Featured Publications

Submitted by galeadmin on Wed, 09/20/2017 - 19:43
2019 Aug;20(8):1035-1045. doi: 10.1038/s41590-019-0408-z. Epub 2019 Jun 24.

Interferon-λ modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus.

Hemann EA, Green R, Turnbull JB, Langlois RA, Savan R, Gale M Jr.

Abstract

Type III interferon (IFN-λ) is important for innate immune protection at mucosal surfaces and has therapeutic benefit against influenza A virus (IAV) infection. However, the mechanisms by which IFN-λ programs adaptive immune protection against IAV are undefined. Here we found that IFN-λ signaling in dendritic cell (DC) populations was critical for the development of protective IAV-specific CD8+ T cell responses. Mice lacking the IFN-λ receptor (Ifnlr1-/-) had blunted CD8+ T cell responses relative to wild type and exhibited reduced survival after heterosubtypic IAV re-challenge. Analysis of DCs revealed IFN-λ signaling directed the migration and function of CD103+ DCs for development of optimal antiviral CD8+ T cell responses, and bioinformatic analyses identified IFN-λ regulation of a DC IL-10 immunoregulatory network. Thus, IFN-λ serves a critical role in bridging innate and adaptive immunity from lung mucosa to lymph nodes to program DCs to direct effective T cell immunity against IAV.

PMID: 31235953

PMCID: PMC6642690 [Available on 2019-12-24]

DOI:10.1038/s41590-019-0408-z

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2019 Aug 13;10(1):3649. doi: 10.1038/s41467-019-11250-5.

RIG-I-like receptors direct inflammatory macrophage polarization against West Nile virus infection.

Stone AEL, Green R, Wilkins C, Hemann EA, Gale M Jr.

Abstract

RIG-I-Like Receptors (RLRs) RIG-I, MDA5, and LGP2, are vital pathogen recognition receptors in the defense against RNA viruses. West Nile Virus (WNV) infections continue to grow in the US. Here, we use a systems biology approach to define the contributions of each RLR in the innate immune response to WNV. Genome-wide RNAseq and bioinformatics analyses of macrophages from mice lacking either RLR reveal that the RLRs drive distinct immune gene activation and response polarization to mediate an M1/inflammatory signature while suppressing the M2/wound healing phenotype. While LGP2 functions to modulate inflammatory signaling, RIG-I and MDA5 together are essential for M1 macrophage polarization in vivo and the control of WNV infection through potential downstream control of ATF4 and SMAD4 to regulate target gene expression for cell polarization. These analyses reveal the RLR-driven signature of macrophage polarization, innate immune protection, and immune programming against WNV infection.

PMID: 31409781

PMCID:PMC6692387

DOI:10.1038/s41467-019-11250-5

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2019 Aug 15;15(8):e1007899. doi: 10.1371/journal.ppat.1007899. eCollection 2019 Aug.

STING is required for host defense against neuropathological West Nile virus infection.

McGuckin Wuertz K, Treuting PM, Hemann EA, Esser-Nobis K, Snyder AG, Graham JB, Daniels BP, Wilkins C, Snyder JM, Voss KM, Oberst A, Lund J, Gale M Jr.

Abstract

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.

PMID: 31415679

PMCID:PMC6695101

DOI:10.1371/journal.ppat.1007899

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2019 Mar 22. pii: S1097-2765(19)30149-2. doi: 10.1016/j.molcel.2019.02.038. [Epub ahead of print]

Interleukin-1β Induces mtDNA Release to Activate Innate Immune Signaling via cGAS-STING.

Aarreberg LD, Esser-Nobis K, Driscoll C, Shuvarikov A, Roby JA, Gale M Jr.
 

Abstract

Interleukin-1 beta (IL-1β) is a pleiotropic mediator of inflammation and is produced in response to a wide range of stimuli. During infection, IL-1β production occurs in parallel with the onset of innate antimicrobial defenses, but the contribution of IL-1β signaling to cell-intrinsic immunity is not defined. Here, we report that exogenous IL-1β induces interferon regulatory factor 3 (IRF3) activation in human myeloid, fibroblast, and epithelial cells. IRF3 activation by IL-1β is dependent upon the DNA-sensing pathway adaptor, stimulator of interferon genes (STING), through the recognition of cytosolic mtDNA by cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). IL-1β treatment results in interferon (IFN) production and activation of IFN signaling to direct a potent innate immune response that restricts dengue virus infection. This study identifies a new function for IL-1β in the onset or enhancement of cell-intrinsic immunity, with important implications for cGAS-STING in integrating inflammatory and microbial cues for host defense.

KEYWORDS: IFN; IL-1; IRF1; IRF3; STING; dengue virus; innate immunity; mitochondria

PMID: 30952515

DOI:10.1016/j.molcel.2019.02.038