IFITM3 protects the heart during influenza virus infection

Kenney, Adam D.; McMichael, Temet M.; Imas, Alexander; Chesarino, Nicholas M.; Zhang, Lizhi; Dorn, Lisa E.; Wu, Qian; Alfaour, Omar; Amari, Foued; Chen, Min; Zani, Ashley; Chemudupati, Mahesh; Accornero, Federica; Coppola, Vincenzo; Rajaram, Murugesan V. S.; Yount, Jacob S.

doi:10.1073/pnas.1900784116

Cited by 67 publications

(86 citation statements)

References 50 publications

(74 reference statements)

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“…APP/PS1 showed increased levels of IRM compared to the other strains and are resilient to neurodegeneration at 8 months 6 . In support of this, mice deficient for IFITM3 are more susceptible to viral infection 46 . Given the multitude of outcomes downstream of the interferon response, it is critical we understand the specific role of IFITM3+ cells in AD.…”

Section: Discussionmentioning

confidence: 90%

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Yang

Onos

Choi

et al. 2020

Preprint

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Microglia are now considered drivers of Alzheimer's disease (AD) pathology. However, single-cell RNA-sequencing (scRNA-seq) of microglia in mice, a key preclinical model organsim, have shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains WSB/EiJ, CAST/EiJ and PWK/PhJ carrying APP/PS1 was performed and demonstrated that genetic diversity significantly altered features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. There was significant variation in abundance of microglial subpopulations, including numbers of disease-associated microglia and interferon-responding microglia across the strains.Further, for each subpopulation, significant gene expression differences were observed between strains, and relative to B6 that included nineteen genes previously associated with human AD including Apoe, Trem2, Bin1 and Sorl1. This resource will be critical in the development of appropriately targeted therapeutics for AD and a range of other neurological diseases. 30 Introduction 31Alzheimer's disease (AD) is defined by the neuropathological accumulation of beta 32 amyloid plaques, neurofibrillary tangles of tau and widespread neuronal loss. AD is the 33 most common cause of adult dementia and is characterized by a wide range of 34 cognitive and behavioral deficits that severely impact quality of life and the ability to self-35 care. Recent work has re-focused the field towards the contribution of brain glial cells to 36 the initiation and spread of these disease-specific pathologies, and specifically on the 37 role of microglia as potentially a causative cell type in driving disease development and 38 progression. Human genome-wide association studies (GWAS) have identified more 39 than 25 variants near genes uniquely expressed in microglia that are predicted to 40 increase susceptibility for AD. In light of this complexity, the mouse represents a critical 41 model system to dissect the role of microglia and other glia in AD. 42 43There has been large debate regarding the alignment of mouse microglia to human 44 microglia in terms of identity, diversity and function. With the more widespread use of 45 single-cell sequencing technology, a number of groups have suggested that the species 46 difference is too great for conclusions drawn from mouse models to inform our 47 understanding of human microglia1,2. Central to this argument is the discovery and 48 description of a specific class of microglia in the mouse, disease-associated microglia 49 (DAM)3. Based upon the current data it is unclear whether the presence or absence of 50 DAM in human AD patients is the result of differences in tissue collection, extraction of 51 cells, genetic diversity of patients, sub-type of AD presented in donors or even the 52 relevant disease1,4. Recent work has demonstrated that single-nucleus RNA 53 sequencing of stored human tissue fails to detect differences in microglia activation 54 between AD and contro...

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Section: Discussionmentioning

confidence: 90%

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Yang

Onos

Choi

et al. 2020

Preprint

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“…To examine whether MG53 plays a physiological role during in vivo viral infection, MG53 wild-type (WT) and knockout (KO) mice were intranasally infected with influenza virus strain PR8 at a dose of 10 tissue culture infectious dose 50 (TCID50). This dose causes weight loss in WT mice, peaking around day 10, followed by a full recovery of body weight 35 . In MG53 KO mice, we observed a more severe decrease in weight following infection and a delayed recovery compared to WT mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

MG53 suppresses interferon-β and inflammation via regulation of ryanodine receptor-mediated intracellular calcium signaling

et al. 2020

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TRIM family proteins play integral roles in the innate immune response to virus infection. MG53 (TRIM72) is essential for cell membrane repair and is believed to be a muscle-specific TRIM protein. Here we show human macrophages express MG53, and MG53 protein expression is reduced following virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. MG53 knockout mice infected with influenza virus show comparable influenza virus titres to wild type mice, but display increased morbidity accompanied by more accumulation of CD45+ cells and elevation of IFNβ in the lung. We find that MG53 knockdown results in activation of NFκB signalling, which is linked to an increase in intracellular calcium oscillation mediated by ryanodine receptor (RyR). MG53 inhibits IFNβ induction in an RyR-dependent manner. This study establishes MG53 as a new target for control of virus-induced morbidity and tissue injury.

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“…45 Indeed, influenza infection is related to heart pathologies. 46 Although SARS-CoV-2 was detected in the brain at 4-DPI, minimal histopathological changes were observed for the majority of mice, except for two mice that presented with multifocal perivascular neutrophils, lymphocytes, microglial cells and necrotic debris, vasculitis, and inflammation that extended to the meninges with hemorrhage. Brain cytokine responses were dominated by TH2 cytokines (IL-4, IL-13, IL-10, IL-27, and IL-33) which may reflect the natural TH2 status of the brain.…”

Section: Perlman S Mccray Personal Communication June 2020)mentioning

confidence: 87%

Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice

Oladunni

Park

Tamayo

et al. 2020

Preprint

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Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease currently lacks a validated small animal model. Here, we show that transgenic mice expressing human angiotensin converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2-transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2-transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 4. K18 hACE2-transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

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IFITM3 protects the heart during influenza virus infection

Cited by 67 publications

References 50 publications

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

MG53 suppresses interferon-β and inflammation via regulation of ryanodine receptor-mediated intracellular calcium signaling

Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice

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