Distinct Mucoinflammatory Phenotype and the Immunomodulatory Long Noncoding Transcripts Associated with SARS-CoV-2 Airway Infection

Respiratory epithelial cells are the primary target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated the 3D human airway tissue model to evaluate innate epithelial cell responses to SARS-CoV-2 infection. A SARS-CoV-2 clinical isolate productively infected the 3D-airway model with a time-dependent increase in viral load (VL) and concurrent upregulation of airway immunomodulatory factors ( IL-6, ICAM-1 , and SCGB1A1 ) and respiratory mucins ( MUC5AC, MUC5B, MUC2 , and MUC4) , and differential modulation of select long noncoding RNAs (lncRNAs i.e., LASI, TOSL, NEAT1 , and MALAT1 ). Next, we examined these immunomodulators in the COVID-19 patient nasopharyngeal swab samples collected from subjects with high- or low-VLs (∼100-fold difference). As compared to low-VL, high-VL patients had prominent mucoinflammatory signature with elevated expression of IL-6, ICAM-1, SCGB1A1, SPDEF, MUC5AC, MUC5B , and MUC4 . Interestingly, LASI, TOSL , and NEAT1 lncRNA expressions were also markedly elevated in high-VL patients with no change in MALAT1 expression. In addition, dual-staining of LASI and SARS-CoV-2 nucleocapsid N1 RNA showed predominantly nuclear/perinuclear localization at 24 hpi in 3D-airway model as well as in high-VL COVID-19 patient nasopharyngeal cells, which exhibited high MUC5AC immunopositivity. Collectively, these findings suggest SARS-CoV-2 induced lncRNAs may play a role in acute mucoinflammatory response observed in symptomatic COVID-19 patients

Immunomodulatory LncRNA on antisense strand of ICAM-1 augments SARS-CoV-2 infection-associated airway mucoinflammatory phenotype

Noncoding RNAs are important regulators of mucoinflammatory response, but little is known about the contribution of airway long noncoding RNAs (lncRNAs) in COVID-19. RNA-seq analysis showed a more than 4-fold increased expression of IL-6 , ICAM-1 , CXCL-8 , and SCGB1A1 inflammatory factors; MUC5AC and  MUC5B mucins; and SPDEF , FOXA3 , and FOXJ1 transcription factors in COVID-19 patient nasal samples compared with uninfected controls. A lncRNA on antisense strand to ICAM-1 or LASI was induced 2-fold in COVID-19 patients, and its expression was directly correlated with viral loads. A SARS-CoV-2-infected 3D-airway model largely recapitulated these clinical findings. RNA microscopy and molecular modeling indicated a possible interaction between viral RNA and LASI lncRNA. Notably, blocking LASI lncRNA reduced the SARS-CoV-2 replication and suppressed MUC5AC mucin levels and associated inflammation, and select LASI -dependent miRNAs (e.g., let-7b-5p and miR-200a-5p) were implicated. Thus, LASI lncRNA represents an essential facilitator of SARS-CoV-2 infection and associated airway mucoinflammatory response. • COVID19 airway mucoinflammatory response strongly correlates with LASI lncRNA level • Silencing LASI lncRNA suppresses SARS-CoV-2 viral load and associated inflammation • LASI lncRNA shows a potential direct interaction with SARS-CoV-2 spike viral RNA • Hosts of airway epithelial miRNAs are modulated by LASI to regulate inflammation Molecular biology; Molecular mechanism of gene regulation; Immunology; Virolog

HIV-1 Productively Infects and Integrates in Bronchial Epithelial Cells

The role of lung epithelial cells in HIV-1-related lung comorbidities remains unclear, and the major hurdle in curing HIV is the persistence of latent HIV reservoirs in people living with HIV (PLWH). The advent of combined antiretroviral therapy has considerably increased the life span; however, the incidence of chronic lung diseases is significantly higher among PLWH. Lung epithelial cells orchestrate the respiratory immune responses and whether these cells are productively infected by HIV-1 is debatable. Normal human bronchial epithelial cells (NHBEs) grown on air-liquid interface were infected with X4-tropic HIV-1 and examined for latency using latency-reversing agents (LRAs). The role of CD4 and CXCR4 HIV coreceptors in NHBEs were tested, and DNA sequencing analysis was used to analyze the genomic integration of HIV proviral genes, Alu-HIVgag-pol, HIV-nef, and HIV-LTR. Lung epithelial sections from HIV-infected humans and SHIV-infected macaques were analyzed by FISH for HIV-gag-pol RNA and epithelial cell-specific immunostaining. NHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1 in a CXCR4/CD4-dependent manner leading to HIV-p24 antigen production; however, NHBEs are induced to express CCR5 by IL-13 treatment. In the presence of cART, HIV-1 induces latency and integration of HIV provirus in the cellular DNA, which is rescued by the LRAs (endotoxin/vorinostat). Furthermore, lung epithelial cells from HIV-infected humans and SHIV-infected macaques contain HIV-specific RNA transcripts. Thus, lung epithelial cells are targeted by HIV-1 and could serve as potential HIV reservoirs that may contribute to the respiratory comorbidities in PLWH

Discovery of an MLLT1/3 YEATS domain chemical probe

YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small molecule chemical probe, SGC‐iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC‐iMLLT is a potent and selective inhibitor of MLLT1/3 ‐ histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small molecule X‐ray co‐crystal structures with the MLLT1 YD are also reported. This first in class probe molecule can be used to understand MLLT1/3 associated biology and the therapeutic potential of small molecule YD inhibitors

Lessons from the 2018-2019 European droughts: a collective need for unifying drought risk management

Drought events and their impacts vary spatially and temporally due to diverse pedo-climatic and hydrologic conditions, as well as variations in exposure and vulnerability, such as demographics and response actions. While hazard severity and frequency of past drought events have been studied in detail, little is known about the effect of drought management strategies on the actual impacts and how the hazard is perceived by relevant stakeholders. In a continental study, we characterised and assessed the impacts and the perceptions of two recent drought events (2018 and 2019) in Europe and examined the relationship between management strategies and drought perception, hazard, and impact. The study was based on a pan-European survey involving national representatives from 28 countries and relevant stakeholders responding to a standard questionnaire. The survey focused on collecting information on stakeholders' perceptions of drought, impacts on water resources and beyond, water availability, and current drought management strategies on national and regional scales. The survey results were compared with the actual drought hazard information registered by the European Drought Observatory (EDO) for 2018 and 2019. The results highlighted high diversity in drought perception across different countries and in values of the implemented drought management strategies to alleviate impacts by increasing national and sub-national awareness and resilience. The study identifies an urgent need to further reduce drought impacts by constructing and implementing a European macro-level drought governance approach, such as a directive, which would strengthen national drought management and mitigate damage to human and natural assets

Lessons from the 2018-2019 European droughts: a collective need for unifying drought risk management

Drought events and their impacts vary spatially and temporally due to diverse pedo-climatic and hydrologic conditions, as well as variations in exposure and vulnerability, such as demographics and response actions. While hazard severity and frequency of past drought events have been studied in detail, little is known about the effect of drought management strategies on the actual impacts and how the hazard is perceived by relevant stakeholders. In a continental study, we characterised and assessed the impacts and the perceptions of two recent drought events (2018 and 2019) in Europe and examined the relationship between management strategies and drought perception, hazard, and impact. The study was based on a pan-European survey involving national representatives from 28 countries and relevant stakeholders responding to a standard questionnaire. The survey focused on collecting information on stakeholders' perceptions of drought, impacts on water resources and beyond, water availability, and current drought management strategies on national and regional scales. The survey results were compared with the actual drought hazard information registered by the European Drought Observatory (EDO) for 2018 and 2019. The results highlighted high diversity in drought perception across different countries and in values of the implemented drought management strategies to alleviate impacts by increasing national and sub-national awareness and resilience. The study identifies an urgent need to further reduce drought impacts by constructing and implementing a European macro-level drought governance approach, such as a directive, which would strengthen national drought management and mitigate damage to human and natural assets

Simulating crop rotations and management across climatic zones in Europe – an intercomparison study using fifteen models

Process based crop simulation models are widely used to assess crop production under current or future climate conditions. Most studies on climate impacts on crop growth are so far focussed on single crops and single-year simulations. However, it is known that the position of crops within a rotation can influence crop growth significantly due to carry-over effects between seasons. We compared crop models on crop rotation effects from five sites across Central Europe providing in total data of 301 cropping seasons and treatments. Treatments comprised irrigation, nitrogen (N) fertilisation, atmospheric [CO2], tillage, residue management, cover crops and soils. Crop rotations were simulated with 15 crop models as single-year simulations and/or continuous simulations over whole crop rotations in “restricted calibration” runs. Lower RMSE between observed and simulated crop yields were obtained for continuous runs as compared to single-year runs. Relatively low carry-over effects were observed due to equilibration of soil water over winter and high N fertilisation levels. Consistently, a sub-set of models applied to an additional rainfed Mediterranean site reproduced larger carry-over effects of soil water. Irrigation, N supply, cover crops and atmospheric [CO2] showed clearer effects than tillage and crop residue management. Model performance varied distinctly between crops showing the necessity to provide experimental data for model calibration also for less prominent crops