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MDA5 knockout

Mingmin She, Haifang Jiang, Xiaoxiang Chen, Xiaoqing Chen, Xianjie Liu, Xueyan Zhang, Bernard Roizman, Grace Guoying Zhou
The stress response genes encoding GADD45γ, and to a lesser extent GADD45β are activated early in infection with HSV-1. Cells depleted of GADD45γ by transfection of shRNA or in which the gene had been knocked out (ΔGADD45γ) yield significantly less virus than untreated infected cells. Consistent with lower virus yields the ΔGADD45γ cells, both uninfected or infected with HSV-1 exhibit significantly higher levels of transcripts encoding a cluster of a network of innate immunity genes that include those encoding IFI16, IFIT1, MDA5 and RIG-I...
January 30, 2019: Journal of Virology
Weijian Ye, Marvin Chew, Jue Hou, Fritz Lai, Stije J Leopold, Hooi Linn Loo, Aniruddha Ghose, Ashok K Dutta, Qingfeng Chen, Eng Eong Ooi, Nicholas J White, Arjen M Dondorp, Peter Preiser, Jianzhu Chen
Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed...
October 2018: PLoS Pathogens
Yonghong Liu, Yuanyuan Liu, Jiaming Wu, Bernard Roizman, Grace Guoying Zhou
Analyses of the levels of mRNAs encoding IFIT1, IFI16, RIG-1, MDA5, CXCL10, LGP2, PUM1, LSD1, STING, and IFNβ in cell lines from which the gene encoding LGP2, LSD1, PML, HDAC4, IFI16, PUM1, STING, MDA5, IRF3, or HDAC 1 had been knocked out, as well as the ability of these cell lines to support the replication of HSV-1, revealed the following: ( i ) Cell lines lacking the gene encoding LGP2, PML, or HDAC4 (cluster 1) exhibited increased levels of expression of partially overlapping gene networks. Concurrently, these cell lines produced from 5 fold to 12 fold lower yields of HSV-1 than the parental cells...
April 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hachung Chung, Jorg J A Calis, Xianfang Wu, Tony Sun, Yingpu Yu, Stephanie L Sarbanes, Viet Loan Dao Thi, Abigail R Shilvock, H-Heinrich Hoffmann, Brad R Rosenberg, Charles M Rice
Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus...
February 8, 2018: Cell
Tanja Blumer, Mairene Coto-Llerena, Francois H T Duong, Markus H Heim
Type I (α and β) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis...
October 27, 2017: Journal of Biological Chemistry
Pak-Yin Lui, Lok-Yin Roy Wong, Ting-Hin Ho, Shannon Wing Ngor Au, Chi-Ping Chan, Kin-Hang Kok, Dong-Yan Jin
MDA5 is a RIG-I-like cytoplasmic sensor of dsRNA and certain RNA viruses, such as encephalomyocarditis virus, for the initiation of the IFN signaling cascade in the innate antiviral response. The affinity of MDA5 toward dsRNA is low, and its activity becomes optimal in the presence of unknown cellular coactivators. In this article, we report an essential coactivator function of dsRNA-binding protein PACT in mediating the MDA5-dependent type I IFN response. Virus-induced and polyinosinic-polycytidylic acid-induced activation of MDA5 were severely impaired in PACT-knockout cells and attenuated in PACT-knockdown cells, but they were potentiated when PACT was overexpressed...
September 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Lei Hei, Jin Zhong
Retinoic acid-inducible gene I (RIG-I)-like receptors are cytosolic pattern recognition receptors (PRRs) that detect non-self-RNA and activate downstream interferon (IFN) signaling. One of the RIG-I-like receptors, laboratory of genetics and physiology 2 (LGP2), was originally thought to be a negative feedback regulator in the RIG-I signaling pathway, but growing evidence indicates that LGP2 is one cofactor of melanoma differentiation-associated protein 5 (MDA5) in MDA5-mediated IFN signaling activation. Our previous work showed that MDA5 was the major PRR to sense hepatitis C virus (HCV) infection in hepatocytes, but the role of LGP2 in HCV infection-induced IFN signaling has not been elucidated...
May 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Shuai Wang, Yong-Kang Yang, Tao Chen, Heng Zhang, Wei-Wei Yang, Sheng-Sheng Song, Zhong-He Zhai, Dan-Ying Chen
Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic sensors crucial for recognizing different species of viral RNAs, which triggers the production of type I interferons (IFNs) and inflammatory cytokines. Here, we identify RING finger protein 123 (RNF123) as a negative regulator of RIG-I and MDA5. Overexpression of RNF123 inhibits IFN-β production triggered by Sendai virus (SeV) and encephalomyocarditis picornavirus (EMCV). Knockdown or knockout of endogenous RNF123 potentiates IFN-β production triggered by SeV and EMCV, but not by the sensor of DNA viruses cGAS RNF123 associates with RIG-I and MDA5 in both endogenous and exogenous cases in a viral infection-inducible manner...
August 2016: EMBO Reports
Lili Yu, Guoyan Liu, Can Yang, Xiangfeng Song, Hui Wang
Viral infections can disturb the functions of adipose tissues and thus result in metabolic diseases. Polyinosinic-polycytidylic acid (poly(I:C)), a synthetic analog of viral double-stranded RNA, induces innate antiviral responses by mimicking viral infection through the activation of pattern recognition receptors (PRRs) such as Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Poly(I:C) also inhibits the differentiation of mouse preadipocytes but the mechanism underlying this process remains unclear...
October 2016: Immunology and Cell Biology
Jana Kamanova, Hui Sun, Maria Lara-Tejero, Jorge E Galán
Salmonella Typhimurium stimulates inflammatory responses in the intestinal epithelium, which are essential for its ability to replicate within the intestinal tract. Stimulation of these responses is strictly dependent on the activity of a type III secretion system encoded within its pathogenicity island 1, which through the delivery of effector proteins, triggers signaling pathways leading to inflammation. One of these effectors is SopA, a HECT-type E3 ligase, which is required for the efficient stimulation of inflammation in an animal model of Salmonella Typhimurium infection...
April 2016: PLoS Pathogens
L Dillon Birdwell, Zachary B Zalinger, Yize Li, Patrick W Wright, Ruth Elliott, Kristine M Rose, Robert H Silverman, Susan R Weiss
UNLABELLED: The oligoadenylate synthetase (OAS)-RNase L pathway is a potent interferon (IFN)-induced antiviral activity. Upon sensing double-stranded RNA, OAS produces 2',5'-oligoadenylates (2-5A), which activate RNase L. Murine coronavirus (mouse hepatitis virus [MHV]) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase (PDE) that cleaves 2-5A, thereby antagonizing RNase L activation. PDE activity is required for robust replication in myeloid cells, as a mutant of MHV (ns2(H126R)) encoding an inactive PDE fails to antagonize RNase L activation and replicates poorly in bone marrow-derived macrophages (BMM), while ns2(H126R) replicates to high titer in several types of nonmyeloid cells, as well as in IFN receptor-deficient (Ifnar1(-/-)) BMM...
January 6, 2016: Journal of Virology
Fiona Semple, Heather MacPherson, Sheila Webb, Fiona Kilanowski, Laura Lettice, Sarah L McGlasson, Ann P Wheeler, Valerie Chen, Glenn L Millhauser, Lauren Melrose, Donald J Davidson, Julia R Dorin
Human β-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six β-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists...
December 2015: PLoS Genetics
Meghan M Painter, James H Morrison, Laurie J Zoecklein, Tommy A Rinkoski, Jens O Watzlawik, Louisa M Papke, Arthur E Warrington, Allan J Bieber, William E Matchett, Kari L Turkowski, Eric M Poeschla, Moses Rodriguez
For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection...
December 2015: PLoS Pathogens
Seong Bum Kim, Jin Young Choi, Jin Hyoung Kim, Erdenebelig Uyangaa, Ajit Mahadev Patil, Sang-Youel Park, John Hwa Lee, Koanhoi Kim, Young Woo Han, Seong Kug Eo
BACKGROUND: Japanese encephalitis (JE), a neuroinflammation caused by zoonotic JE virus, is the major cause of viral encephalitis worldwide and poses an increasing threat to global health and welfare. To date, however, there has been no report describing the regulation of JE progression using immunomodulatory tools for developing therapeutic strategies. We tested whether blocking the 4-1BB signaling pathway would regulate JE progression using murine JE model. METHODS: Infected wild-type and 4-1BB-knockout (KO) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression...
2015: Journal of Neuroinflammation
Zachary B Zalinger, Ruth Elliott, Kristine M Rose, Susan R Weiss
UNLABELLED: Infection with the murine coronavirus mouse hepatitis virus (MHV) activates the pattern recognition receptors melanoma differentiation-associated gene 5 (MDA5) and Toll-like receptor 7 (TLR7) to induce transcription of type I interferon. Type I interferon is crucial for control of viral replication and spread in the natural host, but the specific contributions of MDA5 signaling to this pathway as well as to pathogenesis and subsequent immune responses are largely unknown. In this study, we use MHV infection of the liver as a model to demonstrate that MDA5 signaling is critically important for controlling MHV-induced pathology and regulation of the immune response...
December 2015: Journal of Virology
Sanna M Mäkelä, Pamela Österlund, Veera Westenius, Sinikka Latvala, Michael S Diamond, Michael Gale, Ilkka Julkunen
UNLABELLED: Influenza B virus causes annual epidemics and, along with influenza A virus, accounts for substantial disease and economic burden throughout the world. Influenza B virus infects only humans and some marine mammals and is not responsible for pandemics, possibly due to a very low frequency of reassortment and a lower evolutionary rate than that of influenza A virus. Influenza B virus has been less studied than influenza A virus, and thus, a comparison of influenza A and B virus infection mechanisms may provide new insight into virus-host interactions...
December 2015: Journal of Virology
Edward Sionov, Katrin D Mayer-Barber, Yun C Chang, Keith D Kauffman, Michael A Eckhaus, Andres M Salazar, Daniel L Barber, Kyung J Kwon-Chung
Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic...
August 2015: PLoS Pathogens
Niranjan Butchi, Parul Kapil, Shweta Puntambekar, Stephen A Stohlman, David R Hinton, Cornelia C Bergmann
UNLABELLED: Myd88 signaling is critical to the control of numerous central nervous system (CNS) infections by promoting both innate and adaptive immune responses. Nevertheless, the extent to which Myd88 regulates type I interferon (IFN) versus proinflammatory factors and T cell function, as well as the anatomical site of action, varies extensively with the pathogen. CNS infection by neurotropic coronavirus with replication confined to the brain and spinal cord induces protective IFN-α/β via Myd88-independent activation of melanoma differentiation-associated gene 5 (MDA5)...
September 2015: Journal of Virology
Izabel J M Di Fiore, Gavan Holloway, Barbara S Coulson
Rotavirus infection is a major cause of life-threatening infantile gastroenteritis. The innate immune system provides an immediate mechanism of suppressing viral replication and is necessary for an effective adaptive immune response. Innate immunity involves host recognition of viral infection and establishment of a powerful antiviral state through the expression of pro-inflammatory cytokines such as type-1 interferon (IFN). Macrophages, the front-line cells of innate immunity, produce IFN and other cytokines in response to viral infection...
October 2, 2015: Virus Research
Asiel A Benitez, Maryline Panis, Jia Xue, Andrew Varble, Jaehee V Shim, Amy L Frick, Carolina B López, David Sachs, Benjamin R tenOever
Responding to an influenza A virus (IAV) infection demands an effective intrinsic cellular defense strategy to slow replication. To identify contributing host factors to this defense, we exploited the host microRNA pathway to perform an in vivo RNAi screen. To this end, IAV, lacking a functional NS1 antagonist, was engineered to encode individual siRNAs against antiviral host genes in an effort to rescue attenuation. This screening platform resulted in the enrichment of strains targeting virus-activated transcription factors, specific antiviral effectors, and intracellular pattern recognition receptors (PRRs)...
June 23, 2015: Cell Reports
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