Bradykinin enhances Sindbis virus infection in human brain microvascular endothelial cells

Rust, Naiara Miranda; Papa, Michelle Premazzi; Scovino, Aline Miranda; Silva, Mayara Marques Carneiro da; Calzavara-Silva, Carlos Eduardo; Marques, Ernesto Torres de Azevedo; Pecanha, L. M. T.; Scharfstein, Júlio; Arruda, Luciana Barros de

doi:10.1016/j.virol.2011.10.003

Cited by 15 publications

(15 citation statements)

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“…Activation of the intrinsic pathway is triggered in response to damaged vessel wall surfaces, after contact of vessel walls with lipoprotein particles, bacteria, or other pathogens including viruses (33,39). Infection with RVFV ZH enhanced the expression of the gene coding for coagulation factor VIII, X, and prothrombin ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Benferhat

Josse

Albaud

et al. 2012

J Virol

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dRift Valley fever virus (RVFV) is a highly pathogenic Phlebovirus that infects humans and ruminants. Initially confined to Africa, RVFV has spread outside Africa and presently represents a high risk to other geographic regions. It is responsible for high fatality rates in sheep and cattle. In humans, RVFV can induce hepatitis, encephalitis, retinitis, or fatal hemorrhagic fever. The nonstructural NSs protein that is the major virulence factor is found in the nuclei of infected cells where it associates with cellular transcription factors and cofactors. In previous work, we have shown that NSs interacts with the promoter region of the beta interferon gene abnormally maintaining the promoter in a repressed state. In this work, we performed a genome-wide analysis of the interactions between NSs and the host genome using a genome-wide chromatin immunoprecipitation combined with promoter sequence microarray, the ChIP-on-chip technique. Several cellular promoter regions were identified as significantly interacting with NSs, and the establishment of NSs interactions with these regions was often found linked to deregulation of expression of the corresponding genes. Among annotated NSs-interacting genes were present not only genes regulating innate immunity and inflammation but also genes regulating cellular pathways that have not yet been identified as targeted by RVFV. Several of these pathways, such as cell adhesion, axonal guidance, development, and coagulation were closely related to RVFV-induced disorders. In particular, we show in this work that NSs targeted and modified the expression of genes coding for coagulation factors, demonstrating for the first time that this hemorrhagic virus impairs the host coagulation cascade at the transcriptional level.

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Section: Resultsmentioning

confidence: 99%

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Benferhat

Josse

Albaud

et al. 2012

J Virol

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“…This is to our knowledge the first experimental evidence of all major MAPK signaling pathways being concomitantly activated in the course of CHIKV infection in human cells. The induction of the Ras-Raf-MEK-ERK pathway has been shown for different RNA viruses like hepatitis C virus (53) and dengue virus (54) and also alphaviruses, namely, Sindbis virus (SINV) (20) and Venezuelan equine encephalitis virus (VEEV) (55). This pathway appears to be activated by these different viruses, potentially to confer a prosurvival status to the infected cells in order to maintain a productive infection cycle and generate sufficient progeny virions.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its importance in the replication of many viruses (15)(16)(17)(18), MAPK signaling in the context of alphavirus infections has been only sparsely investigated. Only the activation of ERK in CHIKVinfected mouse astrocytes (19) and in SINV-infected human endothelial cells (20) has been described thus far. Here, we show that all three major branches of MAPK signaling were activated in the course of CHIKV infection.…”

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confidence: 99%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

120

103

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Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a highthroughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections. C hikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease spread by Aedes mosquitoes and characterized by a sudden onset of febrile illness, nausea, headache, and most importantly, severe and persistent musculoskeletal pain (1). It reemerged in tropical Asia and Africa 1 decade ago and since 2013 has infected more than 1.5 million people in the Americas (2). So far, no licensed vaccine or antiviral treatment exists to counter this disease. Over the years, many research groups have focused on...

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“…In some bacterial and viral infections, bradykinin enhances vascular permeability to facilitate pathogen spread [26,27]. However, there are very few studies linking the KKS and C .…”

Section: Introductionmentioning

confidence: 99%

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

et al. 2016

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The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.

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Bradykinin enhances Sindbis virus infection in human brain microvascular endothelial cells

Cited by 15 publications

References 64 publications

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

Large-Scale Chromatin Immunoprecipitation with Promoter Sequence Microarray Analysis of the Interaction of the NSs Protein of Rift Valley Fever Virus with Regulatory DNA Regions of the Host Genome

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

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