Infection with flaviviruses requires BCLXL for cell survival

Suzuki, Tatsuya; Okamoto, Tomoyoshi; Katoh, Hiroshi; Sugiyama, Yukari; Kusakabe, Shinji; Tokunaga, Makoto; Hirano, Junko; Miyata, Yuka; Fukuhara, Takasuke; Ikawa, Masahito; Satoh, Takashi; Yoshio, Sachiyo; Suzuki, Ritsuro; Saijo, Masayuki; Huang, David C.S.; Kanto, Tatsuya; Akira, Shizuo; Matsuura, Yoshiharu

doi:10.1371/journal.ppat.1007299

Cited by 37 publications

(32 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Another striking phenomenon during JEV infection was the extensive activation of all currently known PCD pathways, especially apoptosis, pyroptosis, and necroptosis. JEV infection induces apoptosis in various cell types [20][21][22][23][24], while the impact of JEV infection on the apoptosis of macrophages has not yet been reported. Our results show that JEV infection stimulated macrophage apoptosis by activating both extrinsic and intrinsic apoptosis pathways.…”

Section: Discussionmentioning

confidence: 98%

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Wang

Zhen

Fan

et al. 2020

Viruses

View full text Add to dashboard Cite

The Japanese encephalitis virus (JEV) is a Culex mosquito-borne flavivirus and is the pathogenic agent of Japanese encephalitis, which is the most important type of viral encephalitis in the world. Macrophages are a type of pivotal innate immunocyte that serve as sentinels and respond quickly to pathogen invasions. However, some viruses like JEV can hijack macrophages as a refuge for viral replication and immune escape. Despite their crucial involvement in early JEV infection, the transcriptomic landscapes of JEV-infected macrophages are void. Here, by using an in situ JEV infection model, we investigate the transcriptomic alteration of JEV-infected peritoneal macrophages. We found that, upon JEV infection, the macrophages underwent M1 polarization and showed the drastic activation of innate immune and inflammatory pathways. Interestingly, almost all the programmed cell death (PCD) pathways were activated, especially the apoptosis, pyroptosis, and necroptosis pathways, which were verified by the immunofluorescent staining of specific markers. Further transcriptomic analysis and TUNEL staining revealed that JEV infection caused apparent DNA damage. The transcriptomic analysis also revealed that JEV infection promoted ROS and RNS generation and caused oxidative stress, which activated multiple cell death pathways. Our work uncovers the pivotal pathogenic roles of oxidative stress and multiple PCD pathways in JEV infection, providing a novel perspective on JEV–host interactions.

show abstract

Section: Discussionmentioning

confidence: 98%

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Wang

Zhen

Fan

et al. 2020

Viruses

View full text Add to dashboard Cite

show abstract

“…Suzuki and colleagues proposed that Flavivirus infection induces delayed cell apoptosis and consequently virus spread to neighboring cells leading to higher viral loads and disease severity. Bcl-xL inhibition accelerates apoptosis leading to enhanced viral clearance through macrophage phagocytosis 46 .…”

Section: Discussionmentioning

confidence: 99%

Apoptosis characterization in mononuclear blood leukocytes of HIV patients during dengue acute disease

Torrentes-Carvalho

Sánchez‐Arcila

Azamor

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Dengue virus (DenV) co-circulation in Brazil represents a challenge for treatment and vaccine development. Despite public health impact, the occurrence of coinfections with other viruses is a common event. Increased T cell activation and altered inflammatory response are found during DENV coinfection with Human Immunodeficiency Virus (HIV) impacting HIV-pathogenesis. Even with Antiretroviral therapy (ARt), HiV-treated patients had chronic immune activation and lymphocyte apoptosis. However, apoptotic mechanisms have not been investigated during coinfection with DenV. our attention was attracted to apoptotic cell markers expressions in pBMcs from DenV and DenV/ HIV coinfected patients. We found CD4/CD8 ratio inversion in most coinfected patients. CD4 T and CD8 T-cell subsets from DENV and DENV/HIV groups expressed low levels of anti-apoptotic protein Bcl-2. Furthermore, CD8 CD95 double positive cells frequency expressing low levels of Bcl-2 were significantly higher in these patients. Additionally, the density of Bcl-2 on classical monocytes (CD14 ++ CD16 − ) was significantly lower during DENV infection. Upregulation of pro-apoptotic proteins and anti-apoptotic proteins were found in DenV and DenV/HiV, while catalase, an antioxidant protein, was upregulated mainly in DENV/HIV coinfection. These findings provide evidence of apoptosis triggering during DenV/HiV coinfection, which may contribute to knowledge of immunological response during DenV acute infection in HiV-patients treated with ARt.Dengue virus (DENV) and Human Immunodeficiency Virus (HIV) infections are currently a major public health concern in Brazil. Dengue is caused by any one of four DENV (1-4) serotypes spread by mosquitoes of aedes genus. DENV causes an acute febrile illness of a broad clinical spectrum presenting both asymptomatic and symptomatic forms that can evolve with severe and potentially fatal condition 1 . The hallmark of most serious clinical conditions is the vascular permeability increase that causes plasma leakage, leading to shock and death. Acquired Immunodeficiency Sydrome (AIDS) (is still considered an important cause of morbidity and mortality in the world. HIV infects CD4 T-cells, monocytes/macrophages and to a lesser extent in dendritic cells leading to progressive CD4 T-cell depletion and consequently pronounced immunosuppression in the absence of effective antiretroviral therapy (ART) 2 .Apoptosis, also called type I cell death, is a regulated process of cell death highly conserved among mammals and comprises a controlled self-destruction process to eliminate damaged, neoplastic and virus-infected cells 3 . Apoptosis program regulation is determined by interactions of three members of B-cell lymphoma-2 family proteins (Bcl-2): Bcl-2 homologous 3 (BH3)-only proteins, Bcl-2 proteins and Bcl-2 associated X protein (Bax)/Bcl-2 homologous antagonist/killer (Bak) effectors. It can be triggered by extrinsic [death receptors like p55 tumor necrosis factor TNF receptor-TNFRI, Fas/CD95, TRAIL/APO2-L (TNF-related apoptosis-inducing li...

show abstract

“…A control of the stability and degradation of Bcl-2 is therefore a key in the subtle balance that takes place between pro and anti-apoptotic suits to determine the cell's fate [40]. Previous study showed the importance of Bcl-xL for cells survival, in deficient Bcl-2 cells during ZIKV infection [41], but here we cannot exclude a role for Bcl-2 and/or Bcl-xL protein as our model express these two anti-apoptotic proteins. As we used cycloheximide or blasticidin in our assays, we can therefore assume that the mechanism implemented by ZIKV does not involve a "de novo" synthesis of proteins.…”

Section: Discussionmentioning

confidence: 99%

The ZIKA Virus Controls Cell Death through the Anti-Apoptotic Bcl-2 Family Proteins

Turpin¹,

Frumence²,

Desprès³

et al. 2019

Preprint

View full text Add to dashboard Cite

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to cause severe complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to control programmed cell death whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

show abstract

Infection with flaviviruses requires BCLXL for cell survival

Cited by 37 publications

References 74 publications

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Apoptosis characterization in mononuclear blood leukocytes of HIV patients during dengue acute disease

The ZIKA Virus Controls Cell Death through the Anti-Apoptotic Bcl-2 Family Proteins

Contact Info

Product

Resources

About