Murine macrophage-like P388D1 cells were stimulated with poly(I:C) following treatment with XBY-6 or liposomes alone. Supernatant levels of TNF-α and IL-12p40 were assayed by ELISA. (D) Guinea pigs (n = 6 per group) were treated with thioaptamer XBY-6 in liposomes as described in (12), with either XBY-6 thioaptamer targeting NF-κB p50/p50 (XBY), a control (scrambled) thioaptamer B92 (B92), liposomes alone (LIPO), or no treatment (omitted here for clarity, but described in the text).
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