Inhibition of PI3Kδ Enhances Poly I:C-Induced Antiviral Responses and Inhibits Replication of Human Metapneumovirus in Murine Lungs and Human Bronchial Epithelial Cells

Fujita, Akitaka; Kan-o, Keiko; Tonai, Ken; Yamamoto, Norio; Ogawa, Tomoya; Fukuyama, Satoru; Nakanishi, Yoichi; Matsumoto, Koichiro

doi:10.3389/fimmu.2020.00432

Cited by 12 publications

(14 citation statements)

References 70 publications

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“…Remarkably, blockage or ablation of PD-1 (through the administration of anti-PD-L1 antibodies and the use of PD-1 −/− mice, respectively) prevented the impairment of the activation of CD8 + T cells, leading to enhanced protective responses in subsequent infections with hMPV [ 134 ]. Even more, the restriction of PD-L1 by using a PI3Kδ inhibitor (IC87114) induces the clearance of the virus [ 140 ].…”

Section: Components and Cells Of The Adaptive Immune System Responmentioning

confidence: 99%

Host Components That Modulate the Disease Caused by hMPV

Gálvez

Andrade

Pacheco

et al. 2021

Viruses

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Human metapneumovirus (hMPV) is one of the main pathogens responsible for acute respiratory infections in children up to 5 years of age, contributing substantially to health burden. The worldwide economic and social impact of this virus is significant and must be addressed. The structural components of hMPV (either proteins or genetic material) can be detected by several receptors expressed by host cells through the engagement of pattern recognition receptors. The recognition of the structural components of hMPV can promote the signaling of the immune response to clear the infection, leading to the activation of several pathways, such as those related to the interferon response. Even so, several intrinsic factors are capable of modulating the immune response or directly inhibiting the replication of hMPV. This article will discuss the current knowledge regarding the innate and adaptive immune response during hMPV infections. Accordingly, the host intrinsic components capable of modulating the immune response and the elements capable of restricting viral replication during hMPV infections will be examined.

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Section: Components and Cells Of The Adaptive Immune System Responmentioning

confidence: 99%

Host Components That Modulate the Disease Caused by hMPV

Gálvez

Andrade

Pacheco

et al. 2021

Viruses

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“…Conversely, enhanced PI3K pathway activity caused by PTEN deficiency led to reduced expression of proinflammatory cytokines, such as TNF-a (107), and, consequently, an inability to clear intracellular L. major (108). PI3Kd inhibition was reported to enhance type 1 IFN responses in bronchial epithelial cells induced by the TLR3 ligand Poly(I:C) while concurrently reducing expression of the regulatory molecule PD-L1 (109). Thus, in addition to enhancing innate responses of macrophages and dendritic cells, PI3Kd may also potentially enhance innate antiviral responses in nonimmune cell types.…”

Section: Pi3k and Infectious Diseasesmentioning

confidence: 99%

A Case for Phosphoinositide 3-Kinase–Targeted Therapy for Infectious Disease

Adefemi

Fruman

Marshall

2020

The Journal of Immunology

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PI3Ks activate critical signaling cascades and have multifaceted regulatory functions in the immune system. Loss-of-function and gain-of-function mutations in the PI3Kδ isoform have revealed that this enzyme can substantially impact immune responses to infectious agents and their products. Moreover, reports garnered from decades of infectious disease studies indicate that pharmacologic inhibition of the PI3K pathway could potentially be effective in limiting the growth of certain microbes via modulation of the immune system. In this review, we briefly highlight the development and applications of PI3K inhibitors and summarize data supporting the concept that PI3Kδ inhibitors initially developed for oncology have immune regulatory potential that could be exploited to improve the control of some infectious diseases. This repurposing of existing kinase inhibitors could lay the foundation for alternative infectious disease therapy using available therapeutic agents.

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“…Type I IFNs (IFNa and IFNb) and type III IFNs (IFNl) secreted from infected bronchial epithelial cells stimulate neighboring cells through IFN receptors to express IFN-regulated genes (IRGs), inducing an antiviral state (10,11). We previously showed that viral infection or stimulation with a synthetic dsRNA analog, polyinosinic-polycytidylic acid (poly I: C), increased PD-L1 and PD-L2 expression on human bronchial epithelial cells, and the NF-kB pathway plays an essential role in poly I:C-induced upregulation of PD-L1 (12)(13)(14). Recent studies showed that exogenous type I IFN induces not only PD-L1 expression in endothelial cells, monocytes, and dendritic cells but also PD-L2 expression in cultured melanoma cells (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…PI3Kδ is a class IA PI3K and predominantly expressed in cells of the myeloid and lymphoid lineages ( 18 ). We recently reported that inhibition of PI3Kδ signaling enhanced poly I:C–induced antiviral IFN responses in human primary bronchial epithelial cells (PBECs), which suggests that PI3Kδ may negatively regulate the antiviral IFN response ( 14 ). We have also shown that a selective PI3Kδ inhibitor attenuated poly I:C–induced PD-L1 expression by inhibiting translational induction of PD-L1 via the Akt/mTOR pathway ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that inhibition of PI3Kδ signaling enhanced poly I:C–induced antiviral IFN responses in human primary bronchial epithelial cells (PBECs), which suggests that PI3Kδ may negatively regulate the antiviral IFN response ( 14 ). We have also shown that a selective PI3Kδ inhibitor attenuated poly I:C–induced PD-L1 expression by inhibiting translational induction of PD-L1 via the Akt/mTOR pathway ( 14 ). However, the association between PI3Kδ signaling and poly I:C–induced expressions of PD-L2 on PBECs remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of PI3Kδ Differentially Regulates Poly I:C– and Human Metapneumovirus–Induced PD–L1 and PD–L2 Expression in Human Bronchial Epithelial Cells

et al. 2021

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Bronchial epithelial cells are front sentinels eliciting innate and adaptive immunity to respiratory viral pathogens. Recognition of viral double-stranded RNA induces antiviral interferon (IFN) responses in bronchial epithelial cells. Co-inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) were also induced on bronchial epithelial cells, which bind programmed cell death 1 on T cell and inhibit the function of virus-specific cytotoxic T lymphocyte. A previous study showed that antiviral type I IFN increased PD-L1 and PD-L2 expression in cultured melanoma cells. However, it remains unknown whether antiviral IFNs affect PD-L1 and PD-L2 expression in bronchial epithelial cells. In addition, we previously reported that inhibition of PI3Kδ signaling enhanced antiviral IFN responses in human primary bronchial epithelial cells (PBECs). Here we assessed the effect of exogenous IFNs or a selective PI3Kδ inhibitor IC87114 on PD-L1 and PD-L2 in PBECs stimulated with a synthetic double-stranded RNA poly I:C or human metapneumovirus. Treatment with IFNβ or IFNλ increased PD-L1 and PD-L2, and IFNβ or IFNλ treatment plus poly I:C further increased both expressions. Treatment with IC87114 or transfection with siRNA targeting PI3K p110δ enhanced poly I:C–induced gene and protein expression of PD-L2, whereas IC87114 suppressed poly I:C–induced PD-L1. IC87114 enhanced poly I:C–induced gene expression of IFNβ, IFNλ, and IFN-regulated genes via increased TBK1 and IRF3 phosphorylation. Transfection with siIRF3 counteracted the enhancement of poly I:C–induced PD-L2 by IC87114, whereas IC87114 suppressed poly I:C–induced PD-L1 regardless of transfection with siNC or siIRF3. Similar effects of IC87114 on PD-L1 and PD-L2 expression were observed in human metapneumovirus–infected PBECs. We showed for the first time that type I and type III IFNs induced the expression of PD-L1 and PD-L2 in PBECs. Our findings suggest that during viral infections, inhibition of PI3Kδ differentially regulates PD-L1 and PD-L2 expression in bronchial epithelial cells.

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Inhibition of PI3Kδ Enhances Poly I:C-Induced Antiviral Responses and Inhibits Replication of Human Metapneumovirus in Murine Lungs and Human Bronchial Epithelial Cells

Cited by 12 publications

References 70 publications

Host Components That Modulate the Disease Caused by hMPV

Host Components That Modulate the Disease Caused by hMPV

A Case for Phosphoinositide 3-Kinase–Targeted Therapy for Infectious Disease

Inhibition of PI3Kδ Differentially Regulates Poly I:C– and Human Metapneumovirus–Induced PD–L1 and PD–L2 Expression in Human Bronchial Epithelial Cells

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