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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Host genetics and gut microbiota composition: Baseline gut microbiota composition as a possible prognostic factor for the severity of COVID-19 in patients with familial Mediterranean fever disease

It is known that the gut microbiome of a healthy person affects the process of COVID-19 after getting infected with SARS-CoV-2 virus. It is also believed that colchicine can alleviate the severity of COVID-19. Current investigations aimed to evaluate the associations between the baseline gut microbiota composition of healthy and Familial Mediterranean fever (FMF) - carrier Armenian men populations, and the severity of the COVID-19 disease after their infection with the SARS-CoV-2. The study has a purpose of answering three core questions: i. Do the characteristics of gut microbiome of Armenians affect the course of COVID-19 severity? ii. How does the COVID-19 disease course on go for FMF patients who have been taking colchicine as a medication over the years after getting infected with SARS-CoV-2? iii. Is there an initial gut micribiota structure pattern for non-FMF and FMF patients in the cases when COVID-19 appears in mild form? The gut microbiota composition in non-FMF and FMF patients before the first infection (mild and moderate course of COVID-19) was considered. COVID-19 was diagnosed by SARS-CoV-2 nucleic acid RT-PCR in nasopharyngeal swab and/or sputum. The number of patients with male FMF with mild COVID-19 was approximately two times higher than that of non-FMF male subjects with COVID-19. In addition, an association of COVID-19 disease severity with the baseline gut Prevotella, Clostridium hiranonis, Eubacterium biforme, Veillonellaceae, Coprococcus, and Blautia diversities in the non-FMF and FMF populations were revealed by us, which can be used as risk/prognostic factor for the severity of COVID-19.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.

MERS-CoV↗
DOE OSTI2021

Radiation Toxicity in Patients With Collagen Vascular Disease: A Meta-Analysis of Case-Control Studies

Several retrospective series have reported that patients with collagen vascular disease (CVD) are at increased risk of radiation (RT) toxicity. However, the evidence is mixed, and many series lack control groups. We performed a meta-analysis including only case-cohort or randomized studies that examined the risk of RT toxicity for patients with CVD compared with controls.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis

Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent results have shown that HNF4a defective function and systemic inflammation are major disease drivers of AH. Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein an integrative analysis of hepatic RNAseq and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to identify plasma protein signatures for mild and severe AH patients. Alcohol-related liver disease cirrhosis (ALD)(AC), non-alcoholic fatty liver disease (NALFD), and healthy subjects (HC) were used as comparator groups. Identified proteins primarily involved in hepatocellular function were decreased in AH patients which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators. A protein signature of AH disease severity was identified including thrombin (THRB), hepatocyte growth factor alpha (HGFA), clusterin (CLUS), human serum factor H-related protein (FHR1) and kallistatin (KAIN), which exhibited large abundance shifts between severe and non-severe AH. The combination of THRB and HGFA discriminated between severe and non-severe AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions. This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

The Prediction Model of Risk Factors for COVID-19 Developing into Severe Illness Based on 1046 Patients with COVID-19

This study analyzed the risk factors for patients with COVID-19 developing severe illnesses and explored the value of applying the logistic model combined with ROC curve analysis to predict the risk of severe illnesses at COVID-19 patients’ admissions. The clinical data of 1046 COVID-19 patients admitted to a designated hospital in a certain city from July to September 2020 were retrospectively analyzed, the clinical characteristics of the patients were collected, and a multivariate unconditional logistic regression analysis was used to determine the risk factors for severe illnesses in COVID-19 patients during hospitalization. Based on the analysis results, a prediction model for severe conditions and the ROC curve were constructed, and the predictive value of the model was assessed. Logistic regression analysis showed that age (OR = 3.257, 95% CI 10.466–18.584), complications with chronic obstructive pulmonary disease (OR = 7.337, 95% CI 0.227–87.021), cough (OR = 5517, 95% CI 0.258–65.024), and venous thrombosis (OR = 7322, 95% CI 0.278–95.020) were risk factors for COVID-19 patients developing severe conditions during hospitalization. When complications were not taken into consideration, COVID-19 patients’ ages, number of diseases, and underlying diseases were risk factors influencing the development of severe illnesses. The ROC curve analysis results showed that the AUC that predicted the severity of COVID-19 patients at admission was 0.943, the optimal threshold was −3.24, and the specificity was 0.824, while the sensitivity was 0.827. The changes in the condition of severe COVID-19 patients are related to many factors such as age, clinical symptoms, and underlying diseases. This study has a certain value in predicting COVID-19 patients that develop from mild to severe conditions, and this prediction model is a useful tool in the quick prediction of the changes in patients’ conditions and providing early intervention for those with risk factors.

Lian, Zhichuang↗
DOE OSTI2024

The Exoproteome and Surfaceome of Toxigenic Corynebacterium diphtheriae 1737 and Its Response to Iron Restriction and Growth on Human Hemoglobin

Toxin-producing Corynebacterium diphtheriae strains are the etiological agents of the severe upper respiratory disease, diphtheria. A global phylogenetic analysis revealed that biotype gravis is particularly lethal as it produces diphtheria toxin and a range of other virulence factors, particularly when it encounters low levels of iron at sites of infection. Here, to gain insight into how it colonizes its host, we have identified iron-dependent changes in the exoproteome and surfaceome of C. diphtheriae strain 1737 using a combination of whole-cell fractionation, intact cell surface proteolysis, and quantitative proteomics. In total, we identified 1414 of the predicted 2265 proteins (62%) encoded by its reference genome. For each protein, we quantified its degree of secretion and surface exposure, revealing that exoproteases and hydrolases predominate in the exoproteome, while the surfaceome is enriched with adhesins, particularly DIP2093. Our analysis provides insight into how components in the heme-acquisition system are positioned, showing pronounced surface exposure of the strain-specific ChtA/ChtC paralogues and high secretion of the species-conserved heme-binding HtaA protein, suggesting it functions as a hemophore. Profiling the response of the exoproteome and surfaceome after microbial exposure to human hemoglobin and iron limitation reveals potential virulence factors that may be expressed at sites of infection. Data are available via ProteomeXchange with identifier PXD051674.

cell envelope↗
DOE OSTI2022

Tea consumption and risk of bladder cancer in the Bladder Cancer Epidemiology and Nutritional Determinants (BLEND) Study: Pooled analysis of 12 international cohort studies

Tea has been shown to be associated with reduced risk of several diseases including cardiovascular diseases, stroke, metabolic syndrome, and obesity. However, the results on the relationship between tea consumption and bladder cancer are conflicting. This research aimed to assess the association between tea consumption and risk of bladder cancer using a pooled analysis of prospective cohort data. Individual data from 532,949 participants in 12 cohort studies, were pooled for analyses. Cox regression models stratified by study centre was used to estimate hazard ratios (HR) and corresponding 95% CIs. Fractional polynomial regression models were used to examine the dose–response relationship. A higher level of tea consumption was associated with lower risk of bladder cancer incidence (compared with no tea consumption: HR = 0.87, 95% C.I. = 0.77–0.98 for low consumption; HR = 0.86, 95% C.I. = 0.77–0.96 for moderate consumption; HR = 0.84, 95% C.I. = 0.75–0.95 for high consumption). When stratified by sex and smoking status, this reduced risk was statistically significant among men and current and former smokers. In addition, dose–response analyses showed a lower bladder cancer risk with increment of 100 ml of tea consumption per day (HR-increment = 0.97; 95% CI = 0.96–0.98). A similar inverse association was found among males, current and former smokers while never smokers and females showed non-significant results, suggesting potential sex-dependent effect. Higher consumption of tea is associated with reduced risk of bladder cancer with potential interaction with sex and smoking status. Further studies are needed to clarify the mechanisms for a protective effect of tea (e.g. inhibition of the survival and proliferation of cancer cells and anti-inflammatory mechanisms) and its interaction with smoking and sex.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2003

Resistance of virus to extinction on bottleneck passages: study of a decaying and fluctuating pattern of fitness loss

RNA viruses display high mutation rates and their populations replicate as dynamic and complex mutant distributions, termed viral quasispecies. Repeated genetic bottlenecks, which experimentally are carried out through serial plaque-to-plaque transfers of the virus, lead to fitness decrease (measured here as diminished capacity to produce infectious progeny). Here we report an analysis of fitness evolution of several low fitness foot-and-mouth disease virus clones subjected to 50 plaque-to-plaque transfers. Unexpectedly, fitness decrease, rather than being continuous and monotonic, displayed a fluctuating pattern, which was influenced by both the virus and the state of the host cell as shown by effects of recent cell passage history. The amplitude of the fluctuations increased as fitness decreased, resulting in a remarkable resistance of virus to extinction. Whereas the frequency distribution of fitness in control (independent) experiments follows a log-normal distribution, the probability of fitness values in the evolving bottlenecked populations fitted a Weibull distribution. We suggest that multiple functions of viral genomic RNA and its encoded proteins, subjected to high mutational pressure, interact with cellular components to produce this nontrivial, fluctuating pattern.

Serial Passage↗
DOE OSTI2025

Feed status and skin injury modulate immunopathology, global gene expression, and survival in channel catfish during virulent Aeromonas hydrophila infection

Introduction VirulentAeromonas hydrophilais a major pathogen in channel catfish (Ictalurus punctatus), that causes motileAeromonassepticemia and significant economic losses. We investigated the effect of feeding status and skin integrity on the host immune response, disease survival, and gastrointestinal pathology following a vAh challenge. Methods Using a bath immersion model, channel catfish were divided into four treatment groups: fin clipped and fed (FCF), fin clipped but not fed (FCN), not fin clipped but fed (NCF), and not fin clipped nor fed (NCN) alongside non-challenged control groups The FCF and NCF groups were fed 2 h prior to the challenge, but the FCN and NCN groups were not. Survival analysis, histopathological assessment, and RNA sequencing were conducted across groups at different time intervals throughout the vAh challenge. Results Survival rates were lowest in the FCF and FCN groups (30% and 23% survival, respectively), suggesting that both feeding and skin damage contributed to disease severity. Histopathological analyses revealed more severe intestinal and gastric lesions in fed groups, characterized by epithelial necrosis, hemorrhage, and edema. Transcriptomic analysis among the groups identified significant differentially expressed genes associated with inflammation, apoptosis, and metabolic stress, with notable upregulation of interleukin 1-beta (il-1β), and complement C3 (c3). Gene ontology enrichment highlighted distinct immune activation patterns between fed and unfed groups, with enhanced pathogen recognition and pro-inflammatory responses in unfed fish. Discussion These findings suggest feeding prior to infection may exacerbate disease pathology, potentially by creating a physiological state conducive to facilitate pathogen proliferation and dampened early immune responses, whereas short-term fasting appears to promote early immune activation. This study provides novel insights into the complex interplay between feed status, physical injury, and immune response to vAh infection.

Immunology↗
DOE OSTI2021

Image-Based Methods to Score Fungal Pathogen Symptom Progression and Severity in Excised Arabidopsis Leaves

Image-based symptom scoring of plant diseases is a powerful tool for associating disease resistance with plant genotypes. Advancements in technology have enabled new imaging and image processing strategies for statistical analysis of time-course experiments. There are several tools available for analyzing symptoms on leaves and fruits of crop plants, but only a few are available for the model plant Arabidopsis thaliana (Arabidopsis). Arabidopsis and the model fungus Botrytis cinerea (Botrytis) comprise a potent model pathosystem for the identification of signaling pathways conferring immunity against this broad host-range necrotrophic fungus. Here, we present two strategies to assess severity and symptom progression of Botrytis infection over time in Arabidopsis leaves. Thus, a pixel classification strategy using color hue values from red-green-blue (RGB) images and a random forest algorithm was used to establish necrotic, chlorotic, and healthy leaf areas. Secondly, using chlorophyll fluorescence (ChlFl) imaging, the maximum quantum yield of photosystem II (Fv/Fm) was determined to define diseased areas and their proportion per total leaf area. Both RGB and ChlFl imaging strategies were employed to track disease progression over time. This has provided a robust and sensitive method for detecting sensitive or resistant genetic backgrounds. A full methodological workflow, from plant culture to data analysis, is described.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Identification and mapping of quantitative trait loci for Fusarium head blight resistance in a synthetic hexaploid × hard red spring wheat population

Abstract Fusarium head blight (FHB), caused byFusarium graminearumSchwabe, is one of the most devastating diseases in wheat (Triticum aestivumL.). The synthetic hexaploid wheat line Largo was developed from a cross between the durum wheat [T. turgidumssp.durum(Desf.) Husn.] variety Langdon and theAegilops tauschiiCosson accession PI 268210, and it was previously found to have a moderate level of FHB resistance. This study was conducted to identify quantitative trait loci (QTL) associated with FHB resistance using a population of 188 recombinant inbred lines (RILs) from a cross between Largo and the susceptible wheat line ND495. The RILs were evaluated for Type II resistance in two greenhouse and two field environments. The disease severity and 90K single‐nucleotide polymorphism marker data were used for QTL analysis, which revealed six QTL on chromosomes 1D, 2D, 5B, and 7D. Four QTL (QFhb.rwg‐1D,QFhb.rwg‐5B,QFhb.rwg‐7D.1, andQFhb.rwg‐7D.3) from Largo had minor effects, whereas two QTL (QFhb.rwg‐2DandQFhb.rwg‐7D.2) from ND495 showed large effects on FHB resistance. The result suggested that ND495 may possess suppressor or susceptibility gene(s) suppressing or masking FHB resistance controlled by the resistance QTL. Among these QTL, four coincided with previously reported QTL, includingFhb9, and two (QFhb.rwg‐1DandQFhb.rwg‐7D.1) are likely novel QTL. From the six QTL regions, 10 Kompetitive allele‐specific PCR markers were developed and validated for marker‐assisted selection. The QTL detected from the resistant and susceptible parents enhance our understanding of FHB resistance expression and provide new resources for improving FHB resistance in wheat.

Genetics & Heredity↗
DOE OSTI2021

Pristane promotes anaerobic glycolysis to facilitate proinflammatory activation of macrophages and development of arthritis

Highlights: • Pristane-induced arthritis is dependent on macrophages with M1 phenotype. • Pristane causes mitochondrial dysfunction and metabolic abnormalities in macrophages. • Macrophages treated by pristane show increased glycolysis flux and enzyme activity. • Metabolic reprogramming of macrophages controls M1 polarization and arthritis. Pristane-induced arthritis (PIA) could be adoptively transferred by splenic T cells in rats, and innate immunity should play critical roles in T cell activation. However, in pre-clinical stage, the activation mechanism of innate cells like macrophages remains unclear. Here we found that PIA was dependent on macrophages since cell depletion alleviated disease severity. Splenic macrophages of PIA rats showed M1 phenotypic shifting. The quantitative proteomics analysis suggested that macrophages initiated metabolic reprogramming with the conversion of aerobic oxidation to glycolysis in response to pristane in vivo. Notably, macrophages treated with pristane showed mitochondrial dysregulation and increased glycolysis flux and enzyme activity. Additionally, TNFα production, strongly associating with the glycolysis enzyme Ldha/Ldhb, could be reduced as glycolysis was inhibited or be enhanced as citrate cycle was blocked. This work provides detailed insights into the molecular mechanisms of pristane-mediated metabolic reprogramming in macrophages and suggests a new therapeutic strategy for arthritic disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Transcriptomic Analysis of Arachidonic Acid Pathway Genes Provides Mechanistic Insight into Multi-Organ Inflammatory and Vascular Diseases

Arachidonic acid (AA) metabolites have been associated with several diseases across various organ systems, including the cardiovascular, pulmonary, and renal systems. Lipid mediators generated from AA oxidation have been studied to control macrophages, T-cells, cytokines, and fibroblasts, and regulate inflammatory mediators that induce vascular remodeling and dysfunction. AA is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) to generate anti-inflammatory, pro-inflammatory, and pro-resolutory oxidized lipids. As comorbid states such as diabetes, hypertension, and obesity become more prevalent in cardiovascular disease, studying the expression of AA pathway genes and their association with these diseases can provide unique pathophysiological insights. In addition, the AA pathway of oxidized lipids exhibits diverse functions across different organ systems, where a lipid can be both anti-inflammatory and pro-inflammatory depending on the location of metabolic activity. Therefore, we aimed to characterize the gene expression of these lipid enzymes and receptors throughout multi-organ diseases via a transcriptomic meta-analysis using the Gene Expression Omnibus (GEO) Database. In our study, we found that distinct AA pathways were expressed in various comorbid conditions, especially those with prominent inflammatory risk factors. Comorbidities, such as hypertension, diabetes, and obesity appeared to contribute to elevated expression of pro-inflammatory lipid mediator genes. Our results demonstrate that expression of inflammatory AA pathway genes may potentiate and attenuate disease; therefore, we suggest further exploration of these pathways as therapeutic targets to improve outcomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A simple model of COVID-19 explains disease severity and the effect of treatments

Abstract Considerable effort has been made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue by focusing on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation, identifying the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and reveal conditions that can increase the likelihood of desired clinical outcome from treatment administration. In particular, the analysis suggest that antivirals need to be administered early during infection to have an impact on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Image-based time series analysis to establish differential disease progression for two Fusarium head blight pathogens in oat spikelets with variable resistance

Oat-based value-added products have increased their value as healthy foodstuff. Fusarium head blight (FHB) infections and the mycotoxins accumulated to the oat seeds, however, pose a challenge to oat production. The FHB infections are predicted to become more prevalent in the future changing climates and under more limited use of fungicides. Both these factors increase the pressure for breeding new resistant cultivars. Until now, however, genetic links in oats against FHB infection have been difficult to identify. Therefore, there is a great need for more effective breeding efforts, including improved phenotyping methods allowing time series analysis and the identification of molecular markers during disease progression. To these ends, dissected spikelets of several oat genotypes with different resistance profiles were studied by image-based methods during disease progression by Fusarium culmorum or F. langsethiae species. The chlorophyll fluorescence of each pixel in the spikelets was recorded after inoculation by the two Fusarium spp., and the progression of the infections was analyzed by calculating the mean maximum quantum yield of PSII (F v /F m ) values for each spikelet. The recorded values were (i) the change in the photosynthetically active area of the spikelet as percentage of its initial size, and (ii) the mean of F v /F m values of all fluorescent pixels per spikelet post inoculation, both indicative of the progression of the FHB disease. The disease progression was successfully monitored, and different stages of the infection could be defined along the time series. The data also confirmed the differential rate of disease progression by the two FHB causal agents. In addition, oat varieties with variable responses to the infections were indicated.

oats↗
NASA NTRS2016

Femoral Head Bone Loss Following Short and Long-Duration Spaceflight

Exposure to mechanical unloading during spaceflight is known to have significant effects on the musculoskeletal system. Our ongoing studies with the mouse bone model have identified the failure of normal stem cell-based tissue regeneration, in addition to tissue degeneration, as a significant concern for long-duration spaceflight, especially in the mesenchymal and hematopoietic tissue lineages. The 30-day BionM1 and the 37-day Rodent Research 1 (RR1) missions enabled the possibility of studying these effects in long-duration microgravity experiments. We hypothesized that the inhibition of stem cell-based tissue regeneration in short-duration spaceflight would continue during long-duration spaceflight and furthermore would result in significant tissue alterations. MicroCT analysis of BionM1 femurs revealed 31% decrease in bone volume ratio, a 14% decrease in trabecular thickness, and a 20% decrease in trabecular number in the femoral head of space-flown mice. Furthermore, high-resolution MicroCT and immunohistochemical analysis of spaceflight tissues revealed a severe disruption of the epiphyseal boundary, resulting in endochondral ossification of the femoral head and perforation of articular cartilage by bone. This suggests that spaceflight in microgravity may cause rapid induction of an aging-like phenotype with signs of osteoarthritic disease in the hip joint. However, mice from RR1 exhibited significant bone loss in the femoral head but did not exhibit the severe aging and disease-like phenotype observed during BionM1.This may be due to increased physical activity in the RH hardware. Immunohistochemical analysis of the epiphyseal plate and investigation of cellular proliferation and differentiation pathways within the marrow compartment and whole bone tissue is currently being conducted to determine alterations in stem cell-based tissue regeneration between these experiments. Our results show that the observed inhibition of stem cell-based tissue regeneration persists during long-duration spaceflight. Furthermore, spaceflight femurs from BionM1 indicate onset of an accelerated aging-like phenotype with signs of osteoarthritic disease shown by disruption of the epiphyseal boundary and endochondral ossification. These effects are likely caused by a failure of stem cells to regenerate degraded tissues and may have significant implications for bone and cartilage health following extensive periods of mechanical unloading during long-duration spaceflight.

microgravity↗
DOE OSTI2022

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (n rs495828 = 53 and n rs505922 = 59); strongest association with venous embolism, odds ratio (OR rs495828 1.33 (p = 1.32 x 10 –199 ), and thrombosis OR rs505922 1.33, p = 2.2 x10 -265 . Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10 –191 ; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10 –12 . The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10 -23 , lupus OR 0.84, p = 3.97 x 10 –06 . PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10 –13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2016

Femoral Head Bone Loss Following Short and Long-Duration Spaceflight

Exposure to mechanical unloading during spaceflight is known to have significant effects on the musculoskeletal system. Our ongoing studies with the mouse bone model have identified the failure of normal stem cell-based tissue regeneration, in addition to tissue degeneration, as a significant concern for long-duration spaceflight, especially in the mesenchymal and hematopoietic tissue lineages. The 30-day BionM1 and the 37-day Rodent Research 1 (RR1) missions enabled the possibility of studying these effects in long-duration microgravity experiments. We hypothesized that the inhibition of stem cell-based tissue regeneration in short-duration spaceflight would continue during long-duration spaceflight and furthermore would result in significant tissue alterations. MicroCT analysis of BionM1 femurs revealed 31 decrease in bone volume ratio, a 14 decrease in trabecular thickness, and a 20 decrease in trabecular number in the femoral head of space-flown mice. Furthermore, high-resolution MicroCT and immunohistochemical analysis of spaceflight tissues revealed a severe disruption of the epiphyseal boundary, resulting in endochondral ossification of the femoral head and perforation of articular cartilage by bone. This suggests that spaceflight in microgravity may cause rapid induction of an aging-like phenotype with signs of osteoarthritic disease in the hip joint. However, mice from RR1 exhibited significant bone loss in the femoral head but did not exhibit the severe aging and disease-like phenotype observed during BionM1. This may be due to increased physical activity in the RH hardware. Immunohistochemical analysis of the epiphyseal plate and investigation of cellular proliferation and differentiation pathways within the marrow compartment and whole bone tissue is currently being conducted to determine alterations in stem cell-based tissue regeneration between these experiments. Our results show that the observed inhibition of stem cell-based tissue regeneration persists during long-duration spaceflight. Furthermore, spaceflight femurs from BionM1 indicate onset of an accelerated aging-like phenotype with signs of osteoarthritic disease shown by disruption of the epiphyseal boundary and endochondral ossification. These effects are likely caused by a failure of stem cells to regenerate degraded tissues and may have significant implications for bone and cartilage health following extensive periods of mechanical unloading during long-duration spaceflight.

stem cells↗