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1.
Int J Mol Sci ; 23(7)2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1776254

ABSTRACT

In the novel pandemic of Coronavirus Disease 2019, high levels of pro-inflammatory cytokines lead to endothelial activation and dysfunction, promoting a pro-coagulative state, thrombotic events, and microvasculature injuries. The aim of the present work was to investigate the effect of SARS-CoV-2 on pro-inflammatory cytokines, tissue factor, and chemokine release, with Human Microvascular Endothelial Cells (HMEC-1). ACE2 receptor expression was evaluated by western blot analysis. SARS-CoV-2 infection was assessed by one-step RT-PCR until 7 days post-infection (p.i.), and by Transmission Electron Microscopy (TEM). IL-6, TNF-α, IL-8, IFN-α, and hTF mRNA expression levels were detected by RT-PCR, while cytokine release was evaluated by ELISA. HMEC-1 expressed ACE2 receptor and SARS-CoV-2 infection showed a constant viral load. TEM analysis showed virions localized in the cytoplasm. Expression of IL-6 at 24 h and IFN-α mRNA at 24 h and 48 h p.i. was higher in infected than uninfected HMEC-1 (p < 0.05). IL-6 levels were significantly higher in supernatants from infected HMEC-1 (p < 0.001) at 24 h, 48 h, and 72 h p.i., while IL-8 levels were significantly lower at 24 h p.i. (p < 0.001). These data indicate that in vitro microvascular endothelial cells are susceptible to SARS-CoV-2 infection but slightly contribute to viral amplification. However, SARS-CoV-2 infection might trigger the increase of pro-inflammatory mediators.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Chemokines/genetics , Chemokines/metabolism , Cytokines/metabolism , Endothelial Cells/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , SARS-CoV-2
2.
Cell Mol Life Sci ; 79(3): 187, 2022 Mar 13.
Article in English | MEDLINE | ID: covidwho-1739282

ABSTRACT

Under physiological conditions, hematopoietic stem and progenitor cells (HSPCs) in the bone marrow niches are responsible for the highly regulated and interconnected hematopoiesis process. At the same time, they must recognize potential threats and respond promptly to protect the host. A wide spectrum of microbial agents/products and the consequences of infection-induced mediators (e.g. cytokines, chemokines, and growth factors) can have prominent impact on HSPCs. While COVID-19 starts as a respiratory tract infection, it is considered a systemic disease which profoundly alters the hematopoietic system. Lymphopenia, neutrophilia, thrombocytopenia, and stress erythropoiesis are the hallmark of SARS-CoV-2 infection. Moreover, thrombocytopenia and blood hypercoagulability are common among COVID-19 patients with severe disease. Notably, the invasion of erythroid precursors and progenitors by SARS-CoV-2 is a cardinal feature of COVID-19 disease which may in part explain the mechanism underlying hypoxia. These pieces of evidence support the notion of skewed steady-state hematopoiesis to stress hematopoiesis following SARS-CoV-2 infection. The functional consequences of these alterations depend on the magnitude of the effect, which launches a unique hematopoietic response that is associated with increased myeloid at the expense of decreased lymphoid cells. This article reviews some of the key pathways including the infectious and inflammatory processes that control hematopoiesis, followed by a comprehensive review that summarizes the latest evidence and discusses how SARS-CoV-2 infection impacts hematopoiesis.


Subject(s)
COVID-19/pathology , Hematopoiesis , COVID-19/complications , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , SARS-CoV-2/isolation & purification , Thrombocytopenia/complications
3.
Sci Rep ; 12(1): 4150, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1735291

ABSTRACT

Models of animals that are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can usefully evaluate the efficacy of vaccines and therapeutics. In this study, we demonstrate that infection with the SARS-CoV-2 B.1.351 variant (TY8-612 strain) induces bodyweight loss and inflammatory cytokine/chemokine production in wild-type laboratory mice (BALB/c and C57BL/6 J mice). Furthermore, compared to their counterparts, BALB/c mice had a higher viral load in their lungs and worse symptoms. Importantly, infecting aged BALB/c mice (older than 6 months) with the TY8-612 strain elicited a massive and sustained production of multiple pro-inflammatory cytokines/chemokines and led to universal mortality. These results indicated that the SARS-CoV-2 B.1.351 variant-infected mice exhibited symptoms ranging from mild to fatal depending on their strain and age. Our data provide insights into the pathogenesis of SARS-CoV-2 and may be useful in developing prophylactics and therapeutics.


Subject(s)
COVID-19/pathology , SARS-CoV-2/physiology , Aging , Animals , COVID-19/mortality , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , Disease Models, Animal , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Principal Component Analysis , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Viral Load
4.
Cells ; 11(3)2022 02 08.
Article in English | MEDLINE | ID: covidwho-1674519

ABSTRACT

Cancer cachexia remains a serious public health concern worldwide, particularly as cancer rates rise. Treatment is endangered, and survival is reduced, because this illness is commonly misdiagnosed and undertreated. Although weight loss is the most evident sign of cachexia, there are other early metabolic and inflammatory changes that occur before the most obvious symptoms appear. Cachexia-related inflammation is induced by a combination of factors, one of which is the release of inflammation-promoting chemicals by the tumor. Today, more scientists are beginning to believe that the development of SARS-CoV-2 (COVID-19) related cachexia is similar to cancer-related cachexia. It is worth noting that patients infected with COVID-19 have a significant inflammatory response and can develop cachexia. These correlations provide feasible reasons for the variance in the occurrence and severity of cachexia in human malignancies, therefore, specific therapeutic options for these individuals must be addressed based on disease types. In this review, we highlighted the role of key chemokines, cytokines, and clinical management in relation to cancer cachexia and its long-term impact on COVID-19 patients.


Subject(s)
COVID-19/metabolism , Cachexia/metabolism , Chemokines/metabolism , Cytokines/metabolism , Neoplasms/metabolism , COVID-19/epidemiology , COVID-19/virology , Cachexia/etiology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation Mediators/metabolism , Neoplasms/complications , Pandemics/prevention & control , SARS-CoV-2/physiology
5.
Sci Rep ; 11(1): 22463, 2021 11 17.
Article in English | MEDLINE | ID: covidwho-1592758

ABSTRACT

SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.


Subject(s)
COVID-19/immunology , Neutrophils/immunology , Pseudogenes/immunology , Aged , Chemokines/metabolism , Cohort Studies , Critical Illness , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay/methods , Extracellular Traps/metabolism , Female , Humans , Inflammation/metabolism , Male , Middle Aged , Neutrophils/metabolism , Pseudogenes/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index
6.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1565893

ABSTRACT

In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer nonspecific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here, we demonstrate that intravenous, but not subcutaneous, inoculation of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 (SCV2) and results in reduced viral loads in non-transgenic animals infected with an α variant. The observed increase in host resistance was associated with reductions in SCV2-induced tissue pathology, inflammatory cell recruitment, and cytokine production that multivariate analysis revealed as only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and ensuing immunopathology. While intravenous BCG vaccination is not a clinically acceptable practice, our findings provide an experimental model for identifying mechanisms by which nonspecific stimulation of the pulmonary immune response promotes host resistance to SCV2 lethality.


Subject(s)
BCG Vaccine/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Administration, Intravenous , Angiotensin-Converting Enzyme 2/metabolism , Animals , Chemokines/metabolism , Humans , Inflammation/pathology , Mice, Inbred C57BL , Mice, Transgenic , Viral Load
7.
Int J Mol Sci ; 22(23)2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1560167

ABSTRACT

Streptococcus pneumoniae is an important causative organism of respiratory tract infections. Although periodontal bacteria have been shown to influence respiratory infections such as aspiration pneumonia, the synergistic effect of S. pneumoniae and Porphyromonas gingivalis, a periodontopathic bacterium, on pneumococcal infections is unclear. To investigate whether P. gingivalis accelerates pneumococcal infections, we tested the effects of inoculating P. gingivalis culture supernatant (PgSup) into S. pneumoniae-infected mice. Mice were intratracheally injected with S. pneumoniae and PgSup to induce pneumonia, and lung histopathological sections and the absolute number and frequency of neutrophils and macrophages in the lung were analyzed. Proinflammatory cytokine/chemokine expression was examined by qPCR and ELISA. Inflammatory cell infiltration was observed in S. pneumoniae-infected mice and S. pnemoniae and PgSup mixed-infected mice, and mixed-infected mice showed more pronounced inflammation in lung. The ratios of monocytes/macrophages and neutrophils were not significantly different between the lungs of S. pneumoniae-infected mice and those of mixed-infected mice. PgSup synergistically increased TNF-α expression/production and IL-17 production compared with S. pneumoniae infection alone. We demonstrated that PgSup enhanced inflammation in pneumonia caused by S. pneumoniae, suggesting that virulence factors produced by P. gingivalis are involved in the exacerbation of respiratory tract infections such as aspiration pneumonia.


Subject(s)
Bacteroidaceae Infections/complications , Inflammation/pathology , Lung/pathology , Neutrophil Infiltration/immunology , Pneumonia, Pneumococcal/pathology , Porphyromonas gingivalis/physiology , Streptococcus pneumoniae/physiology , Animals , Bacteroidaceae Infections/microbiology , Chemokines/metabolism , Cytokines/metabolism , Inflammation/etiology , Lung/immunology , Lung/metabolism , Lung/microbiology , Mice , Mice, Inbred C57BL , Pneumonia, Pneumococcal/epidemiology , Pneumonia, Pneumococcal/metabolism , Pneumonia, Pneumococcal/microbiology
8.
Sci Rep ; 11(1): 13464, 2021 06 29.
Article in English | MEDLINE | ID: covidwho-1500743

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus disease 2019 (COVID-19) that emerged in human populations recently. Severely ill COVID-19 patients exhibit the elevation of proinflammatory cytokines, and such an unbalanced production of proinflammatory cytokines is linked to acute respiratory distress syndrome with high mortality in COVID-19 patients. Our study provides evidence that the ORF3a, M, ORF7a, and N proteins of SARS-CoV-2 were NF-κB activators. The viral sequence from infected zoo lions belonged to clade V, and a single mutation of G251V is found for ORF3a gene compared to all other clades. No significant functional difference was found for clade V ORF3a, indicating the NF-κB activation is conserved among COVID-19 variants. Of the four viral proteins, the ORF7a protein induced the NF-κB dictated proinflammatory cytokines including IL-1α, IL-1ß, IL-6, IL-8, IL-10, TNF-α, and IFNß. The ORF7a protein also induced IL-3, IL-4, IL-7, IL-23. Of 15 different chemokines examined in the study, CCL11, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL26, CCL27, and CXCL9 were significantly upregulated by ORF7. These cytokines and chemokines were frequently elevated in severely ill COVID-19 patients. Our data provide an insight into how SARS-CoV-2 modulates NF-κB signaling and inflammatory cytokine expressions. The ORF7a protein may be a desirable target for strategic developments to minimize uncontrolled inflammation in COVID-19 patients.


Subject(s)
Cytokines/metabolism , NF-kappa B/metabolism , SARS-CoV-2/metabolism , Viral Proteins/metabolism , Amino Acid Sequence , COVID-19/pathology , COVID-19/virology , Chemokines/genetics , Chemokines/metabolism , Cytokines/genetics , HeLa Cells , Humans , Point Mutation , SARS-CoV-2/isolation & purification , Sequence Alignment , Severity of Illness Index , Up-Regulation , Viral Matrix Proteins/genetics , Viral Proteins/genetics , Viroporin Proteins/chemistry , Viroporin Proteins/genetics , Viroporin Proteins/metabolism
9.
J Neuroinflammation ; 18(1): 193, 2021 Sep 06.
Article in English | MEDLINE | ID: covidwho-1430430

ABSTRACT

BACKGROUND: The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. METHODS: Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice. RESULTS: We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1ß, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNß, demonstrating a specific sex difference in the anti-viral response in the hippocampus. CONCLUSION: Our data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.


Subject(s)
Poly I-C , Sex Characteristics , Animals , Chemokines/metabolism , Cytokines/metabolism , Female , Hippocampus/metabolism , Male , Mice , Poly I-C/pharmacology
10.
J Infect Dis ; 224(4): 606-615, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1369104

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/metabolism , Systemic Inflammatory Response Syndrome/virology , Adolescent , Age Factors , Antibodies, Viral/immunology , Biomarkers , COVID-19/diagnosis , COVID-19/epidemiology , Child , Child, Preschool , Host-Pathogen Interactions , Humans , Male , RNA, Viral , Serologic Tests , Severity of Illness Index , Sex Factors , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/epidemiology , Viral Load
11.
Int J Mol Sci ; 22(13)2021 Jul 05.
Article in English | MEDLINE | ID: covidwho-1304673

ABSTRACT

Macrophages (Mφs) are instrumental regulators of the immune response whereby they acquire diverse functional phenotypes following their exposure to microenvironmental cues that govern their differentiation from monocytes and their activation. The complexity and diversity of the mycobacterial cell wall have empowered mycobacteria with potent immunomodulatory capacities. A heat-killed (HK) whole-cell preparation of Mycobacterium obuense (M. obuense) has shown promise as an adjunctive immunotherapeutic agent for the treatment of cancer. Moreover, HK M. obuense has been shown to trigger the differentiation of human monocytes into a monocyte-derived macrophage (MDM) type named Mob-MDM. However, the transcriptomic profile and functional properties of Mob-MDMs remain undefined during an activation state. Here, we characterized cytokine/chemokine release patterns and transcriptomic profiles of lipopolysaccharide (LPS)/interferon γ (IFNγ)-activated human MDMs that were differentiated with HK M. obuense (Mob-MDM(LPS/IFNγ)), macrophage colony-stimulating factor M-MDM(LPS/IFNγ)), or granulocyte/macrophage colony-stimulating factor (GM-MDM(LPS/IFNγ)). Mob-MDM(LPS/IFNγ) demonstrated a unique cytokine/chemokine release pattern (interleukin (IL)-10low, IL-12/23p40low, IL-23p19/p40low, chemokine (C-x-C) motif ligand (CXCL)9low) that was distinct from those of M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ). Furthermore, M-MDM(LPS/IFNγ) maintained IL-10 production at significantly higher levels compared to GM-MDM(LPS/IFNγ) and Mob-MDM(LPS/IFNγ) despite being activated with M1-Mφ-activating stimuli. Comparative RNA sequencing analysis pointed to a distinct transcriptome profile for Mob-MDM(LPS/IFNγ) relative to both M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ) that comprised 417 transcripts. Functional gene-set enrichment analysis revealed significant overrepresentation of signaling pathways and biological processes that were uniquely related to Mob-MDM(LPS/IFNγ). Our findings lay a foundation for the potential integration of HK M. obuense in specific cell-based immunotherapeutic modalities such as adoptive transfer of Mφs (Mob-MDM(LPS/IFNγ)) for cancer treatment.


Subject(s)
Chemokines/metabolism , Cytokines/metabolism , Macrophages/immunology , Nontuberculous Mycobacteria/immunology , Cell Differentiation/genetics , Cell Differentiation/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacokinetics , Humans , Immunologic Factors/pharmacology , In Vitro Techniques , Interferon-gamma/pharmacology , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Macrophage Activation/immunology , Macrophage Colony-Stimulating Factor/pharmacology , Macrophages/cytology , Macrophages/metabolism , Transcriptome
12.
Int J Mol Sci ; 22(13)2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1295858

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 2.7 million lives globally. Obesity has been associated with increased severity and mortality of COVID-19. However, the molecular mechanisms by which obesity exacerbates COVID-19 pathologies are not well-defined. The levels of free fatty acids (FFAs) are elevated in obese subjects. This study was therefore designed to examine how excess levels of different FFAs may affect the progression of COVID-19. Biological molecules associated with palmitic acid (PA) and COVID-19 were retrieved from QIAGEN Knowledge Base, and Ingenuity Pathway Analysis tools were used to analyze these datasets and explore the potential pathways affected by different FFAs. Our study found that one of the top 10 canonical pathways affected by PA was the coronavirus pathogenesis pathway, mediated by key inflammatory mediators, including PTGS2; cytokines, including IL1ß and IL6; chemokines, including CCL2 and CCL5; transcription factors, including NFκB; translation regulators, including EEF1A1; and apoptotic mediators, including BAX. In contrast, n-3 fatty acids may attenuate PA's activation of the coronavirus pathogenesis pathway by inhibiting the activity of such mediators as IL1ß, CCL2, PTGS2, and BAX. Furthermore, PA may modulate the expression of ACE2, the main cell surface receptor for the SARS-CoV-2 spike protein.


Subject(s)
COVID-19/metabolism , Fatty Acids, Nonesterified/metabolism , Obesity/metabolism , Palmitic Acid/metabolism , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/epidemiology , COVID-19/pathology , Chemokines/metabolism , Computational Biology/methods , Cytokines/metabolism , Databases, Factual , Fatty Acids, Nonesterified/blood , Humans , Inflammation Mediators/metabolism , Obesity/pathology , Pandemics , SARS-CoV-2/isolation & purification
13.
Int J Mol Sci ; 22(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1288903

ABSTRACT

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.


Subject(s)
COVID-19/pathology , Immunity, Innate , COVID-19/immunology , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , Host-Pathogen Interactions , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Monocytes/cytology , Monocytes/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index
14.
Int J Mol Sci ; 22(12)2021 Jun 21.
Article in English | MEDLINE | ID: covidwho-1282515

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with excess mortality worldwide. The cardiovascular system is the second most common target of SARS-CoV-2, which leads to severe complications, including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism, as well as other major thrombotic events because of direct endothelial injury and an excessive systemic inflammatory response. This review focuses on the similarities and the differences of inflammatory pathways involved in COVID-19 and atherosclerosis. Anti-inflammatory agents and immunomodulators have recently been assessed, which may constitute rational treatments for the reduction of cardiovascular events in both COVID-19 and atherosclerotic heart disease.


Subject(s)
Atherosclerosis/pathology , COVID-19/pathology , Adrenal Cortex Hormones/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Atherosclerosis/complications , Atherosclerosis/drug therapy , Atherosclerosis/prevention & control , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Chemokines/metabolism , Cytokine Release Syndrome/etiology , Cytokines/metabolism , Humans , Prognosis , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism
15.
Front Immunol ; 12: 666223, 2021.
Article in English | MEDLINE | ID: covidwho-1247864

ABSTRACT

BACKGROUND: SARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development. AIM: This systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2). METHOD: The PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers. RESULTS: A high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS. CONCLUSION: This study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients' outcomes in severe cases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration 94 number: CRD42020209931.


Subject(s)
Coronavirus Infections/immunology , Coronavirus/physiology , Cytokine Release Syndrome/immunology , Inflammation/immunology , Animals , Blood Circulation , Chemokines/metabolism , Cytokines/metabolism , Humans , Randomized Controlled Trials as Topic
16.
PLoS One ; 16(5): e0252026, 2021.
Article in English | MEDLINE | ID: covidwho-1243847

ABSTRACT

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.


Subject(s)
COVID-19/pathology , Cytokines/metabolism , Liver/physiopathology , Lung/physiopathology , Obesity/pathology , Aged , Biomarkers/metabolism , Body Mass Index , COVID-19/complications , COVID-19/virology , Chemokines/blood , Chemokines/metabolism , Cytokines/blood , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Hospitalization/statistics & numerical data , Humans , Intensive Care Units , Liver/diagnostic imaging , Lung/diagnostic imaging , Male , Middle Aged , Obesity/complications , Prospective Studies , RNA, Viral/blood , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index
17.
J Infect Dis ; 224(4): 606-615, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1243488

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/metabolism , Systemic Inflammatory Response Syndrome/virology , Adolescent , Age Factors , Antibodies, Viral/immunology , Biomarkers , COVID-19/diagnosis , COVID-19/epidemiology , Child , Child, Preschool , Host-Pathogen Interactions , Humans , Male , RNA, Viral , Serologic Tests , Severity of Illness Index , Sex Factors , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/epidemiology , Viral Load
18.
Phytomedicine ; 87: 153583, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1213465

ABSTRACT

BACKGROUND: A key clinical feature of COVID-19 is a deep inflammatory state known as "cytokine storm" and characterized by high expression of several cytokines, chemokines and growth factors, including IL-6 and IL-8. A direct consequence of this inflammatory state in the lungs is the Acute Respiratory Distress Syndrome (ARDS), frequently observed in severe COVID-19 patients. The "cytokine storm" is associated with severe forms of COVID-19 and poor prognosis for COVID-19 patients. Sulforaphane (SFN), one of the main components of Brassica oleraceae L. (Brassicaceae or Cruciferae), is known to possess anti-inflammatory effects in tissues from several organs, among which joints, kidneys and lungs. PURPOSE: The objective of the present study was to determine whether SFN is able to inhibit IL-6 and IL-8, two key molecules involved in the COVID-19 "cytokine storm". METHODS: The effects of SFN were studied in vitro on bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 Spike protein (S-protein). The anti-inflammatory activity of SFN on IL-6 and IL-8 expression has been evaluated by RT-qPCR and Bio-Plex analysis. RESULTS: In our study SFN inhibits, in cultured IB3-1 bronchial cells, the gene expression of IL-6 and IL-8 induced by the S-protein of SARS-CoV-2. This represents the proof-of-principle that SFN may modulate the release of some key proteins of the COVID-19 "cytokine storm". CONCLUSION: The control of the cytokine storm is one of the major issues in the management of COVID-19 patients. Our study suggests that SFN can be employed in protocols useful to control hyperinflammatory state associated with SARS-CoV-2 infection.


Subject(s)
Bronchi/virology , Interleukin-6/genetics , Interleukin-8/genetics , Isothiocyanates/pharmacology , Spike Glycoprotein, Coronavirus/toxicity , Sulfoxides/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Apoptosis/drug effects , Bronchi/cytology , Bronchi/drug effects , COVID-19/physiopathology , Cell Line , Chemokines/genetics , Chemokines/metabolism , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Gene Expression Regulation/drug effects , Humans , SARS-CoV-2/pathogenicity , Up-Regulation/drug effects
19.
Front Immunol ; 12: 638446, 2021.
Article in English | MEDLINE | ID: covidwho-1211811

ABSTRACT

Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the "cytokine storm" of COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/metabolism , Interferon Regulatory Factors/antagonists & inhibitors , Interferon Regulatory Factors/metabolism , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Interleukin-1 Receptor-Associated Kinases/metabolism , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/physiopathology , Chemokines/metabolism , Cytokines/metabolism , Humans , Signal Transduction/genetics , Signal Transduction/immunology , Virus Diseases/metabolism
20.
Cell ; 184(9): 2316-2331.e15, 2021 04 29.
Article in English | MEDLINE | ID: covidwho-1135277

ABSTRACT

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Protective Agents/pharmacology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Animals , Binding, Competitive , COVID-19/immunology , COVID-19/virology , Chemokines/metabolism , Chlorocebus aethiops , HEK293 Cells , Humans , Immunoglobulin Fab Fragments/metabolism , Immunoglobulin G/metabolism , Lung/metabolism , Mice, Inbred C57BL , Models, Molecular , Mutagenesis/genetics , Neutralization Tests , Protein Domains , Vero Cells
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