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1.
Int J Mol Sci ; 24(10)2023 May 19.
Article in English | MEDLINE | ID: covidwho-20240810

ABSTRACT

Neutrophils are the key players in the innate immune system, being weaponized with numerous strategies to eliminate pathogens. The production of extracellular traps is one of the effector mechanisms operated by neutrophils in a process called NETosis. Neutrophil extracellular traps (NETs) are complex webs of extracellular DNA studded with histones and cytoplasmic granular proteins. Since their first description in 2004, NETs have been widely investigated in different infectious processes. Bacteria, viruses, and fungi have been shown to induce the generation of NETs. Knowledge is only beginning to emerge about the participation of DNA webs in the host's battle against parasitic infections. Referring to helminthic infections, we ought to look beyond the scope of confining the roles of NETs solely to parasitic ensnarement or immobilization. Hence, this review provides detailed insights into the less-explored activities of NETs against invading helminths. In addition, most of the studies that have addressed the implications of NETs in protozoan infections have chiefly focused on their protective side, either through trapping or killing. Challenging this belief, we propose several limitations regarding protozoan-NETs interaction. One of many is the duality in the functional responses of NETs, in which both the positive and pathological aspects seem to be closely intertwined.


Subject(s)
Extracellular Traps , Parasitic Diseases , Humans , Neutrophils , Histones , DNA , Parasitic Diseases/pathology
2.
Nat Immunol ; 24(5): 767-779, 2023 05.
Article in English | MEDLINE | ID: covidwho-20238331

ABSTRACT

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.


Subject(s)
Neutrophils , Sepsis , Humans , Hematopoiesis , Hematopoietic Stem Cells , Gene Expression Regulation
3.
Virulence ; 14(1): 2218077, 2023 12.
Article in English | MEDLINE | ID: covidwho-20238214

ABSTRACT

Neutrophil dysregulation is well established in COVID-19. However, factors contributing to neutrophil activation in COVID-19 are not clear. We assessed if N-formyl methionine (fMet) contributes to neutrophil activation in COVID-19. Elevated levels of calprotectin, neutrophil extracellular traps (NETs) and fMet were observed in COVID-19 patients (n = 68), particularly in critically ill patients, as compared to HC (n = 19, p < 0.0001). Of note, the levels of NETs were higher in ICU patients with COVID-19 than in ICU patients without COVID-19 (p < 0.05), suggesting a prominent contribution of NETs in COVID-19. Additionally, plasma from COVID-19 patients with mild and moderate/severe symptoms induced in vitro neutrophil activation through fMet/FPR1 (formyl peptide receptor-1) dependent mechanisms (p < 0.0001). fMet levels correlated with calprotectin levels validating fMet-mediated neutrophil activation in COVID-19 patients (r = 0.60, p = 0.0007). Our data indicate that fMet is an important factor contributing to neutrophil activation in COVID-19 disease and may represent a potential target for therapeutic intervention.


Subject(s)
COVID-19 , Methionine , Humans , Neutrophil Activation , Peptides , N-Formylmethionine/pharmacology , Racemethionine , Neutrophils , Leukocyte L1 Antigen Complex
4.
Front Immunol ; 14: 1170603, 2023.
Article in English | MEDLINE | ID: covidwho-20237245

ABSTRACT

Neutrophil Extracellular Traps (NETs) are a key form of pro-inflammatory cell death of neutrophils characterized by the extrusion of extracellular webs of DNA containing bactericidal killing enzymes. NETosis is heavily implicated as a key driver of host damage in autoimmune diseases where injurious release of proinflammatory enzymes damage surrounding tissue and releases 70 known autoantigens. Recent evidence shows that both neutrophils and NETosis have a role to play in carcinogenesis, both indirectly through triggering DNA damage through inflammation, and directly contributing to a pro-tumorigenic tumor microenvironment. In this mini-review, we summarize the current knowledge of the various mechanisms of interaction and influence between neutrophils, with particular attention to NETosis, and cancer cells. We will also highlight the potential avenues thus far explored where we can intercept these processes, with the aim of identifying promising prospective targets in cancer treatment to be explored in further studies.


Subject(s)
Autoimmune Diseases , Extracellular Traps , Humans , Neutrophils , Inflammation/metabolism , Cell Death
5.
J Vis Exp ; (195)2023 05 12.
Article in English | MEDLINE | ID: covidwho-20237207

ABSTRACT

Certain stimuli, such as microorganisms, cause neutrophils to release neutrophil extracellular traps (NETs), which are basically web-like structures composed of DNA with granule proteins, such as myeloperoxidase (MPO) and neutrophil elastase (NE), and cytoplasmic and cytoskeletal proteins. Although interest in NETs has increased recently, no sensitive, reliable assay method is available for measuring NETs in clinical settings. This article describes a modified sandwich enzyme-linked immunosorbent assay to quantitatively measure two components of circulating NETs, MPO-DNA and NE-DNA complexes, which are specific components of NETs and are released into the extracellular space as breakdown products of NETs. The assay uses specific monoclonal antibodies for MPO or NE as the capture antibodies and a DNA-specific detection antibody. MPO or NE binds to one site of the capture antibody during the initial incubation of samples containing MPO-DNA or NE-DNA complexes. This assay shows good linearity and high inter-assay and intra-assay precision. We used it in 16 patients with COVID-19 with accompanying acute respiratory distress syndrome and found that the plasma concentrations of MPO-DNA and NE-DNA were significantly higher than in the plasma obtained from healthy controls. This detection assay is a reliable, highly sensitive, and useful method for investigating the characteristics of NETs in human plasma and culture supernatants.


Subject(s)
COVID-19 , Extracellular Traps , Humans , Extracellular Traps/metabolism , Leukocyte Elastase/metabolism , Peroxidase , Neutrophils , Enzyme-Linked Immunosorbent Assay , DNA/metabolism
6.
Front Immunol ; 14: 1186000, 2023.
Article in English | MEDLINE | ID: covidwho-20236819

ABSTRACT

Coronavirus disease 2019 (COVID-19) is known to commonly induce a thrombotic diathesis, particularly in severely affected individuals. So far, this COVID-19-associated coagulopathy (CAC) has been partially explained by hyperactivated platelets as well as by the prothrombotic effects of neutrophil extracellular traps (NETs) released from neutrophils. However, precise insight into the bidirectional relationship between platelets and neutrophils in the pathophysiology of CAC still lags behind. Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare autoimmune disorder caused by auto-antibody formation in response to immunization with adenoviral vector vaccines. VITT is associated with life-threatening thromboembolic events and thus, high fatality rates. Our concept of the thrombophilia observed in VITT is relatively new, hence a better understanding could help in the management of such patients with the potential to also prevent VITT. In this review we aim to summarize the current knowledge on platelet-neutrophil interplay in COVID-19 and VITT.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Humans , Blood Platelets , Neutrophils , COVID-19/complications , Thrombocytopenia/chemically induced , Thrombosis/etiology , Rare Diseases
7.
Biomolecules ; 13(5)2023 04 25.
Article in English | MEDLINE | ID: covidwho-20233944

ABSTRACT

Neutrophils are the most abundant leukocyte in circulation and are the first line of defense after an infection or injury. Neutrophils have a broad spectrum of functions, including phagocytosis of microorganisms, the release of pro-inflammatory cytokines and chemokines, oxidative burst, and the formation of neutrophil extracellular traps. Traditionally, neutrophils were thought to be most important for acute inflammatory responses, with a short half-life and a more static response to infections and injury. However, this view has changed in recent years showing neutrophil heterogeneity and dynamics, indicating a much more regulated and flexible response. Here we will discuss the role of neutrophils in aging and neurological disorders; specifically, we focus on recent data indicating the impact of neutrophils in chronic inflammatory processes and their contribution to neurological diseases. Lastly, we aim to conclude that reactive neutrophils directly contribute to increased vascular inflammation and age-related diseases.


Subject(s)
Extracellular Traps , Nervous System Diseases , Humans , Neutrophils , Cytokines , Phagocytosis , Inflammation
8.
Lab Chip ; 23(13): 3050-3061, 2023 06 28.
Article in English | MEDLINE | ID: covidwho-20242890

ABSTRACT

A feature of severe COVID-19 is the onset of an acute and intense systemic inflammatory response referred to as the "cytokine storm". The cytokine storm is characterized by high serum levels of inflammatory cytokines and the subsequent transport of inflammatory cells to damaging levels in vital organs (e.g., myocarditis). Immune trafficking and its effect on underlying tissues (e.g., myocardium) are challenging to observe at a high spatial and temporal resolution in mouse models. In this study, we created a vascularized organ-on-a-chip system to mimic cytokine storm-like conditions and tested the effectiveness of a novel multivalent selectin-targeting carbohydrate conjugate (composed of DS - dermatan sulfate and IkL - a selectin-binding peptide, termed DS-IkL) in blocking infiltration of polymorphonuclear leukocytes (PMN). Our data shows that cytokine storm-like conditions induce endothelial cells to produce additional inflammatory cytokines and facilitate infiltration of PMNs into tissue. Treatment of tissues with DS-IkL (60 µM) reduced PMN accumulation in the tissue by >50%. We then created cytokine storm-like conditions in a vascularized cardiac tissue-chip and found that PMN infiltration increases the spontaneous beating rate of the cardiac tissue, and this effect is eliminated by treatment with DS-IkL (60 µM). In summary, we demonstrate the utility of an organ-on-a-chip platform to mimic COVID-19 related cytokine storm and that blocking leukocyte infiltration with DS-IkL could be a viable strategy to mitigate associated cardiac complications.


Subject(s)
COVID-19 , Neutrophils , Mice , Animals , Cardiotoxicity , Endothelial Cells , Microphysiological Systems , Cytokines
9.
J Clin Lab Anal ; 37(1): e24808, 2023 Jan.
Article in English | MEDLINE | ID: covidwho-2327024

ABSTRACT

BACKGROUND: A wave of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread in Shanghai, China. Hematological abnormalities have been reported in coronavirus disease 2019 (COVID-19) patients; however, the difference in hematological parameters between COVID-19 patients with fever and patients who are febrile from other causes remains unexplored. METHODS: This retrospective cohort study enrolled 663 SARS-CoV-2 positive patients identified by RT-PCR. Clinical parameters, including age, sex, and threshold cycle values of all COVID-19 patients, and hematological parameters of COVID-19 patients in the fever clinic were abstracted for analysis. RESULTS: Overall, 60.8% of COVID-19 patients were male, and the median age was 45 years. Most of COVID-19 patients were asymptomatic, while 25.8% of patients showed fever and 10.9% of patients had other emergencies. COVID-19 patients with fever had significantly lower white blood cells (WBCs), neutrophils, lymphocytes, platelets and C-reactive protein (CRP), and significantly higher monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and mean platelet volume-to-platelet ratio (MPR) levels, compared with those in SARS-CoV-2 negative patients with fever from other causes (p < 0.05). Neutrophil-to-lymphocyte ratio (NLR), PLR, and systemic inflammatory index (SII) levels were significantly higher in COVID-19 patients with emergencies (p < 0.05). WBCs showed the best performance with an area under the curve (0.756), followed by neutrophils (0.730) and lymphocytes (0.694) in the diagnosis of COVID-19 in the fever clinic. CONCLUSION: WBCs, neutrophils, lymphocytes, platelets, CRP and MLR, PLR, and MPR may be useful in early diagnosis of COVID-19 in the fever clinic.


Subject(s)
COVID-19 , Humans , Male , Middle Aged , Female , COVID-19/epidemiology , SARS-CoV-2 , Retrospective Studies , Emergencies , China/epidemiology , Lymphocytes , Blood Platelets/chemistry , C-Reactive Protein/analysis , Neutrophils/chemistry
10.
Exp Clin Endocrinol Diabetes ; 131(4): 194-197, 2023 Apr.
Article in English | MEDLINE | ID: covidwho-2318159

ABSTRACT

AIM OF THE STUDY: To evaluate fasting plasma glucose (FPG) increase and neutrophil-to-lymphocyte ratio (NLR) as risk predictors of severe clinical outcome of COVID-19 pneumonia in type 2 diabetes mellitus (T2DM) hospitalised patients. PATIENTS AND METHODS: Type 2 diabetes mellitus (T2DM) patients hospitalised between March 2020 and February 2021 were studied retrospectively. The NLR ratio at admission and FPG increase (day 7, day with maximal FPG) were evaluated in association with the clinical progression of SARS-CoV-2 infection. RESULTS: Three hundred patients (165 men, 135 women) were included in the study. The mean age was 67.17±8.65 years. Severe COVID-19 pneumonia was diagnosed in 170 patients (56.7%). Fifty-four patients (18%) were intubated and 49 (16.3%) died. Greater increase in FPG (79.5 vs. 44.5 mg/dL for day 1-7, p<0.001; and 113.5 vs. 75 mg/dL for day 1-day with maximum glucose value, p<0.001) and higher NLR at admission (10.65 vs. 6.85) were seen in patients with need of high-flow oxygen compared to those without need, and they were associated with a higher probability of intubation and death. CONCLUSION: FPG increase and NLR could be significant risk predictors of severe COVID-19 pneumonia in T2DM hospitalised patients.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Male , Humans , Female , Middle Aged , Aged , COVID-19/complications , Diabetes Mellitus, Type 2/complications , Blood Glucose , Retrospective Studies , Neutrophils , SARS-CoV-2 , Fasting , Lymphocytes
11.
Nat Commun ; 14(1): 2610, 2023 05 05.
Article in English | MEDLINE | ID: covidwho-2316557

ABSTRACT

Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.


Subject(s)
COVID-19 , Extracellular Traps , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) , Humans , COVID-19/metabolism , Extracellular Traps/metabolism , Metabolome , Metabolomics , Neutrophils , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/metabolism
12.
Bull Exp Biol Med ; 174(6): 806-809, 2023 Apr.
Article in English | MEDLINE | ID: covidwho-2315974

ABSTRACT

We studied the neutrophils and monocytes obtained from 37 patients with various inflammatory diseases such as psoriasis, acute infectious process in the abdominal cavity (acute appendicitis/abscess of the abdominal cavity, and acute cholecystitis), acute pancreatitis, and post-COVID syndrome after mild COVID infection. The number and the morphological structure of neutrophil extracellular traps (NET) as well as the effect of IgG on NET were examined. NET were visualized and counted by fluorescence microscopy with fluorescent dye SYBR Green. All the studied types of inflammation were accompanied by spontaneous formation of NET. After application of IgG, the number of NET doubled, their size increased, and transformation of net-like traps into the cloud forms was observed. The clouds form structure of the network is not capable of capturing pathogens with subsequent retraction, the products of its enzymatic degradation can be the factors of secondary alteration. The study results demonstrate a previously unknown mechanism of infection resistance.


Subject(s)
COVID-19 , Extracellular Traps , Pancreatitis , Humans , Extracellular Traps/metabolism , Acute Disease , Pancreatitis/metabolism , COVID-19/metabolism , Neutrophils/metabolism , Immunoglobulin G/metabolism
13.
J Clin Lab Anal ; 37(6): e24876, 2023 Mar.
Article in English | MEDLINE | ID: covidwho-2320328

ABSTRACT

OBJECTIVES: We aimed at analyzing the serum levels of citrullinated histone H3 (CitH3) in patients with dermatomyositis (DM) and their association with disease activity. METHODS: Serum CitH3 levels were measured using enzyme-linked immunosorbent assays in serum samples obtained from 93 DM patients and 56 healthy controls (HCs). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminant capacity of CitH3 and other disease variables. The association between CitH3 and disease variables was analyzed using Pearson's rank correlation. RESULTS: Serum CitH3 level was significantly lower in DM patients than in HCs (p < 0.001). The ROC curve analysis revealed that CitH3 strongly discriminated DM patients from HCs (area under the curve [AUC], 0.86), and a combination of CitH3 and the ratio of neutrophil to lymphocyte counts (NLR) showed a greater diagnostic value (AUC, 0.92). Serum CitH3 levels were markedly lower in DM patients with normal muscle enzyme levels than in HCs (all p < 0.001), and when compared to an elevated group, the CitH3 levels were comparable (all p > 0.05). The CitH3 levels showed no difference between DM in active and remission groups. However, in a paired test with 18 hospitalized DM patients, the CitH3 levels were higher in remission state than in active state. Moreover, the CitH3 levels showed no correlation with disease variables that were associated with the disease activity of DM. CONCLUSIONS: Serum CitH3 level may serve as a useful biochemical marker for screening patients with DM from HCs, while its role in monitoring DM disease activity requires further research.


Subject(s)
Dermatomyositis , Histones , Humans , Neutrophils , Biomarkers , ROC Curve
14.
Trends Microbiol ; 31(3): 222-224, 2023 03.
Article in English | MEDLINE | ID: covidwho-2314717

ABSTRACT

The distinct risk factors to deadly infections by Aspergillus fumigatus (Af) in intensive care unit (ICU) patients are well known; however, so far, the mechanistic link between these predisposing conditions has been unknown. Sarden et al. recently unraveled a shared B1a lymphocyte-natural antibody-neutrophil defense pathway to Af, opening new perspectives in diagnostics and therapeutics.


Subject(s)
Aspergillosis , Humans , Aspergillus , Neutrophils , Risk Factors , Aspergillus fumigatus
15.
Eur Rev Med Pharmacol Sci ; 27(8): 3747-3752, 2023 Apr.
Article in English | MEDLINE | ID: covidwho-2314347

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first detected in December 2019 and then spread globally, resulting in a pandemic. Initially, it was unknown if chronic kidney disease (CKD) contributed to the mortality caused by COVID-19. The immunosuppression associated with this disease may minimize the COVID-19-described hyper-inflammatory state or immunological dysfunction, and a high prevalence of comorbidities may lead to a poorer clinical prognosis. Patients with COVID-19 have abnormal circulating blood cells associated with inflammation. Risk stratification, diagnosis, and prognosis primarily rely on hematological features, such as white blood cells and their subpopulations, red cell distribution width, mean platelet volume, and platelet count, in addition to their combined ratios. In non-small-cell lung cancer, the aggregate index of systemic inflammation (AISI), (neutrophils x monocytes x platelets/lymphocytes) is evaluated. In light of the relevance of inflammation in mortality, the objective of this study is to determine the impact of AISI on the hospital mortality of CKD patients. PATIENTS AND METHODS: This study is an observational retrospective study. Data and test outcomes of all CKD patients, stages 3-5, hospitalized for COVID-19 and followed between April and October 2021 were analyzed. RESULTS: Patients were divided into two groups according to death (Group 1-Alive, Group 2-Died). Neutrophil count, AISI and C-reactive protein (CRP) levels were increased in Group-2 [10.3±4.6 vs. 7.65±4.22; p=0.001, 2,084.1 (364.8-2,577.5) vs. 628.9 (53.1-2,275); p=0.00 and 141.9 (20.5-318) vs. 84.75 (0.92-195); p=0.00; respectively]. Receiver operating characteristic (ROC) analysis demonstrated 621.1 as a cut-off value for AISI to predict hospital mortality with 81% sensitivity and 69.1% specificity [area under ROC curve 0.820 (95% CI: 0.733-0.907), p<.005]. Cox regression analysis was used to analyze the effect of risk variables on survival. In survival analysis, AISI and CRP were identified as important survival predictors [hazard ratio (HR): 1.001, 95% CI: 1-1.001; p=0.00 and HR: 1.009, 95% CI: 1.004-1.013; p=0.00]. CONCLUSIONS: This study demonstrated the discriminative effectiveness of AISI in predicting disease mortality in COVID-19 patients with CKD. Quantification of AISI upon admission might assist in the early detection and treatment of individuals with a bad prognosis.


Subject(s)
COVID-19 , Carcinoma, Non-Small-Cell Lung , Kidney Failure, Chronic , Lung Neoplasms , Renal Insufficiency, Chronic , Humans , COVID-19/epidemiology , SARS-CoV-2 , Retrospective Studies , Inflammation , Prognosis , Neutrophils , ROC Curve
16.
Lancet Respir Med ; 10(12): 1100-1101, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2307974
17.
Viruses ; 15(1)2022 Dec 30.
Article in English | MEDLINE | ID: covidwho-2310245

ABSTRACT

The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic "cytokine storm". Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies.


Subject(s)
COVID-19 , Humans , SARS-CoV-2/genetics , Neutrophils , Transcriptome , Pandemics
18.
Viruses ; 15(1)2022 Dec 31.
Article in English | MEDLINE | ID: covidwho-2309156

ABSTRACT

INTRODUCTION: Studies have documented the role of the "neutrophil-to-lymphocyte ratio" (NLR) in influenza virus infection. In addition, morphometric parameters derived from automated analyzers on the volume, scatter and conductivity of monocytes, neutrophils and lymphocytes in many viral etiologies have helped with their early differentiation. With this background, we aimed to characterize the hematological changes of coronavirus-positive cases and also compare them with the healthy controls and patients affected by non-COVID Influenza-like illnesses so that early isolation could be considered. MATERIAL AND METHODS: This was a cross-sectional analytical study carried out in the years 2020-2022. All cases with COVID-19 and non-COVID-19 Influenza-like illnesses and healthy controls above 18 years were included. Cases were diagnosed according to the WHO guidelines. All samples were processed on a Unicel DxH 800 (Beckman Coulter, California, USA) automated hematology analyzer. The demographic, clinical and regular hematological parameters along with additional parameters such as volume, conductivity and scatter (VCS) of the three groups were compared. RESULTS: The 169 COVID-19 cases were in the moderate to severe category. Compared with 140 healthy controls, the majority of the routine hematological values including the NLR (neutrophil-to-lymphocyte ratio) and PLR (platelet-to-lymphocyte ratio) showed statistically significant differences. A cutoff of an absolute neutrophil count of 4350 cell/cumm was found to have a sensitivity of 76% and specificity of 70% in differentiating moderate and severe COVID-19 cases from healthy controls. COVID-19 and the non-COVID-19 Influenza-like illnesses were similar statistically in all parameters except the PLR, mean neutrophilic and monocytic volume, scatter parameters in neutrophils, axial light loss in monocytes and NLR. Interestingly, there was a trend of higher mean volumes and scatter in neutrophils and monocytes in COVID-19 cases as compared to non-COVID-19 Influenza-like illnesses. CONCLUSION: We demonstrated morphological changes in neutrophils, monocytes and lymphocytes in COVID-19 infection and also non-COVID-19 Influenza-like illnesses with the help of VCS parameters. A cutoff for the absolute neutrophils count was able to differentiate COVID-19 infection requiring hospitalization from healthy controls and eosinopenia was a characteristic finding in cases with COVID-19 infection.


Subject(s)
COVID-19 , Hematology , Influenza, Human , Humans , Influenza, Human/diagnosis , Cross-Sectional Studies , Leukocyte Count , Lymphocytes , Neutrophils , Retrospective Studies
19.
Br J Pharmacol ; 180(11): 1460-1481, 2023 06.
Article in English | MEDLINE | ID: covidwho-2308487

ABSTRACT

BACKGROUND AND PURPOSE: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections. EXPERIMENTAL APPROACH: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models. KEY RESULTS: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage. CONCLUSION AND IMPLICATIONS: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.


Subject(s)
COVID-19 , Sepsis , Humans , Mice , Animals , Oseltamivir/adverse effects , Zanamivir/adverse effects , Neuraminidase/metabolism , Neuraminidase/pharmacology , Neutrophils , Matrix Metalloproteinase 9/metabolism , Reactive Oxygen Species , Lipopolysaccharides/pharmacology , Sepsis/chemically induced
20.
Int J Mol Sci ; 24(5)2023 Mar 06.
Article in English | MEDLINE | ID: covidwho-2289605

ABSTRACT

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases.


Subject(s)
Extracellular Traps , Respiration Disorders , Humans , Respiration Disorders/pathology , Neutrophils , Immunity, Innate , Chronic Disease
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