Roles of vimentin in health and disease

In this review, Ridge et al. discuss the essential functions of vimentin IFs revealed from studies of Vim(-/-) mice and cells derived from them.More than 27 yr ago, the vimentin knockout (Vim(-/-)) mouse was reported to develop and reproduce without an obvious phenotype, implying that this major cytoskeletal protein was nonessential. Subsequently, comprehensive and careful analyses have revealed numerous phenotypes in Vim(-/-) mice and their organs, tissues, and cells, frequently reflecting altered responses in the recovery of tissues following various insults or injuries. These findings have been supported by cell-based experiments demonstrating that vimentin intermediate filaments (IFs) play a critical role in regulating cell mechanics and are required to coordinate mechanosensing, transduction, signaling pathways, motility, and inflammatory responses. This review highlights the essential functions of vimentin IFs revealed from studies of Vim(-/-) mice and cells derived from them

Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection

Influenza A virus (IAV) is among the most common causes of pneumonia-related death worldwide. Pulmonary epithelial cells are the primary target for viral infection and replication and respond by releasing inflammatory mediators that recruit immune cells to mount the host response. Severe lung injury and death during IAV infection result from an exuberant host inflammatory response. The linear ubiquitin assembly complex (LUBAC), composed of SHARPIN, HOIL-1L, and HOIP, is a critical regulator of NF-κB–dependent inflammation. Using mice with lung epithelial–specific deletions of HOIL-1L or HOIP in a model of IAV infection, we provided evidence that, while a reduction in the inflammatory response was beneficial, ablation of the LUBAC-dependent lung epithelial–driven response worsened lung injury and increased mortality. Moreover, we described a mechanism for the upregulation of HOIL-1L in infected and noninfected cells triggered by the activation of type I IFN receptor and mediated by IRF1, which was maladaptive and contributed to hyperinflammation. Thus, we propose that lung epithelial LUBAC acts as a molecular rheostat that could be selectively targeted to modulate the immune response in patients with severe IAV-induced pneumonia.Fil: Brazee, Patricia L.. Northwestern University; Estados UnidosFil: Morales Nebreda, Luisa. Northwestern University; Estados UnidosFil: Magnani, Natalia Daniela. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Garcia, Joe G. N.. University of Arizona; Estados UnidosFil: Misharin, Alexander V.. Northwestern University; Estados UnidosFil: Ridge, Karen M.. Northwestern University; Estados UnidosFil: Budinger, G.R. Scott. Northwestern University; Estados UnidosFil: Iwai, Kazuhiro. Kyoto University; JapónFil: Dada, Laura Andrea. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Sznajder, Jacob I.. Northwestern University; Estados Unido

Targeted deletion of keratin 8 in intestinal epithelial cells disrupts tissue integrity and predisposes to tumorigenesis in the colon

Keratin 8 (K8) is the main intestinal epithelial intermediate filament protein with proposed roles for colonic epithelial cell integrity. Here, we used mice lacking K8 in intestinal epithelial cells (floxed K8 and Villin-Cre1000 and Villin-CreERt2) to investigate the cell-specific roles of intestinal epithelial K8 for colonocyte function and pathologies. Intestinal epithelial K8 deletion decreased K8 partner proteins, K18-K20, 75-95%, and the remaining keratin filaments were located at the colonocyte apical regions with type II K7, which decreased 30%. 2-Deoxy-2-[18F]-fluoroglucose positron emission tomography in vivo imaging identified a metabolic phenotype in the lower gut of the conditional K8 knockouts. These mice developed intestinal barrier leakiness, mild diarrhea, and epithelial damage, especially in the proximal colon. Mice exhibited shifted differentiation from enterocytes to goblet cells, displayed longer crypts and an increased number of Ki67 + transit-amplifying cells in the colon. Significant proproliferative and regenerative signaling occurred in the IL-22, STAT3, and pRb pathways, with minor effects on inflammatory parameters, which, however, increased in aging mice. Importantly, colonocyte K8 deletion induced a dramatically increased sensitivity to azoxymethane-induced tumorigenesis. In conclusion, intestinal epithelial K8 plays a significant role in colonocyte epithelial integrity maintenance, proliferation regulation and tumor suppression.</p

Intimate physical contact between people from different households during the COVID-19 pandemic: a mixed-methods study from a large, quasi-representative survey (Natsal-COVID)

OBJECTIVES: Physical distancing as a non-pharmaceutical intervention aims to reduce interactions between people to prevent SARS-CoV-2 transmission. Intimate physical contact outside the household (IPCOH) may expand transmission networks by connecting households. We aimed to explore whether intimacy needs impacted adherence to physical distancing following lockdown in Britain in March 2020. METHODS: The Natsal-COVID web-panel survey (July-August 2020) used quota-sampling and weighting to achieve a quasi-representative population sample. We estimate reporting of IPCOH with a romantic/sexual partner in the 4 weeks prior to interview, describe the type of contact, identify demographic and behavioural factors associated with IPCOH and present age-adjusted ORs (aORs). Qualitative interviews (n=18) were conducted to understand the context, reasons and decision making around IPCOH. RESULTS: Of 6654 participants aged 18-59 years, 9.9% (95% CI 9.1% to 10.6%) reported IPCOH. IPCOH was highest in those aged 18-24 (17.7%), identifying as gay or lesbian (19.5%), and in steady non-cohabiting relationships (56.3%). IPCOH was associated with reporting risk behaviours (eg, condomless sex, higher alcohol consumption). IPCOH was less likely among those reporting bad/very bad health (aOR 0.54; 95% CI 0.32 to 0.93) but more likely among those with COVID-19 symptoms and/or diagnosis (aOR 1.34; 95% CI 1.10 to 1.65). Two-thirds (64.4%) of IPCOH was reported as being within a support bubble. Qualitative interviews found that people reporting IPCOH deliberated over, and made efforts to mitigate, the risks. CONCLUSIONS: Given 90% of people did not report IPCOH, this contact may not be a large additional contributor to SARS-CoV-2 transmission, although heterogeneity exists within the population. Public health messages need to recognise how single people and partners living apart balance sexual intimacy and relationship needs with adherence to control measures

Cytoplasmic keratins couple with and maintain nuclear envelope integrity in colonic epithelial cells

Keratin intermediate filaments convey mechanical stability and protection against stress to epithelial cells. Keratins are essential for colon health, as seen in keratin 8 knockout (K8−/−) mice exhibiting a colitis phenotype. We hypothesized that keratins support the nuclear envelope and lamina in colonocytes. K8−/− colonocytes in vivo exhibit significantly decreased levels of lamins A/C, B1, and B2 in a colon-specific and cell-intrinsic manner. CRISPR/Cas9- or siRNA-mediated K8 knockdown in Caco-2 cells similarly decreased lamin levels, which recovered after reexpression of K8 following siRNA treatment. Nuclear area was not decreased, and roundness was only marginally increased in cells without K8. Down-regulation of K8 in adult K8flox/flox;Villin-CreERt2 mice following tamoxifen administration significantly decreased lamin levels at day 4 when K8 levels had reduced to 40%. K8 loss also led to reduced levels of plectin, LINC complex, and lamin-associated proteins. While keratins were not seen in the nucleoplasm without or with leptomycin B treatment, keratins were found intimately located at the nuclear envelope and complexed with SUN2 and lamin A. Furthermore, K8 loss in Caco-2 cells compromised nuclear membrane integrity basally and after shear stress. In conclusion, colonocyte K8 helps maintain nuclear envelope and lamina composition and contributes to nuclear integrity.</p

Future research directions in pneumonia

Copyright © 2018 by the American Thoracic Society. Pneumonia is a complex pulmonary disease in need of new clinical approaches. Although triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune resistance and tissue resilience then dictate whether and how pneumonia progresses or resolves. Inadequate or inappropriate host responses lead to more severe outcomes such as acute respiratory distress syndrome and to organ dysfunction beyond the lungs and over extended time frames after pathogen clearance, some of which increase the risk for subsequent pneumonia. Improved understanding of such host responses will guide the development of novel approaches for preventing and curing pneumonia and for mitigating the subsequent pulmonary and extrapulmonary complications of pneumonia. The NHLBI assembled a working group of extramural investigators to prioritize avenues of host-directed pneumonia research that should yield novel approaches for interrupting the cycle of unhealthy decline caused by pneumonia. This report summarizes the working group’s specific recommendations in the areas of pneumonia susceptibility, host response, and consequences. Overarching goals include the development of more host-focused clinical approaches for preventing and treating pneumonia, the generation of predictive tools (for pneumonia occurrence, severity, and outcome), and the elucidation of mechanisms mediating immune resistance and tissue resilience in the lung. Specific areas of research are highlighted as especially promising for making advances against pneumonia

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Role and regulation of the Na,K-ATPase in the alveolar epithelium.

Role and regulation of the Na,K-ATPase in the alveolar epithelium