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Enhancement of oncolytic properties of recombinant newcastle disease virus through antagonism of cellular innate immune responses.

ABSTRACT: Newcastle disease virus (NDV) has been previously shown to possess oncolytic activity, causing specific lysis of cancerous but not normal cells. Here we show that despite these findings, the oncolytic efficiency of naturally occurring NDV strains can still be relatively low, as many tumors exhibit strong innate immune responses that suppress viral replication and spread. To overcome this problem, we generated a recombinant fusogenic NDV expressing influenza NS1 protein, a protein exhibiting interferon (IFN)-antagonist and antiapoptotic functions in human and mouse cells. Interestingly, the resultant virus was dramatically enhanced in its ability to form syncytia, lyse a variety of human and mouse tumor cell lines, and suppressed the induction of the cellular IFN responses. Using the aggressive syngeneic murine melanoma model, we show that the NDV-NS1 virus is more effective than virus not expressing NS1 in clearing the established footpad tumors and results in higher overall long-term animal survival. In addition, mice treated with NDV-NS1 exhibited no signs of toxicity to the virus and developed tumor-specific cytotoxic T lymphocyte (CTL) responses. These findings demonstrate that modulation of innate immune responses by NDV results in enhancement of its oncolytic properties and warrant further investigation of this strategy in design of oncolytic NDV vectors against human tumors.

SUBMITTER: Zamarin D

PROVIDER: S-EPMC2835121 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Enhancement of oncolytic properties of recombinant newcastle disease virus through antagonism of cellular innate immune responses.

Zamarin Dmitriy D Martínez-Sobrido Luis L Kelly Kaitlyn K Mansour Mena M Sheng Gang G Vigil Adam A García-Sastre Adolfo A Palese Peter P Fong Yuman Y

Molecular therapy : the journal of the American Society of Gene Therapy 20090210 4

Newcastle disease virus (NDV) has been previously shown to possess oncolytic activity, causing specific lysis of cancerous but not normal cells. Here we show that despite these findings, the oncolytic efficiency of naturally occurring NDV strains can still be relatively low, as many tumors exhibit strong innate immune responses that suppress viral replication and spread. To overcome this problem, we generated a recombinant fusogenic NDV expressing influenza NS1 protein, a protein exhibiting inte ...[more]

PMID: 19209145

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Project description:In recent years, several newly discovered tick-borne viruses causing a wide spectrum of diseases in humans have been ascribed to the Phlebovirus genus of the Bunyaviridae family. The nonstructural protein (NSs) of bunyaviruses is the main virulence factor and interferon (IFN) antagonist. We studied the molecular mechanisms of IFN antagonism employed by the NSs proteins of human apathogenic Uukuniemi virus (UUKV) and those of Heartland virus (HRTV) and severe fever with thrombocytopenia syndrome virus (SFTSV), both of which cause severe disease. Using reporter assays, we found that UUKV NSs weakly inhibited the activation of the beta interferon (IFN-β) promoter and response elements. UUKV NSs weakly antagonized human IFN-β promoter activation through a novel interaction with mitochondrial antiviral-signaling protein (MAVS), confirmed by coimmunoprecipitation and confocal microscopy studies. HRTV NSs efficiently antagonized both IFN-β promoter activation and type I IFN signaling pathways through interactions with TBK1, preventing its phosphorylation. HRTV NSs exhibited diffused cytoplasmic localization. This is in comparison to the inclusion bodies formed by SFTSV NSs. HRTV NSs also efficiently interacted with STAT2 and impaired IFN-β-induced phosphorylation but did not affect STAT1 or its translocation to the nucleus. Our results suggest that a weak interaction between STAT1 and HRTV or SFTSV NSs may explain their inability to block type II IFN signaling efficiently, thus enabling the activation of proinflammatory responses that lead to severe disease. Our findings offer insights into how pathogenicity may be linked to the capacity of NSs proteins to block the innate immune system and illustrate the plethora of viral immune evasion strategies utilized by emerging phleboviruses. IMPORTANCE Since 2011, there has been a large expansion in the number of emerging tick-borne viruses that have been assigned to the Phlebovirus genus. Heartland virus (HRTV) and SFTS virus (SFTSV) were found to cause severe disease in humans, unlike other documented tick-borne phleboviruses such as Uukuniemi virus (UUKV). Phleboviruses encode nonstructural proteins (NSs) that enable them to counteract the human innate antiviral defenses. We assessed how these proteins interacted with the innate immune system. We found that UUKV NSs engaged with innate immune factors only weakly, at one early step. However, the viruses that cause more severe disease efficiently disabled the antiviral response by targeting multiple components at several stages across the innate immune induction and signaling pathways. Our results suggest a correlation between the efficiency of the virus protein/host interaction and severity of disease.

Project description:BackgroundAnaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors for which no effective therapies are currently available. Oncolytic Newcastle disease virus (NDV) has shown the potential to induce oncolytic cell death in a variety of cancer cells of diverse origins. However, whether oncolytic NDV displays antitumor effects in ATC remains to be investigated. We have previously shown that the oncolytic NDV strain FMW (NDV/FMW) induces oncolytic cell death in several cancer types. In the present study, we investigated the oncolytic effects of NDV/FMW in ATC.MethodsIn this study, a recombinant NDV expressing green fluorescent protein (GFP) was generated using an NDV reverse genetics system. The resulting virus was named after rFMW/GFP and the GFP expression in infected cells was demonstrated by direct fluorescence and immunoblotting. Viral replication was evaluated by end-point dilution assay in DF-1 cell lines. Oncolytic effects were examined by biochemical and morphological experiments in cultural ATC cells and in mouse models.ResultsrFMW/GFP replicated robustly in ATC cells as did its parent virus (NDV/FMW) while the expression of GFP protein was detected in lungs and spleen of mice intravenously injected with rFMW/GFP. We further showed that rFMW/GFP infection substantially increased early and late apoptosis in the ATC cell lines, THJ-16 T and THJ-29 T and increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage in ATC cells as assessed by immunoblotting. In addition, rFMW/GFP induced lyses of spheroids derived from ATC cells in three-dimensional (3D) cultures. We further demonstrated that rFMW/GFP infection resulted in the activation of p38 MAPK signaling, but not Erk1/2 or JNK, in THJ-16 T and THJ-29 T cells. Notably, inhibition of p38 MAPK activity by SB203580 decreased rFMW/GFP-induced cleavage of caspase-3 and PARP in THJ-16 T and THJ-29 T cells. Finally, both rFMW/GFP and its parent virus inhibited tumor growth in mice bearing THJ-16 T derived tumors.ConclusionTaken together, these data indicate that both the recombinant reporter virus rFMW/GFP and its parent virus NDV/FMW, display oncolytic activities in ATC cells in vitro and in vivo and suggest that oncolytic NDV may have potential as a novel therapeutic strategy for ATC.

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Enhancement of oncolytic properties of recombinant newcastle disease virus through antagonism of cellular innate immune responses.

Publications

Enhancement of oncolytic properties of recombinant newcastle disease virus through antagonism of cellular innate immune responses.

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