Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

Berghe, Tom Vanden; Hulpiau, Paco; Martens, Liesbet; Vandenbroucke, Roosmarijn E.; Wonterghem, Elien Van; Perry, Seth W.; Bruggeman, Inge; Divert, Tatyana; Choi, Sze Men; Vuylsteke, Marnik; Shestopalov, Valery I.; Libert, Claude; Vandenabeele, Peter

doi:10.1016/j.immuni.2015.06.011

Cited by 161 publications

(191 citation statements)

References 47 publications

(77 reference statements)

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“…S3B), suggesting that AIM2 KO did not affect inflammasome priming by ALVAC in mouse BMDCs. In addition, recent studies reported that targeted mutagenesis in mice is prone to introduce potential passenger mutations in genetically modified mice (33). To further confirm the above observations, we used AIM2−/− mice generated on the C57BL/6 genetic background (20).…”

Section: Resultsmentioning

confidence: 99%

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Liu

Niu

Fan

et al. 2017

The Journal of Immunology

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Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about mechanisms underlying host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of antigen presenting cells (APCs) with two commonly used HIV vaccine vectors, ALVAC and Ad5, and herein reported identification of AIM2 as an innate sensor for ALVAC triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-Type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that different from ALVAC, Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate STING-Type I IFN pathway and to provide inflammasome priming signals. In pre-conditioned APCs, Ad5 vector could stimulate inflammasome activation through AIM2-independent mechanism. Therefore, our study identifies AIM2 inflammasome and cGAS/IFI16-STING-Type I IFN pathway as novel mechanism for host innate immunity to ALVAC vaccine vector.

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Section: Resultsmentioning

confidence: 99%

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Liu

Niu

Fan

et al. 2017

The Journal of Immunology

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“…For the accuracy of experiments, all of the control mice were littermates (18). The TLR4 lps-del mice (C57BL/10ScN background, The Jackson Laboratory Number: 003752), ages 6 to 8 weeks and carrying a spontaneous deletion of TLR4, and littermates were purchased from the experimental animal center of Nanjing University (Nanjing, China; refs.…”

Section: Animal Treatmentsmentioning

confidence: 99%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

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Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicininduced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631-42. Ó2016 AACR.

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“…Findings that BAD-deficient mice are less sensitive in a model of systemic TNF-mediated hepatitis (Yan et al 2013) could not be confirmed in an independent study (Ottina et al 2015). Of note, responses to TNF or glucose are strongly influenced by the genetic background of the mouse model used and, when poorly controlled for, can contribute to sometimes inconsistent findings (Leiter 2002;Vanden Berghe et al 2015). Combined deletion of BAD plus BIM (Kelly et al 2010) or BMF (Baumgartner et al 2013), respectively, did not result in any particular developmental phenotypes and revealed only mildly increased cell death resistance upon cytokine withdrawal, B-cell-specific lymphadenopathy, and increased susceptibility to spontaneous as well as radiation-induced tumorigenesis.…”

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confidence: 99%

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

Tuzlak

Kaufmann

2016

Genes Dev.

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“Programmed cell death or ‘apoptosis’ is critical for organogenesis during embryonic development and tissue homeostasis in the adult. Its deregulation can contribute to a broad range of human pathologies, including neurodegeneration, cancer, or autoimmunity…” These or similar phrases have become generic opening statements in many reviews and textbooks describing the physiological relevance of apoptotic cell death. However, while the role in disease has been documented beyond doubt, facilitating innovative drug discovery, we wonder whether the former is really true. What goes wrong in vertebrate development or in adult tissue when the main route to apoptotic cell death, controlled by the BCL2 family, is impaired? Such scenarios have been mimicked by deletion of one or more prodeath genes within the BCL2 family, and gene targeting studies in mice exploring the consequences have been manifold. Many of these studies were geared toward understanding the role of BCL2 family proteins and mitochondrial apoptosis in disease, whereas fewer focused in detail on their role during normal development or tissue homeostasis, perhaps also due to an irritating lack of phenotype. Looking at these studies, the relevance of classical programmed cell death by apoptosis for development appears rather limited. Together, these many studies suggest either highly selective and context-dependent contributions of mitochondrial apoptosis or significant redundancy with alternative cell death mechanisms, as summarized and discussed here.

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Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

Cited by 161 publications

References 47 publications

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

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