IFITM3 restricts the morbidity and mortality associated with influenza

Everitt, Aaron R.; Clare, Simon; Pertel, Thomas; John, Sinu P.; Wash, R.; Smith, Sarah E.; Chin, Christopher R.; Feeley, Eric M.; Sims, Jennifer S.; Adams, David J.; Wise, Helen; Kane, Leanne; Goulding, David; Digard, Paul; Anttila, Vesa; Baillie, J Kenneth; Walsh, Tim; Hume, David; Palotie, Aarno; Xue, Yali; Colonna, Vincenza; Tyler‐Smith, Chris; Dunning, Jake; Gordon, Stephen B.; Smyth, Rosalind L; Openshaw, Peter; Dougan, Gordon; Brass, Abraham L.; Kellam, Paul

doi:10.1038/nature10921

Cited by 665 publications

(701 citation statements)

References 33 publications

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“…Our results, together with emerging reports on other pattern recognition receptors33, 36, 42, strongly support further clinical studies on the roles of innate immunity in controlling influenza and to explore potential applications of receptor targeting, especially as preventive interventions 2, 4, 37…”

Section: Discussionsupporting

confidence: 82%

“…We plan to compare TLR and RLR expressions between different naturally occurring respiratory viral infections (e.g., influenza versus RSV) in future, as available data suggest that these might be different 3, 26. Factors determining TLR expression in an individual should be further studied 3, 42. We report that in some old patients (>65 years of age, P = 0·025), despite successful cytokine and ligand stimulation studies, the number of DCs in circulation was too few and signals too weak (due to aging and/or site “migration”) to allow full‐range TLR analysis 6, 39.…”

Section: Discussionmentioning

confidence: 99%

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Role of human Toll‐like receptors in naturally occurring influenza A infections

Lee

Wong

Hui

et al. 2013

Influenza Resp Viruses

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BackgroundWe investigated the roles of Toll‐like receptors (TLRs) in naturally occurring influenza.MethodsA prospective, case – control study was conducted. Adults hospitalized with virologically confirmed influenza A infections (onset <48 hours, before treatment) were compared with age‐/gender‐matched controls. TLRs (2, 3, 4, 7, 8, 9) expression in monocytes and dendritic cells (DCs – total, myeloid, plasmacytoid) was quantitated using flow cytometry. Gene expression of RLRs (RIG‐1, MDA‐5) was evaluated using real‐time PCR. Concomitant signaling molecules expression, plasma cytokine/chemokine concentrations, and respiratory tract viral loads were measured. PBMCs were cultured and stimulated ex vivo with TLR‐specific ligands for cytokine responses.ResultsForty two patients with influenza (24 A/H3N2, 18 A/H1N1pdm09) and 20 controls were studied. Patients' mean age was 68 ± 16 years; 81% had respiratory/cardiovascular complications. There were increased cellular expressions of TLR9, TLR8, TLR3, and TLR7 during influenza; TLR2 and TLR4 were suppressed. Results were similar for both virus strains. Higher TLR expression levels at presentation significantly correlated with lower viral loads (Spearman's rho: −0·46 to −0·69 for TLR9, TLR8, and TLR3; P‐values <0·05). Multivariate regression models (adjusted for age, comorbidity, disease severity, time from onset) confirmed their independent associations. Increased signaling molecules (phospho‐MAPKs, IκB) and inflammatory cytokines (IL‐6, sTNFR‐1, CCL2/MCP‐1; CXCL10/IP‐10, IFN‐γ) correlated with increased TLR expression. RLRs were upregulated simultaneously. PBMCs of patients with influenza showed significant, dynamic changes in their cytokine responses upon TLR stimulation, compared with controls.ConclusionsOur results suggest that TLRs play an important role in early, innate viral inhibition in naturally occurring influenza. Inflammatory cytokine responses are concomitantly induced. These findings support investigation of TLR targeting as a novel intervention approach for prophylaxis against influenza.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Role of human Toll‐like receptors in naturally occurring influenza A infections

Lee

Wong

Hui

et al. 2013

Influenza Resp Viruses

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“…Our findings did not support an association between rs7478728 (25) showed that mice lacking IFITM3 gene display fulminant viral pneumonia following infection with a low-pathogenicity influenza virus. Similarly, in an in vitro study, an increase in viral replication was observed in the absence of IFITM3, and re-introduction of IFITM3 limited the replication of the influenza A virus (25).…”

Section: Discussioncontrasting

confidence: 96%

Evaluation of interferon-induced transmembrane protein-3 (IFITM3) rs7478728 and rs3888188 polymorphisms and the risk of pulmonary tuberculosis

et al. 2016

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Abstract. The current study aimed to examine the possible association between the interferon-induced transmembrane protein-3 (IFITM3) gene polymorphisms and risk of pulmonary tuberculosis (PTB) in a sample population. This case-control study was conducted on 188 PTB patients and 169 healthy subjects. The rs7478728 and rs3888188 variants of IFITM3 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. The findings showed no significant association between rs7478728 polymorphism and risk of PTB. Regarding rs3888188 polymorphism, the TG genotype as well as G allele significantly increased the risk of PTB [odds ratio (OR)=2.48, 95% confidence interval (CI): 1.42-4.53; P=0.002, and OR=2.26, 95% CI: 1.33-3.86; P= 0.003, respectively]. In conclusion, the findings revealed that rs3888188 polymorphism increased the risk of PTB in a sample of Iranian population. Additional investigation with larger sample sizes and different ethnicities are needed to verify our findings. IntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) infection, is a public health problem globally (1,2). According to the WHO report on the worldwide control of TB, approximately 8.6 million new cases occurred in 2012 (3). Although almost 33% of the population is infected with TB, only 5-10% of infected cases develop active TB (3), which suggests a major role of genetic factors in host immunity.Interferon-γ (IFNγ) is produced and released by host cells in response to the presence of numerous pathogens (4). It plays a key role in macrophage activation during MTB infection (5).Individuals defective in the genes for IFNγ or IFNγ receptor (IFNγR) have been indicated to be susceptible for mycobacterial infections including MTB (6). Previously, we showed an association between IFNγ and IFNγR variants and risk of pulmonary TB (PTB) (7,8).Interferon-induced transmembrane protein-3 (IFITM3) is a double transmembrane protein that can be upregulated by IFNs and participates in INF-triggered processes, such as homotypic cell adhesion, anti-proliferative activities in tumor pathogenesis, and the innate immune response to virus infections (9-13). The IFITM3 gene is mapped to an IFITM gene cluster on chromosome 11p15.5 (14). In a genome wide scan, Stein et al (15) identified that one of the TB-linked loci was located in this chromosome region. To the best of our knowledge, there is only one report regarding the impact of IFITM gene polymorphisms on the risk of TB (16). Therefore, the present study aimed to examine the possible associations between polymorphisms of IFITM3 gene and susceptibility to PTB in a sample of Iranian population. Materials and methodsPatients. This case-control study was performed on 188 PTB patients and 169 age-and gender-matched healthy individuals. The enrollment process and study design are described elsewhere (17-23). Briefly, the cases were chosen from PTB patients admitted to a University-Affiliated Hospital (Bou-Ali Hospital, Zahedan, Iran, referral center for TB) with no clinical sy...

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“…Gene-knockout studies, however, revealed that neither Fragilis nor Stella is essential for PGC specification (Payer et al 2003;Lange et al 2008). Instead, Stella has been found to be a critical factor to protect the maternal genome and paternally imprinted genes from genome-wide DNA demethylation that occurs in the zygotes (Nakamura et al 2007), whereas Fragilis has a critical function in restricting the replication of multiple pathogenic viruses including influenza (Brass et al 2009;Everitt et al 2012).…”

mentioning

confidence: 99%

Primordial Germ Cells in Mice

Saitou

Yamaji

2012

Cold Spring Harbor Perspectives in Biology

330

304

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SUMMARYGerm cell development creates totipotency through genetic as well as epigenetic regulation of the genome function. Primordial germ cells (PGCs) are the first germ cell population established during development and are immediate precursors for both the oocytes and spermatogonia. We here summarize recent findings regarding the mechanism of PGC development in mice. We focus on the transcriptional and signaling mechanism for PGC specification, potential pluripotency, and epigenetic reprogramming in PGCs and strategies for the reconstitution of germ cell development using pluripotent stem cells in culture. Continued studies on germ cell development may lead to the generation of totipotency in vitro, which should have a profound influence on biological science as well as on medicine.

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IFITM3 restricts the morbidity and mortality associated with influenza

Cited by 665 publications

References 33 publications

Role of human Toll‐like receptors in naturally occurring influenza A infections

Role of human Toll‐like receptors in naturally occurring influenza A infections

Evaluation of interferon-induced transmembrane protein-3 (IFITM3) rs7478728 and rs3888188 polymorphisms and the risk of pulmonary tuberculosis

Primordial Germ Cells in Mice

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