Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice

ABSTRACT Lymph-borne Friend murine leukemia virus (FrMLV) exploits the sentinel macrophages in the draining popliteal lymph node (pLN) to infect highly permissive innate-like B-1 cells and establish infection in mice. The reason for FrMLV sensitivity of B-1 cells and their impact on viral spread is unknown. Here we demonstrate that Toll-like receptor 7 (TLR7) sensing and type I interferon (IFN-I) signaling in B-1 cells contribute to FrMLV susceptibility. FrMLV infection in B-1 cell-deficient mice (bumble; IκBNS dysfunctional) was significantly lower than that in the wild-type mice and was rescued by adoptive transfer of wild-type B-1 cells. This rescue of FrMLV infection in bumble mice was dependent on intact TLR7 sensing and IFN-I signaling within B-1 cells. Analyses of infected cell types revealed that the reduced infection in bumble mice was due predominantly to compromised virus spread to the B-2 cell population. Our data reveal how FrMLV exploits innate immune sensing and activation in the B-1 cell population for infection and subsequent spread to other lymphocytes. IMPORTANCE Viruses establish infection in hosts by targeting highly permissive cell types. The retrovirus Friend murine leukemia virus (FrMLV) infects a subtype of B cells called B-1 cells that permit robust virus replication. The reason for their susceptibility had remained unknown. We found that innate sensing of incoming virus and the ensuing type I interferon response within B-1 cells are responsible for their observed susceptibility. Our data provide insights into how retroviruses coevolved with the host to co-opt innate immune sensing pathways designed to fight virus infections for establishing infection. Understanding early events in viral spread can inform antiviral intervention strategies that prevent the colonization of a host.

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The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype

10.1101/466755 ◽

2018 ◽

Author(s):

Priya Hari ◽

Fraser R. Millar ◽

Nuria Tarrats ◽

Jodie Birch ◽

Curtis J. Rink ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Innate Immune ◽

Toll Like Receptor ◽

Cycle Arrest ◽

Secretory Phenotype ◽

Immune Sensing ◽

Molecular Patterns ◽

Innate Immune Sensing

ABSTRACTCellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

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G100R Mutation within 4070A Murine Leukemia Virus Env Increases Virus Receptor Binding, Kinetics of Entry, and Viral Transduction Efficiency

Journal of Virology ◽

10.1128/jvi.77.1.739-743.2003 ◽

2003 ◽

Vol 77 (1) ◽

pp. 739-743 ◽

Cited By ~ 4

Author(s):

Chi-Wei Lu ◽

Lucille O'Reilly ◽

Monica J. Roth

Keyword(s):

Viral Entry ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Cell Types ◽

Transduction Efficiency ◽

Target Cells ◽

Multiple Cell ◽

Viral Transduction ◽

Kinetics Of ◽

Murine Leukemia

ABSTRACT Passage of 4070A murine leukemia virus (MuLV) in D17 cells resulted in a G-to-R change at position 100 within the VRA of the envelope protein (Env). Compared with 4070A MuLV, virus with the G100R Env displayed enhanced binding on target cells, internalized the virus more rapidly, and increased the overall viral titer in multiple cell types. This provides a direct correlation between binding strength and efficiency of viral entry. Deletion of a His residue at the SU N terminus eliminated the transduction efficiency by the G100R virus, suggesting that the G100R virus maintains the regulatory characteristics of 4070A viral entry. The improved transduction efficiency of G100R Env would be an asset for gene delivery systems.

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TBK1, a central kinase in innate immune sensing of nucleic acids and beyond

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa051 ◽

2020 ◽

Vol 52 (7) ◽

pp. 757-767 ◽

Cited By ~ 3

Author(s):

Ruyuan Zhou ◽

Qian Zhang ◽

Pinglong Xu

Keyword(s):

Nucleic Acids ◽

Cell Biology ◽

Innate Immune ◽

Type I ◽

Interferon Stimulated Genes ◽

Immune Sensing ◽

Mitochondrial Antiviral Signaling ◽

I Kappa B Kinase ◽

Innate Immune Sensing ◽

Mitochondrial Antiviral Signaling Protein

Abstract Sensing of intracellular and extracellular environments is one of the fundamental processes of cell. Surveillance of aberrant nucleic acids, derived either from invading pathogens or damaged organelle, is conducted by pattern recognition receptors (PRRs) including RIG-I-like receptors, cyclic GMP-AMP synthase, absent in melanoma 2, and a few members of toll-like receptors. TANK-binding kinase 1 (TBK1), along with its close analogue I-kappa-B kinase epsilon, is a central kinase in innate adaptor complexes linking activation of PRRs to mobilization of transcriptional factors that transcribe proinflammatory cytokines, type I interferon (IFN-α/β), and myriads interferon stimulated genes. However, it still remains elusive for the precise mechanisms of activation and execution of TBK1 in signaling platforms formed by innate adaptors mitochondrial antiviral signaling protein (MAVS), stimulator of interferon genes protein (STING), and TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as its complex regulations. An atlas of TBK1 substrates is in constant expanding, setting TBK1 as a key node of signaling network and a dominant player in contexts of cell biology, animal models, and human diseases. Here, we review recent advancements of activation, regulations, and functions of TBK1 under these physiological and pathological contexts.

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Inhibition of Murine Leukemia Virus Envelope Protein (Env) Processing by Intracellular Expression of the Env N-Terminal Heptad Repeat Region

Journal of Virology ◽

10.1128/jvi.79.8.4782-4792.2005 ◽

2005 ◽

Vol 79 (8) ◽

pp. 4782-4792 ◽

Cited By ~ 6

Author(s):

Wu Ou ◽

Jonathan Silver

Keyword(s):

Influenza Virus ◽

Envelope Protein ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Proteolytic Processing ◽

Structural Motif ◽

Type I ◽

Alpha Helices ◽

Intracellular Expression ◽

Murine Leukemia

ABSTRACT A conserved structural motif in the envelope proteins of several viruses consists of an N-terminal, alpha-helical, trimerization domain and a C-terminal region that refolds during fusion to bind the N-helix trimer. Interaction between the N and C regions is believed to pull viral and target membranes together in a crucial step during membrane fusion. For several viruses with type I fusion proteins, C regions pack as alpha-helices in the grooves between N-helix monomers, and exogenously added N- and C-region peptides block fusion by inhibiting the formation of the six-helix bundle. For other viruses, including influenza virus and murine leukemia virus (MLV), there is no evidence for comparably extended C-region alpha-helices, although a short, non-alpha-helical interaction structure has been reported for influenza virus. We tested candidate N-helix and C-region peptides from MLV for their ability to inhibit cell fusion but found no inhibitory activity. In contrast, intracellular expression of the MLV N-helix inhibited fusion by efficiently blocking proteolytic processing and intracellular transport of the envelope protein. The results highlight another mechanism by which the N-helix peptides can inhibit fusion.

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Functional Murine Leukemia Virus Vectors Pseudotyped with the Visna Virus Envelope Show Expanded Visna Virus Cell Tropism

Journal of Virology ◽

10.1128/jvi.75.23.11464-11473.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11464-11473 ◽

Cited By ~ 17

Author(s):

Linda Bruett ◽

Janice E. Clements

Keyword(s):

Murine Leukemia Virus ◽

Fluorescent Protein ◽

Leukemia Virus ◽

Cell Types ◽

Pseudotyped Virus ◽

Virus Envelope ◽

Virus Receptor ◽

Virus Vectors ◽

Visna Virus ◽

Murine Leukemia

ABSTRACT Pseudotype virus vectors serve as a powerful tool for the study of virus receptor usage and entry. We describe the development of murine leukemia virus (MuLV) particles pseudotyped with the visna virus envelope glycoprotein and encoding a green fluorescent protein reporter as a tool to study the expression of the visna virus receptor. Functional MuLV/visna virus pseudotypes were obtained when the cytoplasmic tail of the visna virus envelope TM protein was truncated to 3, 7, or 11 amino acids in length. MuLV/visna virus particles were used to transduce a panel of cell types from various organisms, including sheep, goat, human, hamster, mouse, monkey, and quail. The majority of the cells examined were susceptible to MuLV/visna pseudotype viruses, supporting the notion that the visna virus cellular receptor is a widely expressed protein found in many species. Of 16 different cell types tested, only mouse embryo fibroblast NIH 3T3 cells, hamster ovary CHO cells, and the human promonocyte cell line U937 cells were not susceptible to transduction by the pseudotyped virus. The production of functional MuLV/visna virus pseudotypes has provided a sensitive, biologically relevant system to study visna virus cell entry and envelope-receptor interactions.

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Innate immune sensing of cancer: clues from an identified role for type I IFNs

Cancer Immunology Immunotherapy ◽

10.1007/s00262-012-1305-6 ◽

2012 ◽

Vol 61 (8) ◽

pp. 1343-1347 ◽

Cited By ~ 33

Author(s):

Thomas F. Gajewski ◽

Mercedes B. Fuertes ◽

Seng-Ryong Woo

Keyword(s):

Innate Immune ◽

Type I ◽

Type I Ifns ◽

Immune Sensing ◽

Innate Immune Sensing

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Introduction of a cis-Acting Mutation in the Capsid-Coding Gene of Moloney Murine Leukemia Virus Extends Its Leukemogenic Properties

Journal of Virology ◽

10.1128/jvi.73.12.10472-10479.1999 ◽

1999 ◽

Vol 73 (12) ◽

pp. 10472-10479 ◽

Cited By ~ 12

Author(s):

Muriel Audit ◽

Jérôme Déjardin ◽

Barbara Hohl ◽

Christine Sidobre ◽

Thomas J. Hope ◽

...

Keyword(s):

Murine Leukemia Virus ◽

Leukemia Virus ◽

Rapid Development ◽

Latency Period ◽

Leukemic Cell ◽

Cell Types ◽

Moloney Murine Leukemia Virus ◽

Newborn Mice ◽

Enhancer Region ◽

Murine Leukemia

ABSTRACT Inoculation of newborn mice with the retrovirus Moloney murine leukemia virus (MuLV) results in the exclusive development of T lymphomas with gross thymic enlargement. The T-cell leukemogenic property of Moloney MuLV has been mapped to the U3 enhancer region of the viral promoter. However, we now describe a mutant Moloney MuLV which can induce the rapid development of a uniquely broad panel of leukemic cell types. This mutant Moloney MuLV with synonymous differences (MSD1) was obtained by introduction of nucleotide substitutions at positions 1598, 1599, and 1601 in the capsid gene which maintained the wild-type (WT) coding potential. Leukemias were observed in all MSD1-inoculated animals after a latency period that was shorter than or similar to that of WT Moloney MuLV. Importantly, though, only 56% of MSD1-induced leukemias demonstrated the characteristic thymoma phenotype observed in all WT Moloney MuLV leukemias. The remainder of MSD1-inoculated animals presented either with bona fide clonal erythroid or myelomonocytic leukemias or, alternatively, with other severe erythroid and unidentified disorders. Amplification and sequencing of U3 and capsid-coding regions showed that the inoculated parental MSD1 sequences were conserved in the leukemic spleens. This is the first report of a replication-competent MuLV lacking oncogenes which can rapidly lead to the development of such a broad range of leukemic cell types. Moreover, the ability of MSD1 to transform erythroid and myelomonocytic lineages is not due to changes in the U3 viral enhancer region but rather is the result of acis-acting effect of the capsid-coding gagsequence.

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