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A defective viral genome strategy elicits broad protective immunity against respiratory viruses.

ABSTRACT: RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC8598942 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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A defective viral genome strategy elicits broad protective immunity against respiratory viruses.

Xiao Yinghong Y Lidsky Peter V PV Shirogane Yuta Y Aviner Ranen R Wu Chien-Ting CT Li Weiyi W Zheng Weihao W Talbot Dale D Catching Adam A Doitsh Gilad G Su Weiheng W Gekko Colby E CE Nayak Arabinda A Ernst Joel D JD Brodsky Leonid L Brodsky Elia E Rousseau Elsa E Capponi Sara S Bianco Simone S Nakamura Robert R Jackson Peter K PK Frydman Judith J Andino Raul R

Cell 20211118 25

RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication f ...[more]

PMID: 34852237

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Project description:Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a promising strategy for infection treatment through targeting host immunity. However, the limited understanding of the function and regulatory mechanism of host factors involved in immune defense against infections has impeded HDT development. Here, we identify the ubiquitin ligase (E3) TRIM27 (tripartite motif-containing 27) as a host protective factor against Mtb by enhancing host macroautophagy/autophagy flux in an E3 ligase activity-independent manner. Mechanistically, upon Mtb infection, nuclear-localized TRIM27 increases and functions as a transcription activator of TFEB (transcription factor EB). Specifically, TRIM27 binds to the TFEB promoter and the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity toward TFEB, eventually inducing autophagy-related gene expression as well as autophagy flux activation to clear the pathogen. Furthermore, TFEB activator 1 can rescue TRIM27 deficiency-caused decreased autophagy-related gene transcription and attenuated autophagy flux, and accordingly suppressed the intracellular survival of Mtb in cell and mouse models. Taken together, our data reveal that TRIM27 is a host defense factor against Mtb, and the TRIM27-CREB1-TFEB axis is a potential HDT-based TB target that can enhance host autophagy flux.Abbreviations: ATG5: autophagy related 5; BMDMs: bone marrow-derived macrophages; CFU: colony-forming unit; ChIP-seq: chromatin immunoprecipitation followed by sequencing; CREB1: cAMP responsive element binding protein 1; CTSB: cathepsin B; E3: ubiquitin ligase; EMSA: electrophoretic mobility shift assay; HC: healthy control; HDT: host-directed therapy; LAMP: lysosomal associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TPR cation channel 1; Mtb: Mycobacterium tuberculosis; NLS: nuclear localization signal; PBMCs: peripheral blood mononuclear cells; PRKA/PKA: protein kinase cAMP-activated; qRT-PCR: quantitative real-time PCR; RFP: RET finger protein; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TRIM: tripartite motif; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.

Dataset Information

A defective viral genome strategy elicits broad protective immunity against respiratory viruses.

Publications

A defective viral genome strategy elicits broad protective immunity against respiratory viruses.

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