Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex, hospitalization, IgG antibody to SARS-CoV-2 receptor binding domain and C-reactive protein were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters or other biomarkers. Among adults >8 weeks after SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted.
Matthew S. Durstenfeld, Michael J. Peluso, J. Daniel Kelly, Sithu Win, Shreya Swaminathan, Danny Li, Victor M. Arechiga, Victor Antonio Zepeda, Kaiwen Sun, Shirley J. Shao, Christopher Hill, Mireya I. Arreguin, Scott Lu, Rebecca Hoh, Viva W. Tai, Ahmed Chenna, Brandon C. Yee, John W. Winslow, Christos J. Petropoulos, John Kornak, Timothy J. Henrich, Jeffrey N. Martin, Steven G. Deeks, Priscilla Y. Hsue
The ongoing COVID-19 pandemic calls for more effective diagnostic tools. T cell response assessment serves as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, healthy unexposed, and SARS-CoV-2 exposed donors. We identified 75 immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes, and described association with more than one HLA allele for 14 of these. Exclusion of two cross-reactive epitopes that generated a response in pre-pandemic samples, left us with a 73-epitope set that offered excellent diagnostic specificity without losing sensitivity compared to full-length antigens, which evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic ‘Corona-T-test’ which achieved a diagnostic accuracy of 95% in a clinical trial. In a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, we observed a complete absence of T cell response to our epitope panel. In combination with strong reactivity to full-length antigens, this suggests that a cross-reactive response might protect these individuals.
Aleksei Titov, Regina Shaykhutdinova, Olga V. Shcherbakova, Yana V. Serdyuk, Savely A. Sheetikov, Ksenia V. Zornikova, Alexandra V. Maleeva, Alexandra Khmelevskaya, Dmitry V. Dianov, Naina T. Shakirova, Dmitry B. Malko, Maxim Shkurnikov, Stepan Nersisyan, Alexander Tonevitsky, Ekaterina Khamaganova, Anton V. Ershov, Elena Y. Osipova, Ruslan V. Nikolaev, Dmitry E. Pershin, Viktoria A. Vedmedskia, Mikhail Maschan, Victoria R. Ginanova, Grigory A. Efimov
Erythropoietin (EPO) has multiple non-erythropoietic functions including immune modulation, but EPO’s effects in transplantation remain incompletely understood. We tested the mechanisms linking EPO administration to prolongation of murine heterotopic heart transplantation using wild type (WT) and conditional EPO receptor (EPOR) knockout mice as recipients. In WT controls, peri-transplant administration of EPO synergized with CTLA4-Ig to prolong allograft survival (P < 0.001), reduce frequencies of donor-reactive effector CD8+ T cells in the spleen (P < 0.001) and in the graft (P < 0.05), and increase frequencies and total numbers of donor-reactive regulatory T cells (TREG, P < 0.01 for each) vs. CTLA4-Ig alone. Studies performed in conditional EPOR knockout recipients showed that each of these differences required EPOR expression in myeloid cells, but not in T cells. Analysis of mRNA isolated from spleen monocytes showed that EPO/EPOR ligation upregulated macrophage-expressed, anti-inflammatory, regulatory and pro-efferocytosis genes, and downregulated selected pro-inflammatory genes. Together, the data support the conclusion that EPO promotes TREG-dependent murine cardiac allograft survival by crucially altering the phenotype and function of macrophages. Coupled with our previous documentation that EPO promotes TREG expansion in humans, the data support the need for testing the addition of EPO to costimulatory blockade-containing immunosuppression regimens in an effort to prolong human transplant survival.
Julian K. Horwitz, Sofia Bin, Robert L. Fairchild, Karen S, Keslar, Zhengzi Yi, Weijia Zhang, Vasile I. Pavlov, Yansui Li, Joren C. Madsen, Paolo Cravedi, Peter S. Heeger
Hereditary hemorrhagic telangiectasia (HHT) patients have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent study showed that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with decrease in SMCs and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung AVFs with enlarged liver vessels. Evaluation of the retina vessels at post-natal day 5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO vs. WT mice, there was a significant decrease in Tgfb1, Eng and Alk1 expression, phosphorylated-SMAD (pSMAD)1/5/8, with an increase in apoptosis. TGF-β1 stimulated aortic SMCs from Nrp1SM22KO vs. WT mice have decreased pSMAD1/5/8 upon and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In sum, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, pSMAD1/5/8 signaling, and cell death associated with AVM formation.
Sreenivasulu Kilari, Ying Wang, Avishek Singh, Rondell P. Graham, Vivek Iyer, Scott M. Thompson, Michael S. Torbenson, Debabrata Mukhopadhyay, Sanjay Misra
Atrial natriuretic peptide (ANP), encoded by Nppa, is a vasodilatory hormone that promotes salt excretion. Genome-wide association studies identified Nppa as a causative factor of blood pressure development, and in humans, ANP levels were suggested as an indicator of salt sensitivity. This study aimed to provide insights into the effects of ANP on cardiorenal function in salt-sensitive hypertension. To address this question, hypertension was induced in SSNPPA-/- (knockout of Nppa in the Dahl Salt-Sensitive (SS) rat background) or SSWT (wild type Dahl SS) rats by a high salt diet challenge (HS, 4% NaCl for 21 days). Chronic infusion of ANP in SSWT rats attenuated the increase in blood pressure and cardiorenal damage. Overall, SSNPPA-/- strain demonstrated higher blood pressure and intensified cardiac fibrosis (with no changes in ejection fraction) compared to SSWT rats. Furthermore, SSNPPA-/- rats exhibited kidney hypertrophy and higher glomerular injury scores, reduced diuresis, and lower sodium and chloride excretion than SSWT when fed a HS diet. Additionally, the activity of epithelial Na+ channel (ENaC) was found to be increased in the collecting ducts of the SSNPPA-/- rats. Taken together, these data show promise for the therapeutic benefits of ANP and ANP-increasing drugs for treating salt-sensitive hypertension.
Daria V. Ilatovskaya, Vladislav Levchenko, Kristen Winsor, Gregory R. Blass, Denisha R. Spires, Elizaveta Sarsenova, Iuliia Polina, Adrian Zietara, Mark Paterson, Alison J. Kriegel, Alexander Staruschenko
To elicit effective anti-tumor responses, CD8+ T cells need to infiltrate tumors and sustain their effector function within the immunosuppressive tumor microenvironment. Here we evaluate the role of MNK kinase activity in regulating CD8+ T cell infiltration and anti-tumor activity in pancreatic and thyroid tumors. We first show that human pancreatic and thyroid tumors with increased MNK kinase activity are associated with decreased infiltration by CD8+ T cells. We then show that while MNK inhibitors increase CD8+ T cells in these tumors, they induce a T cell exhaustion phenotype in the tumor microenvironment. Mechanistically, we show that the exhaustion phenotype is not caused by upregulation of PD-L1 but by tumor-associated macrophages (TAMs) becoming more immunosuppressive following MNK inhibitor treatment. Reversal of CD8+ T cell exhaustion by an anti-PD-1 antibody or TAM depletion synergizes with MNK inhibitors to control tumor growth and prolong animal survival. Importantly, we show in ex vivo human pancreatic tumor slice cultures that MNK inhibitors increase the expression of markers associated with immunosuppressive TAMs. Together, these findings demonstrate a previously unknown role of MNK kinases in modulating a pro-tumoral phenotype in macrophages and identify combination regimens involving MNK inhibitors to enhance anti-tumor immune responses.
Thao N.D. Pham, Christina Spaulding, Mario A. Shields, Anastasia E. Metropulos, Dhavan N. Shah, Mahmoud G. Khalafalla, Daniel R. Principe, David J. Bentrem, Hidayatullah G. Munshi
Wound repair following acute injury requires a coordinated inflammatory response. Type I interferon (IFN) signaling is important for regulating the inflammatory response post- skin injury. IFN kappa (IFNκ), a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFNκ in the context of normal or dysregulated wound healing is unclear. Here, we found that Infκ expression is upregulated in keratinocytes early post-injury and is essential for normal tissue repair. Under diabetic conditions, IFNκ was decreased in wound keratinocytes, and early inflammation was impaired. Further, we found that the histone methyltransferase MLL1 is upregulated early following injury and regulates Infκ expression in diabetic wound keratinocytes via an H3K4me3 mediated mechanism. Using a series of in vivo studies with a genetically engineered mouse model (Mll1fl/fl K14cre-) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated Infκ and MLL1 is decreased in T2D keratinocytes. Importantly, we find the administration of IFNκ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and re-epithelialization. These findings have significant implications for understanding the complex role type I interferons play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest IFNκ may be a viable therapeutic target to improve diabetic wound repair.
Sonya J. Wolf, Christopher O. Audu, Amrita Joshi, Aaron D. denDekker, William J. Melvin, Frank M. Davis, Xianying Xing, Rachael Wasikowski, Lam Tsoi, Steven Kunkel, Johann E. Gudjonsson, Mary X. O'Riordan, J. Michelle Kahlenberg, Katherine A. Gallagher
Post-exertional malaise (PEM) is a hallmark symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We monitored the evolution of 1,157 plasma metabolites in 60 ME/CFS cases (45 females, 15 males) and in 45 matched healthy control subjects (30 females, 15 males) before and after two maximal Cardiopulmonary Exercise Test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four timepoints allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of ME/CFS cases compared to the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid- as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component to the homeostasis of many organs in the body, including the brain.
Arnaud Germain, Ludovic Giloteaux, Geoffrey E. Moore, Susan M. Levine, John K. Chia, Betsy A. Keller, Jared Stevens, Carl J. Franconi, Xiangling Mao, Dikoma C. Shungu, Andrew Grimson, Maureen R. Hanson
Arterial stiffness predicts cardiovascular disease and all-cause mortality but its treatment remains challenging. Mice treated with angiotensin-II (Ang-II) develop hypertension, arterial stiffness, vascular dysfunction, and a downregulation of Rho-related BTB domain-containing protein 1 (RhoBTB1) in the vasculature. RhoBTB1 is associated with blood pressure regulation but its function is poorly understood. We tested the hypothesis that restoring RhoBTB1 can attenuate arterial stiffness, hypertension, and vascular dysfunction in Ang-II-treated mice. Genetic complementation of RhoBTB1 in the vasculature was achieved utilizing mice expressing a tamoxifen-inducible, smooth muscle-specific RhoBTB1 transgene. RhoBTB1 restoration efficiently and rapidly alleviated arterial stiffness, but not hypertension or vascular dysfunction. Mechanistic studies revealed that RhoBTB1 had no substantial effect on several classical arterial stiffness contributors such as collagen deposition, elastin content, and vascular smooth muscle remodeling. Instead, Ang-II increased actin polymerization in the aorta which was reversed by RhoBTB1. Changes in the levels of two regulators of actin polymerization, Cofilin and Vasodilator Stimulated Phosphoprotein (VASP), in response to RhoBTB1 were consistent with an actin depolymerization mechanism. Our study reveals an important function of RhoBTB1 and demonstrates its vital role in antagonizing established arterial stiffness and further supports a functional and mechanistic separation between hypertension, vascular dysfunction, and arterial stiffness.
Shi Fang, Jing Wu, John J. Reho, Ko-Ting Lu, Daniel T. Brozoski, Gaurav Kumar, Alec M. Werthman, Sebastiao Donato Silva Jr, Patricia C. Muskus Veitia, Kelsey K. Wackman, Angela J Mathison, Bi Qing Teng, Chien-Wei Lin, Frederick W. Quelle, Curt D. Sigmund
The lung airways are constantly exposed to inhaled toxic substances, resulting in cellular damage that is repaired by local expansion of resident bronchiolar epithelial club cells. Disturbed bronchiolar epithelial damage repair lays at the core of many prevalent lung diseases including chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, and lung cancer. However, it is still not known how bronchiolar club cell energy-metabolism contributes to this process. Here we show that Adipose TriGlyceride Lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis, is critical for normal club cell function in mice. Deletion of the gene encoding ATGL, Pnpla2 (Atgl), induced substantial triglyceride accumulation, decreased mitochondrial numbers and decreased mitochondrial respiration in club cells. This defect manifested as bronchiolar epithelial thickening and increased airway resistance under baseline conditions. After naphthalene induced epithelial denudation, a regenerative defect was apparent. Mechanistically, dysfunctional PPARα lipid-signaling underlies this phenotype because, (i) ATGL was needed for PPARα lipid-signalling in regenerating bronchioles, and (ii) administration of the specific PPARα agonist WY14643 restored normal bronchiolar club cell ultrastructure and regenerative potential. Our data emphasize the importance of the cellular energy-metabolism for lung epithelial regeneration and highlight the significance of ATGL mediated lipid catabolism for lung health.
Manu Manjunath Kanti, Isabelle Striessnig-Bina, Beatrix I. Wieser, Silvia Schauer, Gerd Leitinger, Thomas O. Eichmann, Martina Schweiger, Margit Winkler, Elke Winter, Andrea Lana, Iris Kufferath, Leigh M. Marsh, Grazyna Kwapiszewska, Rudolf Zechner, Gerald Hoefler, Paul W. Vesely
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