Human cancer cells have specifically lost the ability to induce the synergistic state caused by tumor necrosis factor plus interferon-β

Bartee, Eric; McFadden, Grant

doi:10.1016/j.cyto.2009.06.006

Cited by 46 publications

(58 citation statements)

References 13 publications

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“…We thus infected HFs with CHIKV at an MOI of 10 as described above. At 4,8,16, and 24 h postinfection, the cell culture media was replaced ("pulsed") with medium containing puromycin for 15 min and "chased" for 60 min with puromycin-free medium, after which whole-cell lysates were harvested and subjected to SDS-PAGE. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and Protein Kinase R-Independent Translational Shutoff

White

Sali

Alvarado

et al. 2011

J Virol

115

125

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Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that is undergoing reemergence in areas around the Indian Ocean. Despite the current and potential danger posed by this virus, we know surprisingly little about the induction and evasion of CHIKV-associated antiviral immune responses. With this in mind we investigated innate immune reactions to CHIKV in human fibroblasts, a demonstrable in vivo target of virus replication and spread. We show that CHIKV infection leads to activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent transcription of IRF3-dependent antiviral genes, including beta interferon (IFN-␤). IRF3 activation occurs by way of a virus-induced innate immune signaling pathway that includes the adaptor molecule interferon promoter stimulator 1 (IPS-1). Despite strong transcriptional upregulation of these genes, however, translation of the corresponding proteins is not observed. We further demonstrate that translation of cellular (but not viral) genes is blocked during infection and that although CHIKV is found to trigger inactivation of the translational molecule eukaryotic initiation factor subunit 2␣ by way of the double-stranded RNA sensor protein kinase R, this response is not required for the block to protein synthesis. Furthermore, overall diminution of cellular RNA synthesis is also observed in the presence of CHIKV and transcription of IRF3-dependent antiviral genes appears specifically blocked late in infection. We hypothesize that the observed absence of IFN-␤ and antiviral proteins during infection results from an evasion mechanism exhibited by CHIKV that is dependent on widespread shutoff of cellular protein synthesis and a targeted block to late synthesis of antiviral mRNA transcripts. Tanzania in 1953 (52, 69). The virus causes an acute febrile illness associated with severe joint pain that can persist long after viral clearance (9,26,42,47,49,62,68,75). In 2005 and 2006 CHIKV reemerged on a number of Indian Ocean islands and subsequently in India in 2006 and 2007 (78). Since these locations are popular tourist destinations, such outbreaks represent significant threats to European countries from travelerassociated infections. Because the virus is transmitted most commonly via mosquitoes (23, 67), changing patterns of vector distribution and abundance in response to climate change (36) and increased vector-human contact following human encroachment into undeveloped areas renders CHIKV an emerging pathogen of high potential danger for future generations. Unfortunately, information regarding many basic aspects of CHIKV molecular biology, immunology, and pathology are lacking. Chikungunya virus (CHIKV) was first isolated inCHIKV is a member of the family Togaviridae and genus Alphavirus. The enveloped virion contains an icosahedral nucleocapsid and an ϳ12-kb plus-strand single-stranded RNA genome that includes a 5Ј cap and 3Ј polyadenylation. The genome includes two open reading frames (ORFs) separately encoding polyproteins th...

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Section: Resultsmentioning

confidence: 99%

“…HFs were grown on coverslips in 24-well plates and treated as described above. The cells were washed twice with PBS, fixed for 30 min in 3.7% formaldehyde, washed, and quenched for 10 min using 50 mM NH 4 Cl. Cells were permeabilized with 0.1% Triton X-100 for 7 min and washed three times with PBS containing 2% bovine serum albumin (BSA).…”

mentioning

confidence: 99%

Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and Protein Kinase R-Independent Translational Shutoff

White

Sali

Alvarado

et al. 2011

J Virol

115

125

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“…2–7 Yet, MYXV productively infects cultured cancer cells from several species. 8–11 Although MYXV-encoded protein expression has been observed in noncancerous cells after intracranial injection of recombinant MYXV, protein expression is transient and no clinical disease is observed.…”

Section: Introductionmentioning

confidence: 99%

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

Doty¹,

Liu²,

McFadden³

et al. 2013

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Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy.

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“…The host range determinants that mediate this cancer-specific tropism of MYXV outside the rabbit host are still being investigated, but at least two different intracellular pathways have been implicated in this cellular discrimination to date: (i) the failure of many cancer cells to induce an effective antiviral response, such as the synergistic interferon and tumor necrosis factor pathway that effectively aborts MYXV replication in primary nontransformed human cells (18,19), and (ii) the constitutive activation of Akt in many cancer cells that favors permissive virus replication (20,21). We have also recently shown that MYXV can selectively infect and kill primary human leukemic stem and progenitor cells while sparing normal human stem and progenitor cells derived from bone marrow in terms of differentiation potential in vitro and the ability to engraft recipient NOD/ scid/IL2 receptor gamma-chain knockout (NSG) mice in vivo (22).…”

mentioning

confidence: 99%

Myxoma and Vaccinia Viruses Bind Differentially to Human Leukocytes

Chan

Bartee²,

Moreb

et al. 2013

J Virol

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Human cancer cells have specifically lost the ability to induce the synergistic state caused by tumor necrosis factor plus interferon-β

Cited by 46 publications

References 13 publications

Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and Protein Kinase R-Independent Translational Shutoff

Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and Protein Kinase R-Independent Translational Shutoff

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

Myxoma and Vaccinia Viruses Bind Differentially to Human Leukocytes

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