Aggressive Inflammatory Response Research Articles

Joint-specific rheumatoid arthritis fibroblast-like synoviocyte regulation identified by integration of chromatin access and transcriptional activity.

The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific fibroblast-like synoviocyte (FLS) biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated transcriptomic and chromatin accessibility data from FLS to identify the transcription factors and pathways. Networks were constructed by integration of chromatin accessibility and gene expression data. Analysis revealed joint-specific patterns of FLS phenotype, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an "activated" state relative to the "resting" state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia. The vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed. The VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy. Our findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics.

Racial Disparity and Blood Group Antigens; COVID-19 High Mortality Rate in Black and Duffy Antigen

Abstract Introduction/Objective As of March 5th, 2022, the novel coronavirus disease 2019 (COVID-19) has been confirmed in 464,809,377 people worldwide, with an approximately 1.31% mortality rate. COVID-19 infection is associated with an aggressive inflammatory response and release of a large amount of pro-inflammatory cytokines known as “cytokine storm.” Cytokine storm is the release of interferons, interleukins, tumor necrosis factors, chemokines, and several other mediators. Chemokines are small protein molecules that act as chemoattractants, leading to the migration of immune cells to an infection site so they can target and destroy invading bodies such as microbes. The Duffy antigen is a broad receptor of chemokines in human blood. Early on, it was found that the overwhelming majority of people of African descent had the erythrocyte phenotype Fy(a-b-) (henceforth Duffy (-)): 68% in African Americans and 88-100% in African people (including more than 90% of West African people). Methods/Case Report Subjects under study: This retrospective cohort study analyzed the data from total patients with confirmed COVID-19 infection in the US through March 5th, 2022.The US population 13.4% black, non-Hispanic, 76.3% white, non-Hispanic, Asian 5.9%, 18.5% Hispanic or Latino, and 4.3 all other races. The primary outcomes were hospitalization and in-hospital death. Results (if a Case Study enter NA) Results: A total of 79,555,007 patients in the US were tested Covid-19 positive and 968,839 mortalities with a death rate of 1.21%. 661,678 deaths were excluded because they did not have racial details. Among the 968,839 patients who died of Covid-19, 411,078 (62.1%) were white, 89,784 (13.6%) were black, 114,455 (17.3%) were Hispanic or Latino, 5,970(4.2%) were Asian and 7,045(4.8%) all other races. The actual death rate per 100,000 is 313 in white, 330 in black, 254 in Hispanic or Latino, 156 in Asian, and 276 in all other races. Conclusion Despite black Americans representing only 13.4% of the total population, they have been heavily hit by the COVID-19 pandemic. The reasons for the especially severe forms of the disease in Black Americans have not been fully uncovered. People with the Duffy (-) phenotype are a high-risk group for the Chemokine Storm. One hypothesis that arguably gives the blood group marker and chemokine decoy receptor Duffy protein plays a central role in stimulating the Chemokine Storm as present in the severe forms of the COVID-19 disease.

FRI613 Sex Differences In Human Islet Transcriptional Responses To Inflammation

Abstract Disclosure: K.L. Webster: None. W. Wu: None. B. Webb-Robertson: None. E. Nakayasu: None. S. Sarkar: None. C. Evans-Molina: None. S.A. Tersey: None. J. Enriquez: None. S.R. Hammes: None. R.G. Mirmira: None. Higher female incidence of autoimmune disease is often attributed to sex hormone-immune cell interactions or X chromosome immune genes escaping inactivation. Type 1 diabetes (T1D), however, occurs slightly more often in males, and studies show that female sex protects beta cell health under conditions of stress. It is now thought that beta cells themselves trigger loss of immune tolerance in T1D and that the state of beta cell differentiation and health dictates their susceptibility to autoimmunity. Here, we hypothesized that sex influences beta cell response to inflammation during T1D development. We utilized prior bulk RNA sequencing data on human islets from 10 donors (6 males, 4 females) treated for 18h with or without proinflammatory cytokines (PIC: IL-1b, IFNy) to mimic T1D inflammation. Hierarchical clustering grouped samples largely by PIC treatment but also by sex. To identify differentially expressed genes (DEGs) for each sex in response to PIC, we filtered for genes with fold change>1.5 and false discovery rate<0.05. A total of 3754 DEGs were detected in male islets with PIC treatment, while just 1117 were detected in female islets. Of these, 1016 genes were shared between sexes, and many related to cytokine signaling and immune responses. Only 101 DEGs were unique to females, and these were enriched in terms related to leukocyte aggregation, glutamate signaling, and responses to steroid hormone stimuli. 2738 DEGs unique to males were enriched in terms related to inflammation, NOTCH signaling, differentiation, and estrogen biosynthesis. Notably, the gene encoding double-stranded RNA sensor MDA5 (Ifih1), whose activity induces antiviral type I IFN responses and has been linked to T1D, showed a greater average increase with PIC in males (9.99-fold vs. 6.64-fold in females, p<0.05). By gene set enrichment analysis, control and PIC-treated female islets were enriched in differentiation and development pathways, while male islets were enriched in protein translation and steroid metabolism. To probe the role of sex steroid signaling in islet inflammatory response, we measured expression of Esr1 (encoding ERa) via qRT-PCR in mouse islets in response to PIC (IFNy, IL-1b, TNFa). In non-diabetic C57BL6/J mice, islets from both males and females increased Esr1 with PIC (3.63- and 4.39-fold, p<0.05). However, in pre-diabetic NOD mice, in which female mice are highly susceptible to autoimmune diabetes, islets from neither sex increased Esr1. Interestingly, islets from C57BL6/J mice of both sexes decreased expression of Ar (encoding androgen receptor) upon PIC treatment, a response also absent in NOD mice. These data suggested that Esr1 might be protective- and Ar detrimental- for beta cell function, but not in a sex-dependent manner. Collectively, these data demonstrate a sexual dimorphism in islet response to inflammation, with evidence of a more aggressive inflammatory response in males. Presentation: Friday, June 16, 2023

Immune response modulation in inflammatory bowel diseases by Helicobacter pylori infection.

Many studies point to an association between Helicobacter pylori (H. pylori) infection and inflammatory bowel diseases (IBD). Although controversial, this association indicates that the presence of the bacterium somehow affects the course of IBD. It appears that H. pylori infection influences IBD through changes in the diversity of the gut microbiota, and hence in local chemical characteristics, and alteration in the pattern of gut immune response. The gut immune response appears to be modulated by H. pylori infection towards a less aggressive inflammatory response and the establishment of a targeted response to tissue repair. Therefore, a T helper 2 (Th2)/macrophage M2 response is stimulated, while the Th1/macrophage M1 response is suppressed. The immunomodulation appears to be associated with intrinsic factors of the bacteria, such as virulence factors - such oncogenic protein cytotoxin-associated antigen A, proteins such H. pylori neutrophil-activating protein, but also with microenvironmental changes that favor permanence of H. pylori in the stomach. These changes include the increase of gastric mucosal pH by urease activity, and suppression of the stomach immune response promoted by evasion mechanisms of the bacterium. Furthermore, there is a causal relationship between H. pylori infection and components of the innate immunity such as the NLR family pyrin domain containing 3 inflammasome that directs IBD toward a better prognosis.

FTY720 attenuates acute colitis via colonic T cells reduction and inhibition of M1 macrophages polarization independent of CCR2-mediated monocytes input

Ulcerative colitis (UC) is a complex multifactorial disease, of which the exact etiology is not fully understood. The inappropriate aggressive inflammatory response is closely related to the disease progression of UC. FTY720 is a sphingosine-1-phosphate receptor agonist and acts as a key immunomodulator in inflammation. This study aims to investigate the protective influence of FTY720 on inflammation in the DSS-induced colitis model. In the present study, the C57BL/6 mice and the CCR2−/− mice were exposed to 5% Dextran Sodium Sulfate (DSS) drinking water for 6 days followed by an injection of FTY720 (1 mg/kg/d) or vehicle (PBS) 6 times starting on the next day. The body weight, stool consistency, and occult blood were assessed daily. The inflammatory cytokines level in colon tissues and serum were assessed. Leukocyte subsets of bone marrow (BM), spleen, and colon were analyzed by flow cytometry. Our results demonstrated that FTY720 ameliorated the aberrant immune responses by trapping T cells and inhibiting the polarization of M1 macrophages in colitis mice. The effect of FTY720 on the increased number of colonic macrophages did not dependent on CCR2-mediated monocyte influx, despite most monocytes being reduced after DSS administration in the inflamed colon of CCR2−/− mice. Rather, depletion of CCR2 did not impact the protective influence of FTY720 on colonic injury in acute colitis. All these findings unravel a beneficial function of FTY720 in the inflammatory response to DSS-induced acute colitis, provided further insights into monocyte migration and might provide potential opportunities for UC therapeutic intervention.

Impact of Lymphatic Pump Treatment and Methotrexate on Inflammation, Cytokine Production, and Leukocyte Infiltration in a Rat Model of Rheumatoid Arthritis

Abstract Rheumatoid Arthritis in autoimmune disease afflicting synovial joints leading to chronic joint damage. While the specific mechanisms have not been fully identified, the immune system and inflammatory factors are actively involved. T cells release cytokines and chemokines, such as TNF-alpha, IL-1 and IL-6, CINC-1 and CINC-2, and B cells produce self-reactive antibodies including rheumatoid factor and anti-citrullinated protein antibodies. All these factors result in a pronounced and aggressive inflammatory response within the joints. Lymphatic pump treatment (LPT) promotes lymphatic flow within the body, causing a flushing out of the immune-complexes and pro-inflammatory cells. Using a rat AIA model, the goal was to determine if LPT in conjunction with methotrexate had a greater impact on rheumatoid arthritis symptoms than methotrexate alone. A 21-day AIA rat study was performed using LPT and methotrexate treatments on days 14–21. Ankle circumference and articular index scores were recorded daily as a measurement of inflammation. ELISAs of arthritic ankles homogenates and serum were used to analyze cytokine, chemokine, and autoantibody concentrations. Immune cell infiltration into the ankles was determined using immunohistochemistry. We found that LPT with methotrexate treatment did not significantly alter ankle circumference, articular index scores, immune cell infiltration, cytokine, chemokine, or antibody concentrations compared to methotrexate alone. Overall, methotrexate combined with LPT treatments on days 14–21 did not significantly alter disease progression, however, it is possible that earlier LPT treatment may have a more significant impact on disease progression. College of Graduate Studies Biomedical Sciences program at Midwestern University, Downers Grove, IL.

Use of tocilizumab in COVID-19 pneumonia hospitalized patients. Cohort study

IntroductionIn COVID 19, an aggressive inflammatory response called cytokine release storm has been described. It is mainly mediated by the activation of Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), mainly observed in critically ill patients. Among the multiple treatments proposed throughout these two years of pandemic, we highlight the use of Tocilizumab (TCZ). ObjectivesTo evaluate in-hospital mortality, transfer to critical care unit (CCU), invasive mechanical ventilation requirement (IMV), and hospital stay in patients treated with TCZ versus conventional treatments (CT). MethodsRetrospective, descriptive, and analytical cohort study. Hospitalized patients, May to July 2021. Branches: treated with TCZ versus CT. Statistical analysis: Epi Info 7.2. ResultsNinety patients, 51 TCZ branch and 39 CT branch. Age 48.2 years (± 11.7), males 74 (82.2%). Comorbidities 66 (73.3%): High blood pressure (HBP) 32 (35.6%), Diabetes mellitus 13 (14.4%), BMI>30, 51 (56.7%). Medical Clinic Admission (MC) 85 (94.4%). Days post-symptom onset 7.9 (± 2.6). Severity of COVID 19: severe 61 (67.8%), critical 26 (28.9%). CCU admission 26 (29.9%). IMV 16 (17.8%). Deaths 7 (7.9%). Hospital stay 12.9 (± 6.6) days. Comparative analysis TCZ versus CT: MC admission 50 (98%) versus 35 (89.7%) p .08. CCU admission 12 (23.5%) versus 14 (38.9%) p .1. IMV 4 (7.8%) versus 12 (30.8%) p .005. Death 1 (2.0%) versus 6 (15.8%) p .02. Mortality in univariate analysis (p<.05): APACHE II, BMI>30, TCZ, IMV, and CCU admission. TCZ was a protective factor against RR of death .86 (.74–.99). The IMV requirement was a RR factor for death 2.0 (1.23–3.42). Cox logistic regression, independent survival factors: use of TCZ, absence of obesity, and no IMV, p .0000. ConclusionsIMV was found to be a risk factor for mortality. TCZ did not show a decrease in CCU requirement, but it did prove to be a protective factor against mortality. However, this is a non-randomized study so it should be interpreted with caution.

Remodeling of the osteoimmune microenvironment after biomaterials implantation in murine tibia: Single-cell transcriptome analysis.

Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C + CCR2hi monocytes, and S100a8hi macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant. The enrichment of mature neutrophils, FcgR1hi and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response. Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration. Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis. These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of ‘osteoimmune-smart’ biomaterials in the bone regeneration field.

ACUTE PULMONARY EMBOLISM IN A PATIENT WITH A NORMAL D-DIMER

ACUTE PULMONARY EMBOLISM IN A PATIENT WITH A NORMAL D-DIMER

P233 COVID-19-a ssociated Mucormycosis: an experience of invasive fungal sinusitis from a tertiary care referral center in Northern India

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PMObjectivesThe study was aimed to determine the patient demographics, risk factors, which include comorbidities, presenting symptoms and signs, medications used to treat COVID-19, species of Mucorales isolated, and the management outcome of COVID-19-associated mucormycosis.MethodsIt was a 6-month retrospective, propensity score-matched, comparative study conducted at a tertiary care center, involving 124 patients with COVID-19 associated mucormycosis admitted between April and September 2021, who were suffering from or had a history of COVID-19 infection.ResultsAmong the 124 patients, 87 were male, and 37 were female. A total of 72.6% of patients received steroids, while 73.4% received antibiotics, and 55.6% received oxygen during COVID-19 management. The most common comorbidities were diabetes mellitus (83.9%) and hypertension (30.6%). A total of 92.2% had mucor, 16.9% had Aspergillus, 12.9% had both, and one patient had hyalohyphomycosis on fungal smear and culture. The comparative study showed the significant role of serum ferritin, glycemic control, steroid use, and duration in COVID-19-associated invasive fungal disease (P <.001). Headache and facial pain (68, 54.8%) were the most common symptoms. The most involved sinonasal site was the maxillary sinus (90, 72.6%). Direct KOH microscopy for fungus was positive in 100% of the cases, 82.2% were Mucorales; 12.9% showed mixed fungal hyphae (mucormycetes and Aspergillus spp.), 4% Aspergillus and hyaline septate non-Aspergillus fungus hyphae were seen in 0.8%. Mucoraceous fungi isolated were R. arrhizus, R. microsporus, R. homothallicus, Rhizomucor pusillus, and Leithemia corymbifera. The overall survival rate at the 3-month follow-up was 79.9%.ConclusionCOVID-19-related aggressive inflammatory response, uncontrolled glycemic level, and rampant use of steroids are the most important predisposing factors in developing COVID-19-associated invasive fungal sinusitis caused by Mucorales. A high index of suspicion, aggressive surgical and antifungal therapy resulted in the successful outcomes for most of the patients.

Mechanical Complication of Acute Myocardial Infarction Secondary to COVID-19 Disease.

The aggressive inflammatory response to COVID-19 can result in airway damage, respiratory failure, cardiac injury, and multiorgan failure, which lead to death in susceptible patients. Cardiac injury and acute myocardial infarction (AMI) secondary to COVID-19 disease can lead to hospitalization, heart failure, and sudden cardiac death. When serious collateral damage from tissue necrosis or bleeding occurs, mechanical complications of myocardial infarction and cardiogenic shock can ensue. While prompt reperfusion therapies have decreased the incidence of these serious complications, patients who present late following the initial infarct are at increased for mechanical complications, cardiogenic shock, and death. The health outcomes for patients with mechanical complications are dismal if not recognized and treated promptly. Even if they survive serious pump failure, their CICU stay is often prolonged, and their index hospitalization and follow-up visits may consume significant resources and impact the health care system.

Transcriptional Landscape Established by the Euchromatic Histone‐lysine N‐methyltransferase Pathway During Pancreas Ontogenesis and Pancreatitis

The Euchromatic Histone‐lysine N‐Methyltransferase 1/2 (EHMT1/2) complex, responsible for catalyzing mono‐ and di‐methylation of histone H3K9, has emerged as key regulator of embryogenesis and carcinogenesis. We have recently shown that EHMT2 inactivation antagonizes oncogenic KRAS‐mediated pancreatic cancer initiation and promotion by altering growth and immune gene expression networks. The current study unravels the transcriptional landscape regulated by EHMT2 during pancreatic development and acute pancreatitis. We performed conditional knockout of EHMT2 in the pancreas using the Pdx1‐Cre model, comparing perinatal (10‐day‐old) vs. young adult mice (4‐week‐old). Notably, despite carrying EHMT2 inactivation, both the whole animal and pancreas develop normally through adulthood. The transcriptional landscape resulting from EHMT2 inactivation, however, is different in perinatal mice from young adults, suggesting that this epigenomic regulator plays a role in modulating distinct gene networks during the development of this organ. Congruent with a role for EHMT2 in gene silencing, we show that its inactivation in both life stages primarily resulted in gene expression signatures dominated by upregulated transcripts. Notably, among these genes, we find pancreas‐specific clusters, including those encoding zymogen granules, during the transition to young adult, suggesting that EHMT2 facilitates acinar cell‐fate decisions. DEGs from young adults with EHMT2 loss displayed prominent activation of TP53 signaling‐related and DNA damage response gene networks that were not present in the perinatal cohort, demonstrating that cell cycle arrest accompanies this differentiation event. We also find de‐repression of genes that participate in early endodermal development, metabolism, and inflammation. Studies on acute pancreatitis, induced by repeated injections of the CCK‐agonist peptide, caerulein, show that EHMT2 inactivation results in more severe disease compared to that in controls, as measured by histological scoring of edema, inflammatory cell infiltrate, and necrosis. More importantly, and congruent with our histological assessment, EHMT2 inactivation in acinar epithelial cells regulates the expression of key inflammation‐associated genes that reprograms the non‐epithelial responses to pancreatitis. Digital cytology analysis demonstrated that the transcriptional landscape resulting from EHMT2 inactivation triggers a more aggressive inflammatory response for the pancreas. This data demonstrates that, although not critical to development of the organ, EHMT2 is involved in pancreas‐specific gene expression. Lastly, during pancreatitis, EHMT2 behaves as an important regulator of inflammation, extending our knowledge of epigenomic mechanisms underlying development, homeostasis, and diseases of the pancreas.

Changes in Cerebral Blood Flow and Diffusion-Weighted Imaging Lesions After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a common subtype of stroke and places a great burden on the family and society with a high mortality and disability rate and a poor prognosis. Many findings from imaging and pathologic studies have suggested that cerebral ischemic lesions visualized on diffusion-weighted imaging (DWI) in patients with ICH are not rare and are generally considered to be associated with poor outcome, increased risk of recurrent (ischemic and hemorrhagic) stroke, cognitive impairment, and death. In this review, we describe the changes in cerebral blood flow (CBF) and DWI lesions after ICH and discuss the risk factors and possible mechanisms related to the occurrence of DWI lesions, such as cerebral microangiopathy, cerebral atherosclerosis, aggressive early blood pressure lowering, hyperglycemia, and inflammatory response. We also point out that a better understanding of cerebral DWI lesions will be a key step toward potential therapeutic interventions to improve long-term recovery for patients with ICH.

The Spectrum of Invasive Fungal Sinusitis in COVID-19 Patients: Experience from a Tertiary Care Referral Center in Northern India.

This study aimed to determine the patient demographics, risk factors, which include comorbidities, medications used to treat COVID-19, and presenting symptoms and signs, and the management outcome of COVID-19-associated invasive fungal sinusitis. A retrospective, propensity score-matched, comparative study was conducted at a tertiary care center, involving 124 patients with invasive fungal sinusitis admitted between April 2021 and September 2021, suffering from or having a history of COVID-19 infection. Among the 124 patients, 87 were male, and 37 were female. A total of 72.6% of patients received steroids, while 73.4% received antibiotics, and 55.6% received oxygen during COVID-19 management. The most common comorbidities were diabetes mellitus (83.9%) and hypertension (30.6%). A total of 92.2% had mucor, 16.9% had aspergillus, 12.9% had both, and one patient had hyalohyphomycosis on fungal smear and culture. The comparative study showed the significant role of serum ferritin, glycemic control, steroid use, and duration in COVID-19-associated invasive fungal disease (p < 0.001). Headache and facial pain (68, 54.8%) were the most common symptoms. The most involved sinonasal site was the maxillary sinus (90, 72.6%). The overall survival rate at the three-month follow-up was 79.9%. COVID-19-related aggressive inflammatory response, uncontrolled glycemic level, and rampant use of steroids are the most important predisposing factors in developing COVID-19-associated invasive fungal sinusitis.

Short Communication: S100A8 and S100A9, Biomarkers of SARS-CoV-2 Infection and Other Diseases, Suppress HIV Replication in Primary Macrophages.

S100A8 and S100A9 are members of the Alarmin family; these proteins are abundantly expressed in neutrophils, form a heterodimer complex, and are secreted in plasma on pathogen infection or acute inflammatory diseases. Recently, both proteins were identified as novel biomarkers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and were shown to play key roles in inducing an aggressive inflammatory response by mediating the release of large amounts of pro-inflammatory cytokines, called the "cytokine storm." Although co-infection with SARS-CoV-2 in people living with HIV-1 may result in an immunocompromised status, the role of the S100A8/A9 complex in HIV-1 replication in primary T cells and macrophages is still unclear. Here, we evaluated the roles of the proteins in HIV replication to elucidate their functions. We found that the complex had no impact on virus replication in both cell types; however, the subunits of S100A8 and S100A9 inhibit HIV in macrophages. These findings provide important insights into the regulation of HIV viral loads during SARS-CoV-2 co-infection.

Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells.

Interleukin-mediated deep cytokine storm, an aggressive inflammatory response to SARS-CoV-2 virus infection in COVID-19 patients, is correlated directly with lung injury, multi-organ failure, and poor prognosis of severe COVID-19 patients. Curcumin (CUR), a phenolic antioxidant compound obtained from turmeric (Curcuma longa L.), is well-known for its strong anti-inflammatory activity. However, its in vivo efficacy is constrained due to poor bioavailability. Herein, we report that CUR-encapsulated polysaccharide nanoparticles (CUR–PS-NPs) potently inhibit the release of cytokines, chemokines, and growth factors associated with damage of SARS-CoV-2 spike protein (CoV2-SP)-stimulated liver Huh7.5 and lung A549 epithelial cells. Treatment with CUR–PS-NPs effectively attenuated the interaction of ACE2 and CoV2-SP. The effects of CUR-PS-NPs were linked to reduced NF-κB/MAPK signaling which in turn decreased CoV2-SP-mediated phosphorylation of p38 MAPK, p42/44 MAPK, and p65/NF-κB as well as nuclear p65/NF-κB expression. The findings of the study strongly indicate that organic NPs of CUR can be used to control hyper-inflammatory responses and prevent lung and liver injuries associated with CoV2-SP-mediated cytokine storm.

Reduced frequency and functional potency of CD49d− T regulatory cells in patients with newly diagnosed type 2 diabetes mellitus

This study set out to check the quantitative and qualitative properties of peripheral CD4+CD25+CD49d− T regulatory (CD49d− Treg) cells in type 2 diabetes mellitus (T2DM) patients.This work comprised 35 newly diagnosed patients and 35 healthy controls (HCs). The frequency of FoxP3 expressing CD49d− Treg cells was determined by flow cytometry. The gene expression of FoxP3 and CD49d was assessed by real-time PCR. Suppression assays with purified CD49d− Treg cells and CD4+CD25− T conventional (Tconv) cells were done by flow cytometry. The supernatants of Tconv/CD49d− Treg co-cultures were tested for IFN-γ, IL-4, IL-17, and IL-10 using ELISA.The frequency of CD49d− Treg cells (by both CD4+CD25+CD49d− and CD4+CD25++CD49d− phenotypes) observed to be reduced in patients versus HCs. In the patients, decreased protein and gene expression of FoxP3 was seen in CD49d− Treg cells. Suppressive potency of CD49d− Treg cells to inhibit Tconv cells proliferation was diminished, and inversely related to fasting plasma glucose and hemoglobin A1c in the patients. Tconv cells from T2DM patients released higher amount of IL-17 and lower concentration of IL-10 versus HCs. In Tconv/CD49d− Tregs co-cultures, decreased IL-17 and increased IL-10 levels were seen in HCs, but not T2DM patients.CD49d− Treg cells from the patients have a fundamental defect and Treg cells fail to inhibit the aggressive inflammatory responses.

Клинико-морфологический анализ трисомий и полиплоидий, как наиболее распространенных хромосомных аномалий хориона при неразвивающейся беременности

Aim. To compare the clinical and morphological characteristics of missed abortion with the most frequent variants of chromosomal abnormalities (trisomies and polyploidies) and with a normal chorion karyotype. Materials and Methods. A comparative analysis of the frequency of chromosomal abnormalities of chorion in 273 cases of early pregnancy loss was carried out in St. Petersburg in 2005-2008 and 2015-2019. It was found that within 10 years the frequency and structure of chromosomal abnormalities remained unchanged. In this connection, it was decided to analyze the clinicoanamnestic and morphological data in patients with early missed abortion with the most frequent variants of the chorionic karyotype: group A – normal chorionic karyotype (104 cases), group B – chorionic trisomy (114), group C – chorionic polyploidy (26). Results. History of recurrent miscarriage, chromosomal abnormalities of the chorion and congenital malformations of the fetus during previous pregnancies were reliably more frequent in patients of group A (with a normal chorionic karyotype). In abortion material of group A, the least pronounced inflammatory changes in the endometrium, decidual tissue and chorionic villi were detected, compared with other groups, however, signs of hormonal disorders in the form of insufficient gravid transformation of the endometrium were more common. Trisomies of the chorion were characterized by the highest mean age of the patients, no other clinical and anamnestic peculiarities were observed, morphologically this group was characterized by moderate inflammatory changes in the endometrium and decidual tissue and pronounced edema of the chorionic villi. In chorion polyploidies, chronic endometritis was more often identified anamnestically, and morphologically this group was characterized by the most pronounced inflammatory changes in chorionic villi, more pronounced lymphoid-macrophagal infiltration of the endometrium and decidual tissue with accumulations of a large number of leukocytes in them of microabscess and necrosis types. With this, the length of stay of an unviable gestational sac in the uterine cavity did not differ between the groups. Conclusions. Morphologically, all the studied groups had peculiarities permitting to suspect one or another chromosomal abnormality in case of impossibility to perform a cytogenetic examination. More aggressive inflammatory response in the endometrium in missed abortion in chromosomal abnormalities (especially in polyploidies) may play a role in chronization of the inflammatory process in the endometrium, therefore, such patients should undergo a preconception preparation, when planning the next pregnancy.

SARS-CoV-2 signaling pathway map: A functional landscape of molecular mechanisms in COVID-19.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has been declared a pandemic by WHO. The clinical manifestation and disease progression in COVID-19 patients varies from minimal symptoms to severe respiratory issues with multiple organ failure. Understanding the mechanism of SARS-CoV-2 interaction with host cells will provide key insights into the effective molecular targets for the development of novel therapeutics. Recent studies have identified virus-mediated phosphorylation or activation of some major signaling pathways, such as ERK1/2, JNK, p38, PI3K/AKT and NF-κB signaling, that potentially elicit the cytokine storm that serves as a major cause of tissue injuries. Several studies highlight the aggressive inflammatory response particularly ‘cytokine storm’ in SARS-CoV-2 patients. A depiction of host molecular dynamics triggered by SARS-CoV-2 in the form of a network of signaling molecules will be helpful for COVID-19 research. Therefore, we developed the signaling pathway map of SARS-CoV-2 infection using data mined from the recently published literature. This integrated signaling pathway map of SARS-CoV-2 consists of 326 proteins and 73 reactions. These include information pertaining to 1,629 molecular association events, 30 enzyme catalysis events, 43 activation/inhibition events, and 8,531 gene regulation events. The pathway map is publicly available through WikiPathways: https://www.wikipathways.org/index.php/Pathway:WP5115.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-021-00632-4.