IFITM Genes, Variants, and Their Roles in the Control and Pathogenesis of Viral Infections

Zhao, Xiongyan; Li, Jiarui; Winkler, Cheryl A.; An, Ping; Guo, Ju Tao

doi:10.3389/fmicb.2018.03228

Cited by 134 publications

(131 citation statements)

References 78 publications

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“…Some other ISGs target post-entry steps of viral life cycle, as exemplified by TRIM5α and Mx that block the nucleocapsid uncoating, RNase L and ISG20 that degrade viral RNA, PKR that inhibits viral protein translation, BST2 and Viperin that inhibit virion assembly or budding (reviewed in [7]). Although the critical role of these antiviral ISGs in control of viral infections has been demonstrated in animal models and human diseases [14], the roles and mechanisms of many other ISGs in controlling virus infections remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

Chen

Hou

Jiang

et al. 2019

Emerging Microbes & Infections

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Interferons (IFNs) control viral infections by inducing expression of IFN-stimulated genes (ISGs) that restrict distinct steps of viral replication. We report herein that gamma-interferon-inducible lysosomal thiol reductase (GILT), a lysosome-associated ISG, restricts the infectious entry of selected enveloped RNA viruses. Specifically, we demonstrated that GILT was constitutively expressed in lung epithelial cells and fibroblasts and its expression could be further induced by type II interferon. While overexpression of GILT inhibited the entry mediated by envelope glycoproteins of SARS coronavirus (SARS-CoV), Ebola virus (EBOV) and Lassa fever virus (LASV), depletion of GILT enhanced the entry mediated by these viral envelope glycoproteins. Furthermore, mutations that impaired the thiol reductase activity or disrupted the N-linked glycosylation, a posttranslational modification essential for its lysosomal localization, largely compromised GILT restriction of viral entry. We also found that the induction of GILT expression reduced the level and activity of cathepsin L, which is required for the entry of these RNA viruses in lysosomes. Our data indicate that GILT is a novel antiviral ISG that specifically inhibits the entry of selected enveloped RNA viruses in lysosomes via disruption of cathepsin L metabolism and function and may play a role in immune control and pathogenesis of these viruses.

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Section: Introductionmentioning

confidence: 99%

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

Chen

Hou

Jiang

et al. 2019

Emerging Microbes & Infections

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“…Specifically, inhibition of TMPESS2-enhanced CoV entry implies that LY6E most likely blocks virus entry at plasma membrane or in early endosomes. Moreover, IFITMs impede viral fusion by decreasing membrane fluidity and curvature (37). AmphoB can bind cholesterol in cell membranes to increase membrane fluidity and planarity and consequentially rescue IFITM inhibition of virus entry (52).…”

Section: Discussionmentioning

confidence: 99%

“…Interferons (IFNs) are the primary antiviral cytokines that mediate innate and adaptive immune control of virus infection by inducing hundreds of genes, many of which encode antiviral effectors (36). In the last decades, several IFN-inducible proteins, including three IFN-induced transmembrane (IFITM) proteins (37), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT) (38), 25-Hydroxycholesterol hydrolase (25HC) (39), ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2) (40) and lymphocyte antigen 6 family member E (LY6E) (41) had been identified to restrict or enhance the entry of a variety of viruses. Interestingly, while IFITM proteins inhibit the entry of all the other human CoVs, HCoV-OC43 hijacks human IFITM2 or IFITM3 as entry factors to facilitate its infection of host cells (42, 43).…”

Section: Introductionmentioning

confidence: 99%

LY6E Restricts the Entry of Human Coronaviruses, including the currently pandemic SARS-CoV-2

Zhao

Zheng

Chen

et al. 2020

Preprint

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25C3A is a sub-clone of human hepatoblastoma HepG2 cell line with the strong contact inhibition 26 of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-27 OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into 28 C3A cells. In an effort to search for the host cellular protein(s) mediating the differential 29 susceptibility of the two cell lines to HCoV-OC43 infection, we found that ADAP2, GILT and 30 LY6E, three cellular proteins with known activity of interfering virus entry, expressed at 31 significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression 32 of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-OC43. While 33 overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-34 OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to 35HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry 36 mediated by the envelope spike proteins of other human coronaviruses, including the currently 37 pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or 38 amphotericin treatment significantly neutralized the IFITM3 restriction of human coronavirus 39 entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The 40 work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that 41 controls CoV infection and pathogenesis via a distinct mechanism.

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“…The Mac V cluster was characterized by expression of Plac8 45 ( Figure 1E), a gene expressed by a recently identified population of "CD64+ CD16.2+ non-classical monocytes" in the adult mouse lung 44 , suggesting a monocytic phenotype. Mac V monocytes also expressed a panel of unique transcripts induced by type I interferon (IFN), important for modulating host responses to viral pathogens (Ifitm2, Ifitm3, Ifitm6, Ifi27l2a) 46 ( Figure 5A), as well as genes that constrain inflammation (Cd300a, Nr4a1, Lst1) ( Figure 4A and Supplemental Table 5). This dual immune signature was similar to that seen in Mac II and III, emphasizing the importance of a finely tuned inflammatory response in the developing lung.…”

Section: Mac V Monocytes Are Characterized By Developmental Gene Exprmentioning

confidence: 99%

Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung revealed at single cell resolution

Domingo-Gonzalez

Zanini

Che

et al. 2020

Preprint

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22At birth, the lungs experience a sudden transition from a pathogen-free, hypoxic, fluid-23 filled environment to a pathogen-rich, rhythmically distended air-liquid interface. While many 24 studies focus on adult tissue, the heterogeneity of immune cells in the perinatal lung remains 25 unexplored. Here, we combine single cell transcriptomics with in situ hybridization to present an 26 atlas of the murine lung immune compartment during a critical period of lung development. We 27show that the late embryonic lung is dominated by specialized proliferative macrophages with a 28 surprising physical interaction with the developing vasculature. These macrophages disappear 29 after birth and are replaced by a complex and dynamic mixture of macrophage subtypes, dendritic 30 cells, granulocytes, and lymphocytes. Detailed characterization of macrophage diversity revealed 31 a precise orchestration of five distinct subpopulations across postnatal development to fill context-32 specific functions in tissue remodeling, angiogenesis, and immunity. These data both broaden the 33 putative roles for immune cells in the developing lung and provide a framework for understanding 34 how external insults alter immune cell phenotype during a period of rapid lung growth and 35 heightened vulnerability. 36 37Immune cells play a central role in the development of many organs. Innate and adaptive 52 immune cells regulate epithelial architecture during mammary gland development by promoting 53 terminal end bud elongation and impairing ductal invasion 5 . Lymphocytes play a key role in 54 oligodendrogenesis and synapse formation 6 , and macrophages inform kidney 7 , brain 8 , and retina 9 55 organogenesis. In highly vascularized organs, macrophages localize to the tips of vascular sprouts 56 to enhance vascular network complexity 9 , promote angiogenesis 10 , and regulate vascular 57 patterning 11 . Although proximal lung branching occurs during early gestation, the development of 58 distal airspaces capable of gas exchange begins only just before birth during the saccular stage of 59 development. These saccules are subsequently divided into millions of alveoli after birth during 60 alveolarization, the final stage of development characterized by rapid lung parenchymal and 61 vascular growth 12 . Whether temporal regulation of specific immune populations informs lung 62 immune function or the significant pulmonary parenchymal and vascular growth and remodeling 63 occurring during early postnatal life remains unknown. 64The prevailing notion is that the neonatal immune compartment is immature 13 . Limited 65 immune competence, including attenuated innate immunity 14 , poor immuno-stimulatory function 66 of antigen presenting cells 15 , and skewed adaptive immune responses may underlie the heightened 67 susceptibility of infants to viral and bacterial infections 13 . Although the neonatal immune system 68 can be induced to manifest adult-like responses under certain conditions 16 , this type-2-skewed 69 immune environment likely facilitates i...

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IFITM Genes, Variants, and Their Roles in the Control and Pathogenesis of Viral Infections

Cited by 134 publications

References 78 publications

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

LY6E Restricts the Entry of Human Coronaviruses, including the currently pandemic SARS-CoV-2

Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung revealed at single cell resolution

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