Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections

Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance.

Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.Support was provided by the Wellcome Trust (A.C.H., J.L.H., G.R) and Cancer Research UK (A.C.H.), Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust (L.A.-D.; A.C.H.); Marie Curie and EMBO fellowships (M.S.).This is the final published version. It first appeared at http://www.nature.com/ncomms/2015/150519/ncomms8090/full/ncomms8090.html

Constituting Citizenship Through the Emotions: Singaporean Transmigrants in London

10.1080/00045600903102857Annals of the Association of American Geographers994788-80

The Cytoplasmic Location of Chicken Mx Is Not the Determining Factor for Its Lack of Antiviral Activity

Chicken Mx belongs to the Mx family of interferon-induced dynamin-like GTPases, which in some species possess potent antiviral properties. Conflicting data exist for the antiviral capability of chicken Mx. Reports of anti-influenza activity of alleles encoding an Asn631 polymorphism have not been supported by subsequent studies. The normal cytoplasmic localisation of chicken Mx may influence its antiviral capacity. Here we report further studies to determine the antiviral potential of chicken Mx against Newcastle disease virus (NDV), an economically important cytoplasmic RNA virus of chickens, and Thogoto virus, an orthomyxovirus known to be exquisitely sensitive to the cytoplasmic MxA protein from humans. We also report the consequences of re-locating chicken Mx to the nucleus.Chicken Mx was tested in virus infection assays using NDV. Neither the Asn631 nor Ser631 Mx alleles (when transfected into 293T cells) showed inhibition of virus-directed gene expression when the cells were subsequently infected with NDV. Human MxA however did show significant inhibition of NDV-directed gene expression. Chicken Mx failed to inhibit a Thogoto virus (THOV) minireplicon system in which the cytoplasmic human MxA protein showed potent and specific inhibition. Relocalisation of chicken Mx to the nucleus was achieved by inserting the Simian Virus 40 large T antigen nuclear localisation sequence (SV40 NLS) at the N-terminus of chicken Mx. Nuclear re-localised chicken Mx did not inhibit influenza (A/PR/8/34) gene expression during virus infection in cell culture or influenza polymerase activity in A/PR/8/34 or A/Turkey/50-92/91 minireplicon systems.The chicken Mx protein (Asn631) lacks inhibitory effects against THOV and NDV, and is unable to suppress influenza replication when artificially re-localised to the cell nucleus. Thus, the natural cytoplasmic localisation of the chicken Mx protein does not account for its lack of antiviral activity

Disability activism and the politics of scale

In this paper, we examine the role of spatial scale in mediating and shaping political struggles between disabled people and the state. Specifically, we draw on recent theoretical developments concerning the social construction of spatial scale to interpret two case studies of disability activism within Canada and Ireland. In particular, we provide an analysis of how successful the disability movement in each locale has been at 'jumping scale' and enacting change, as well as examining what the consequences of such scaling-up have been for the movement itself. We demonstrate that the political structures operating in each country markedly affect the scaled nature of disability issues and the effectiveness of political mobilization at different scales

Postcolonial manifestations of African spatiality in Europe : the invisible 'public' spaces of Ghent

The focus of this chapter is on everyday spaces of African migration in the mid-sized city of Ghent. One manifestation of African spatiality is discussed in-depth in relation to its (in)visibility and publicity: an African shop located in an ordinary terraced house. With no less than 12 activities taking place in the building, the shop is rather a “public” place than solely a space of commercial transactions, although this is not signaled in very visible ways. By analyzing the modest stylistic appropriations of the façade and the significant re-arrangements of the buildings’ interior spaces that challenge more conventional usages of spaces in Ghent’s ordinary houses, this chapter puts this African shop to the fore as emblematic of how the process of materialization of transnational lifestyles and connections is always a balancing act between the visibility necessary for functioning as a (semi-)pubic place and the invisibility required to circumvent hegemonic regulatory regimes

The Role of Host Genetics in Susceptibility to Influenza: A Systematic Review

Background: The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380). Methods and Findings: PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven. Conclusion: The fundamental question ‘‘Is susceptibility to severe influenza in humans heritable?’ ’ remains unanswered. No

Evolutionary Repercussions of Avian Culling on Host Resistance and Influenza Virulence

Keeping pandemic influenza at bay is a global health priority. Of particular concern is the continued spread of the influenza subtype H5N1 in avian populations and the increasing frequency of transmission to humans. To decrease this threat, mass culling is the principal strategy for eradicating influenza in avian populations. Although culling has a crucial short-term epidemiological benefit, evolutionary repercussions on reservoir hosts and on the viral population have not been considered.To explore the epidemiological and evolutionary repercussions of mass avian culling, we combine population genetics and epidemiological influenza dynamics in a mathematical model parameterized by clinical, epidemiological, and poultry data. We model the virulence level of influenza and the selection on a dominant allele that confers resistance against influenza [1, 2] in a poultry population. Our findings indicate that culling impedes the evolution of avian host resistance against influenza. On the pathogen side of the coevolutionary race between pathogen and host, culling selects for heightened virulence and transmissibility of influenza.Mass culling achieves a short-term benefit at the expense of long-term detriments: a more genetically susceptible host population, ultimately greater mortality, and elevated influenza virulence