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SARS-CoV-2 proteins

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    SARS-CoV-2 Vaccines Elicit Durable Immune Responses in Infant Rhesus Macaques

    Authors: Carolina Garrido Garrado; Alan D Curtis; Maria Dennis; Sachi H Pathak; Hongmei Gao; David Montefiori; Mark Tomai; Christopher B Fox; Pamela A Kozlowski; Trevor Scobey; Jennifer E Munt; Michael L Mallory; Pooja T Saha; Michael G Hudgens; Lisa C Lindesmith; Ralph S. Baric; Olubukola M Abiona; Kizzmekia S Corbett; Darin Edwards; Andrea Carfi; Genevieve Fouda; Koen K. A. Van Rompay; Kristina De Paris; Sallie R Permar

    doi:10.1101/2021.04.05.438479 Date: 2021-04-06 Source: bioRxiv

    Early life SARS-CoV-2 vaccination has the potential to provide lifelong protection and achieve herd immunity. To evaluate SARS-CoV-2 infant vaccination, we immunized two groups of 8 infant rhesus macaques (RMs) at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein PROTEIN, either encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or mixed with 3M-052-SE, a TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. High magnitude S-binding IgG and neutralizing infectious dose 50 (ID50) >103 were elicited by both vaccines. S-specific T cell responses were dominated by IL-17 HGNC, IFN-g HGNC, or TNF-a HGNC. Antibody and cellular responses were stable through week 22. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines are promising pediatric SARS-CoV-2 vaccine candidates to achieve durable protective immunity.

    Genetic variability associated with OAS1 HGNC expression in myeloid cells increases the risk of Alzheimer's disease MESHD and severe COVID-19 MESHD outcomes

    Authors: Naciye Magusali; Andrew C Graham; Thomas M Piers; Pantila Panichnantakul; Umran Yaman; Maryam Shoai; Regina H Reynolds; Juan A. Botia; Keeley J Brookes; Tamar Guetta-Baranes; Eftychia Bellou; Sevinc Bayram; Dimitra Sokolova; Mina Ryten; Carlo Sala Frigerio; Valentina Escott-Price; Kevin Morgan; Jennifer M Pocock; John Hardy; Dervis A Salih

    doi:10.1101/2021.03.16.435702 Date: 2021-03-18 Source: bioRxiv

    Genome-wide association studies of late-onset Alzheimer's disease MESHD ( AD MESHD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD MESHD. Recently, we and others have shown that genes associated with variants that confer risk for AD MESHD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. This allowed us to predict new risk genes for AD MESHD, including the interferon-responsive oligoadenylate synthetase 1 ( OAS1 HGNC). However, the function of OAS1 HGNC within microglia and its genetic pathway are not known. Using genotyping from 1,313 individuals with sporadic AD MESHD and 1,234 control individuals, we confirm that the OAS1 HGNC variant, rs1131454, is associated with increased risk for AD MESHD and decreased OAS1 HGNC expression. Moreover, we note that the same locus was recently associated with critical illness MESHD in response to COVID-19 MESHD, linking variants that are associated with AD MESHD and a severe response to COVID-19 MESHD. By analysing single-cell RNA-sequencing (scRNA-seq) data of isolated microglia from APPNL-G-F knock-in and wild-type C57BL/6J mice, we identify a transcriptional network that is significantly upregulated with age and amyloid deposition, and contains the mouse orthologue Oas1a, providing evidence that Oas1a plays an age-dependent function in the innate immune system. We identify a similar interferon-related transcriptional network containing OAS1 HGNC by analysing scRNA-seq data from human microglia isolated from individuals with AD MESHD. Finally, using human iPSC-derived microglial cells (h-iPSC-Mg), we see that OAS1 HGNC is required to limit the pro-inflammatory response of microglia. When stimulated with interferon-gamma HGNC ( IFN-{gamma} HGNC), we note that cells with lower OAS1 HGNC expression show an exaggerated pro-inflammatory response, with increased expression and secretion of TNF HGNC-. Collectively, our data support a link between genetic risk for AD MESHD and susceptibility to critical illness with COVID-19 MESHD centred on OAS1 HGNC and interferon signalling, a finding with potential implications for future treatments of both AD MESHD and COVID-19 MESHD, and the development of biomarkers to track disease progression.

    The Significance of KL-6 HGNC as Prognosis Monitoring Biomarker in Patients With Severe COVID-19 MESHD From Stabilized Stage Toward Convalescence

    Authors: Long He; Liu Lu; Ming Zong; Huang Zhou; Lan Wang; Nian Zhen Chen; Jia Yi Yuan; Er Peng Jiang; Liang Zheng; Qiang Li; Lie Ying Fan; Zhong Min Liu

    doi:10.21203/rs.3.rs-191056/v1 Date: 2021-01-30 Source: ResearchSquare

    Background: This study aims to identify some biomarkers for monitoring the recovery of lung injury MESHD in severe COVID-19 MESHD patients from stabilized stage toward convalescence.Methods: We enrolled participants who diagnosed with severe COVID-19 MESHD (n = 28) and health volunteers (n = 25) from Taikang Tongji (Wuhan) Hospital. The patients were in a stabilized stage and had a course of 48.1±12.8 days. We followed these patients for 90 days. The blood routine, cytokines ( IL-1β HGNC, IL-2 HGNC, IL-4 HGNC, IL-5 HGNC, IL-6 HGNC, IL-10 HGNC, IL-12p70, IL-17A HGNC, TNF-α HGNC, IFN-α, IFN-γ HGNC), type II alveolar epithelium injury MESHD indicators ( Surfactant protein A HGNC ( SP-A HGNC), Krebs von den Lungen-6 HGNC von MESHD den Lungen-6 ( KL-6 HGNC)) and chest CT were tested on the 1, 30, 60, and 90 days after enrollment. Results: In stabilized stage, the parameters of blood routine and some cytokines ( IL-1β HGNC, IL-2 HGNC, IL-4 HGNC, IL-12p70, TNF-α HGNC) had bounced back to normal (p>0.05). Some cytokines ( IL-5 HGNC, IL-6 HGNC, IL-10 HGNC, IL-17A HGNC, IFN-α, IFN-γ HGNC) and type II alveolar epithelium injury MESHD indicators ( SP-A HGNC and KL-6 HGNC) were still higher than normal (p<0.05). During the stabilized stage to convalescence, in spite of the variation of monocyte count, monocyte/lymphocyte ratio, IL-5 HGNC, IL-10 HGNC, IL-12p70, IL-17A HGNC IFN-γ HGNC, IFN-α, SP-A HGNC and KL-6 HGNC were downward trend (p<0.05), only KL-6 HGNC level (p<0.05) could simultaneously reflect the lung injury MESHD volume which be measured by CT. Conclusions: Our preliminary data indicated that KL-6 HGNC could be an effective prognostic biomarker for monitoring the recovery of lung function in patients with severe COVID-19 MESHD from stabilized stage toward convalescence.

    Cerebrospinal fluid in COVID-19 MESHD neurological complications: no cytokine storm or neuroinflammation.

    Authors: Maria A. Garcia; Paula V. Barreras; Allie Lewis; Gabriel Pinilla; Lori J. Sokoll; Thomas Kickler; Heba Mostafa; Mario Caturegli; Abhay Moghekar; Kathryn C. Fitzgerald; - Hopkins Neuro-COVID-19 Group; Carlos A Pardo

    doi:10.1101/2021.01.10.20249014 Date: 2021-01-12 Source: medRxiv

    BACKGROUND. Neurological complications MESHD occur in COVID-19 MESHD. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 MESHD subjects with neurological complications MESHD and determine presence of neuroinflammatory changes implicated in pathogenesis. METHODS. Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 MESHD subjects with neurological complications categorized by diagnosis ( stroke MESHD, encephalopathy MESHD, headache MESHD) and illness severity (critical, severe, moderate, mild). COVID-19 MESHD CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders MESHD and stroke MESHD controls (n=82). Cytokines ( IL-6 HGNC, TNF-alpha HGNC, IFN-gamma HGNC, IL-10 HGNC, IL-12p70, IL-17A HGNC), inflammation MESHD and coagulation markers (high-sensitivity- C Reactive Protein HGNC [hsCRP], ferritin, fibrinogen HGNC, D-dimer, Factor VIII) and neurofilament light chain ( NF-L HGNC), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA. RESULTS. CSF from COVID-19 MESHD subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis MESHD or specific increases in pro-inflammatory markers or cytokines ( IL-6 HGNC, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 MESHD subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines ( IL-6 HGNC, TNF-alpha HGNC;, IL-12p70) and IL-10 HGNC in CSF of COVID-19 MESHD and non- COVID-19 MESHD stroke MESHD subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke MESHD and critical COVID-19 MESHD. CSF-hsCRP was present almost exclusively in COVID-19 MESHD cases. CONCLUSION. The paucity of neuroinflammatory changes in CSF of COVID-19 MESHD subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation MESHD in pathogenesis of neurological complications in COVID-19 MESHD. Elevated CSF-NF-L indicates neuroaxonal injury MESHD in COVID-19 MESHD cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.

    Humoral and cell-mediated response in colostrum after exposure to severe acute respiratory syndrome coronavirus 2 MESHD

    Authors: Vignesh Narayanaswamy; Brian Pentecost; Dominique Alfandari; Emily Chin; Kathleen Minor; Alyssa Kastrinakis; Tanya Lieberman; Kathleen F Arcaro; Heidi Leftwich

    doi:10.1101/2021.01.03.20248715 Date: 2021-01-04 Source: medRxiv

    BackgroundColostrum provides an immune sharing between a mother and her infant. The transfer in colostrum of antibodies against SARS-CoV-2 and the elicited cytokines may provide crucial protection to the infant. There is limited literature on the immune response to SARS-CoV-2 present in colostrum. ObjectiveTo evaluate the presence of antibodies specific to SARS-CoV-2 and the associated cytokines in colostrum from women who tested positive for the virus. Study DesignBetween March and September 2020 we obtained bilateral colostrum samples collected on spot cards within 48 hours of delivery from 15 new mothers who had previously tested positive for SARS-CoV-2. Five of these 15 COVID-19 MESHD positive women also provided bilateral liquid colostrum within 1-2 days of providing the spot card samples. Archived bilateral colostrum samples collected from 8 women during 2011-2013 were used as pre- COVID-19 MESHD controls. All samples were tested for reactivity to the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike PROTEIN protein using an ELISA that measures SARS-CoV-2 RBD-specific IgA, IgG, and IgM, and for concentrations of 10 inflammatory cytokines ( IFN{gamma HGNC}, TNF HGNC, IL-1{beta HGNC}, IL-2 HGNC, IL-4 HGNC, IL-6 HGNC, IL-8 HGNC, IL-10 HGNC, IL-12, IL-13 HGNC) using a multiplex electrochemiluminescent sandwich assay. ResultsBilateral colostrum samples from 73%, 73% and 33% of the 15 COVID-19 MESHD mothers exhibited IgA, IgG, and IgM reactivity to RBD respectively. Colostrum samples from two of the 8 pre-pandemic controls showed IgA and IgG reactivity to RBD. Additionally, COVID-19 MESHD mothers had significantly higher levels of 9 of the 10 inflammatory markers (all except IFN{gamma HGNC}) as compared to the pre- COVID-19 MESHD controls. Comparable results were obtained with both the spot card-eluates and liquid samples. ConclusionsA strong humoral immune response is present in the colostrum of women who were infected with SARS-CoV-2 before delivering. High levels of 9 inflammatory markers were also present in the colostrum. The evolution and duration of the antibody response, as well as dynamics of the cytokine response, remain to be determined. Our results also indicate that future large-scale studies can be conducted with milk easily collected on paper spot cards.

    Altered Transcript Levels of Cytokines in COVID-19 MESHD Patients

    Authors: Majid Samsami; Alireza Fatemi; Reza Jalili Khoshnoud; Karim Kohansal; Arezou Sayad; Shabnam Soghala; Shahram Arsang-Jang; Mohammad Taheri; Soudeh Ghafouri-Fard

    doi:10.21203/rs.3.rs-126215/v1 Date: 2020-12-10 Source: ResearchSquare

    The pandemic caused by severe acute respiratory syndrome coronavirus 2 MESHD and the related disorder i.e. “ coronavirus disease 2019 MESHD” ( COVID-19 MESHD) have encouraged researchers to unravel the molecular mechanism of disease severity. Several lines of evidence support the impact of "cytokine storm" in the pathogenesis of severe forms of the disorder MESHD. We aimed to assess the expression levels of nine cytokine coding in COVID-19 MESHD patients admitted in a hospital. Expression levels of IFN-G HGNC, IL-2 HGNC, IL-4 HGNC, IL-6 HGNC, IL-17 HGNC, TGF-B HGNC, IL-8 HGNC and IL-1B HGNC were significantly higher in COVID-19 MESHD patients compared with healthy controls and in both female and male patients compared with sex-matched controls. However, expression of none of these cytokines was different between ICU-admitted patients and other patients except for IL-6 HGNC whose expression was lower in the former group compared with the latter (ratio of means = 0.33, P value = 4.82E-02). Expression of TNF-A HGNC was not different between COVID-19 MESHD patients and healthy controls. Then, we assessed diagnostic power of cytokine coding genes in differentiating between COVID-19 MESHD patients and controls. The area under curve (AUC) values range from 0.94 for IFN-G HGNC to 1.0 for IL-2 HGNC and IL-1B HGNC. After combining the transcript levels of all cytokines, AUC, sensitivity and specificity values reached 1.0, 1.0 and 0.99, respectively. For differentiation between ICU-admitted patients and other patients, IL-4 HGNC with AUC value of 0.68, had the best diagnostic power among cytokine coding genes. Expression of none of cytokine coding genes was correlated with the assessed clinical/demographic data including age, gender, ICU admission, or CRP HGNC/ESR levels. Our study provides further evidence for contribution of “cytokine storm” in the pathobiology of moderate/severe forms of COVID-19 MESHD.

    Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection MESHD

    Authors: Nina Le Bert; Hannah E Clapham; Anthony T Tan; Wan Ni Chia; Christine YL Tham; Jane M Lim; Kamini Kunasegaran; Linda Tan; Charles-Antoine Dutertre; Nivedita Shankar; Joey ME Lim; Louisa Jin Sun; Marina Zahari; Zaw M Tun; Vishakha Kumar; Beng Lee Lim; Siew Hoon Lim; Adeline Chia; Yee-Joo Tan; Paul Anantharajah Tambyah; Shirin Kalimuddin; David CB Lye; Jenny GH Low; Lin-Fa Wang; Wei Yee Wan; Li Yang Hsu; Antonio Bertoletti; Clarence C Tam; Martina Recalde; Paula Casajust; Jitendra Jonnagaddala; Vignesh Subbian; David Vizcaya; Lana YH Lai; Fredrik Nyberg; Daniel R. Morales; Jose D. Posada; Nigam H. Shah; Mengchun Gong; Arani Vivekanantham; Aaron Abend; Evan P Minty; Marc A. Suchard; Peter Rijnbeek; Patrick B Ryan; Daniel Prieto-Alhambra

    doi:10.1101/2020.11.25.399139 Date: 2020-11-27 Source: bioRxiv

    The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection MESHD without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic individuals (n=85) with that of symptomatic COVID-19 MESHD patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M PROTEIN, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion ( IL-2 HGNC, IFN-{gamma HGNC}, IL-4 HGNC, IL-6 HGNC, IL-1{beta}, TNF- and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic individuals. However, we detected an increased IFN-{gamma HGNC} and IL-2 HGNC production in asymptomatic compared to symptomatic individuals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 HGNC and pro-inflammatory cytokines ( IL-6 HGNC, TNF HGNC- and IL-1{beta} HGNC) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2 infected MESHD individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 HGNC might help to reduce inflammatory events during viral clearance.

    SLAMF7 HGNC engagement super-activates macrophages in acute and chronic inflammation

    Authors: Accelerating Medicines Partnership (AMP) RA/SLE Network; Andrew Howe; James B Gilchrist; Dapeng Sun; Michael Knight; Laura C Zanetti-Domingues; Benji Bateman; Anna-Sophia Krebs; Long Chen; Julika Radecke; Yuewen Sheng; Vivian D Li; Tao Ni; Ilias Kounatidis; Mohamed A Koronfel; Marta Szynkiewicz; Maria Harkiolaki; Marisa L Martin-Fernandez; William James; Peijun Zhang

    doi:10.1101/2020.11.05.368647 Date: 2020-11-05 Source: bioRxiv

    Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation MESHD. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 HGNC as a receptor associated with a super-activated macrophage state in rheumatoid arthritis MESHD. We implicated IFN-gamma HGNC as a key regulator of SLAMF7 HGNC expression. Engaging this receptor drove an exuberant wave of inflammatory cytokine expression, and induction of TNF-alpha HGNC following SLAMF7 HGNC engagement amplified inflammation MESHD through an autocrine signaling loop. We observed SLAMF7 HGNC-induced gene programs not only in macrophages from rheumatoid arthritis MESHD patients, but in gut macrophages from active Crohn's disease MESHD patients and lung macrophages from severe COVID-19 MESHD patients. This suggests a central role for SLAMF7 HGNC in macrophage super-activation with broad implications in pathology.

    COVID-19 MESHD cytokines and the hyperactive immune response: Synergism of TNF-α HGNC and IFN-γ HGNC in triggering inflammation, tissue damage, and death

    Authors: Evan Peter Williams; Lillian Zalduondo; Colleen Beth Jonsson; Alex R Schuurman; Jan Verhoeff; Saskia D van Asten; Hetty J Bontkes; Siebe G Blok; Janwillem Duitman; Harm Jan Bogaard; Leo Heunks; Rene Lutter; Tom van der Poll; Juan J Garcia Vallejo; Qiqi Cao; Fangjin Chen; Yuqing Chen; Xuelian Cheng; Guohong Deng; Wenyu Ding; Yingmei Feng; Rui Gan; Chuang Guo; Shuai He; Chen Jiang; Juanran Liang; Yi-Min Li; Jun Lin; Yun Ling; Haofei Liu; Jianwei Liu; Nianping Liu; Yang Liu; Meng Luo; Qiang Ma; Qibing Song; Wujianan Sun; Gaoxiang Wang; Feng Wang; Ying Wang; Xiaofeng Wen; Qian Wu; Xiaowei Xie; Xinxin Xiong; Xudong Xing; Hao Xu; Chonghai Yin; Dongdong Yu; Kezhuo Yu; Biao Zhang; Tong Zhang; Jincun Zhao; Peidong Zhao; Jianfeng Zhou; Wei Zhou; Sujuan Zhong; Xiaosong Zhong; Shuye Zhang; Lin Zhu; Ping Zhu; Bing Zou; Jiahua Zou; Zengtao Zuo; Fan Bai; Xi Huang; Xiuwu Bian; Penghui Zhou; Qinghua Jiang; Zhiwei Huang; Jin-Xin Bei; Lai Wei; Xindong Liu; Tao Cheng; Xiangpan Li; Fu-Sheng Wang; Hongyang Wang; Bing Su; Kun Qu; Xiaoqun Wang; JieKai Chen; Ronghua Jin; Zemin Zhang

    doi:10.1101/2020.10.29.361048 Date: 2020-10-29 Source: bioRxiv

    The COVID-19 MESHD COVID-19 MESHD pandemic has caused significant morbidity and mortality. Currently, there is a critical shortage of proven treatment options and an urgent need to understand the pathogenesis of multi-organ failure MESHD and lung damage MESHD. Cytokine storm is associated with severe inflammation MESHD and organ damage during COVID-19 MESHD. However, a detailed molecular pathway defining this cytokine storm is lacking, and gaining mechanistic understanding of how SARS-CoV-2 elicits a hyperactive inflammatory response is critical to develop effective therapeutics. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection MESHD, we found that the combined production of TNF- and IFN-{gamma} specifically induced inflammatory cell death MESHD, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8 HGNC-mediated apoptosis, and MLKL HGNC-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 HGNC and caspase-8 HGNC or RIPK3 HGNC and FADD HGNC were resistant to this cell death. Mechanistically, the STAT1 HGNC/ IRF1 HGNC axis activated by TNF- and IFN-{gamma} co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of PANoptosis protected mice from TNF- and IFN-{gamma}-induced lethal cytokine shock MESHD that mirrors the pathological symptoms of COVID-19 MESHD. In vivo neutralization of both TNF- and IFN-{gamma} in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection MESHD, but also sepsis MESHD, hemophagocytic lymphohistiocytosis MESHD, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings reveal that blocking the COVID-19 MESHD cytokine-mediated inflammatory cell death MESHD signaling pathway identified in this study may benefit patients with COVID-19 MESHD or other cytokine storm-driven syndromes by limiting inflammation MESHD and tissue damage. The findings also provide a molecular and mechanistic description for the term cytokine storm. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases MESHD and cancers MESHD where TNF- and IFN-{gamma} synergism play key pathological roles.

    LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC

    Authors: Gregory Thomas; Elizabeth Frederick; Lisa Thompson; Raphael Bar-Or; Yetti Mulugeta; Melissa Hausburg; Michael Roshon; Charles Mains; David Bar-Or

    doi:10.21203/rs.3.rs-86515/v1 Date: 2020-10-01 Source: ResearchSquare

    Background Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 ( Th1 HGNC) products, such as IFNγ HGNC, TNFα HGNC, IL1-β HGNC, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis MESHD and the hyper-inflammatory response associated with COVID-19 MESHD. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release. Methods ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα HGNC or IL-1β HGNC relative potency were then employed to confirm the involvement of enriched pathways and TFs.Results LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines ( TNFα HGNC, IL-1β HGNC, IL-12, CXCL9 HGNC, CXCL10 HGNC, and CXCL11 HGNC) associated with pro-inflammatory M1/ Th1 HGNC immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor ( PPAR)γ HGNC and aryl hydrocarbon receptor HGNC ( AhR HGNC), indicate these pathways are involved in the LMWF5A mechanism of action by reducing LMWF5A drug potency as measured by TNFα HGNC and IL-1β HGNC release. Conclusion In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ HGNC and AhR HGNC. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A act through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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