Metabolic programs define dysfunctional immune responses in severe COVID-19 patients

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Pulmonary cell response to bacterial challenge in mutant mice with some hereditary alterations resembling cystic fibrosis

Animal models make it possible to perform studies that normally can not be done in human beings. In the present work, the cellular response pattern of the lungs both to the environment and to a challenger strain of bacteria were analyzed in two mouse mutations-cribriform degeneration ($\text{cri}$) and motheaten (me)-. The mice were submitted to an infective aerosol containing $\text{Staphylococcus aureus}$ and were killed either immediately or 4 h after exposure; pulmonary washings were performed in these animals as well as in non-infected controls. The results showed neither quantitative differences in the total cell count nor in cell viability between the different groups. However, there were qualitative changes in the differential cell content characterized by a neutrophilic response in $\text{cri}$/$\text{cri}$ mice and a giant cell response in $\text{me}$/$\text{me}$ mice. Since most of the cystic fibrosis patients suffer from chronic lung infection, with a persistently high proportion of neutrophils, these findings point to the $\text{cri}$/$\text{cri}$ mouse as a promising animal model for cystic fibrosis studies.     

Hemolin expression in the silk glands of Galleria mellonella in response to bacterial challenge and prior to cell disintegration

Hemolin, a member of the immunoglobulin protein superfamily, functions in Lepidoptera as an opsonin in defence against potential pathogens and seems to play a role in tissue morphogenesis. We show that hemolin gene is expressed in several organs of Galleria mellonella larvae, including the nervous system and the silk glands. The expression in the silk glands of the wandering larvae and their isolated abdomens is enhanced within 6 h after an injection of bacteria, lipopolysaccharides, or peptidoglycans. The magnitude of silk gland response to bacterial challenge is similar to that seen in the fat body. A profound rise of hemolin expression without bacterial inoculation occurs in the silk glands of isolated abdomens when they are induced to pupate by a topical application of 20-hydroxyecdysone (20E). The induction of pupation is associated with silk gland programming for disintegration by apoptosis and phagocytosis. Administration of a juvenile hormone agonist prevents pupation and abolishes the stimulatory 20E effect on the hemolin expression. Hemolin protein can be immunodetected in the silk glands as well as in the spun-out cocoon silk. The results suggest that silk glands are a component of the insect immune system and that hemolin may mark the apoptic cells for the elimination by hemocytes.     

Sex differences in the immune response to acute COVID-19 respiratory tract infection

Determine if sex differences exist in clinical characteristics and outcomes of adults hospitalized for coronavirus disease 2019 (COVID-19) in a US healthcare system. Case series study. Sequentially hospitalized adults admitted for COVID-19 at two tertiary care academic hospitals in New Orleans, LA, between 27 February and 15 July 2020. Measures included demographics, comorbidities, presenting symptoms, and laboratory results. Outcomes included intensive care unit admission (ICU), invasive mechanical ventilation (IMV), and in-hospital death. We included 776 patients (median age 60.5 years; 61.4% women, 75% non-Hispanic Black). Rates of ICU, IMV, and death were similar in both sexes. In women versus men, obesity (63.8 vs 41.6%, P < 0.0001), hypertension (77.6 vs 70.1%, P = 0.02), diabetes (38.2 vs 31.8%, P = 0.06), chronic obstructive pulmonary disease (COPD, 22.1 vs 15.1%, P = 0.015), and asthma (14.3 vs 6.9%, P = 0.001) were more prevalent. More women exhibited dyspnea (61.2 vs 53.7%, P = 0.04), fatigue (35.7 vs 28.5%, P = 0.03), and digestive symptoms (39.3 vs 32.8%, P = 0.06) than men. Obesity was associated with IMV at a lower BMI (> 35) in women, but the magnitude of the effect of morbid obesity (BMI ≥ 40) was similar in both sexes. COPD was associated with ICU (adjusted OR (aOR), 2.6; 95%CI, 1.5–4.3) and IMV (aOR, 1.8; 95%CI, 1.2–3.1) in women only. Diabetes (aOR, 2.6; 95%CI, 1.2–2.9), chronic kidney disease (aOR, 2.2; 95%CI, 1.3–5.2), elevated neutrophil-to-lymphocyte ratio (aOR, 2.5; 95%CI, 1.4–4.3), and elevated ferritin (aOR, 3.6; 95%CI, 1.7–7.3) were independent predictors of death in women only. In contrast, elevated D-dimer was an independent predictor of ICU (aOR, 7.3; 95%CI, 2.7–19.5), IMV (aOR, 6.5; 95%CI, 2.1–20.4), and death (aOR, 4.5; 95%CI, 1.2–16.4) in men only. This study highlights sex disparities in clinical determinants of severe outcomes in COVID-19 patients that may inform management and prevention strategies to ensure gender equity.     

Fostering mesenchymal stem cell therapy to halt cytokine storm in COVID-19

The coronavirus disease 2019 (COVID-19) has been threatening the globe since the end of November 2019. The disease revealed cracks in the health care system as health care providers across the world were left without guidelines on definitive usage of pharmaceutical agents or vaccines. The World Health Organization (WHO) declared COVID-19 as a pandemic on the 11th of March 2020. Individuals with underlying systemic disorders have reported complications, such as cytokine storms, when infected with the virus. As the number of positive cases and the death toll across the globe continue to rise, various researchers have turned to cell based therapy using stem cells to combat COVID-19. The field of stem cells and regenerative medicine has provided a paradigm shift in treating a disease with minimally invasive techniques that provides maximal clinical and functional outcome for patients. With the available evidence of immunomodulatory and immune-privilege actions, mesenchymal stem cells (MSCs) can repair, regenerate and remodulate the native homeostasis of pulmonary parenchyma with improved pulmonary compliance. This article revolves around the usage of novel MSCs therapy for combating COVID-19.     

Emergency response to the outbreak of COVID-19: the Korean case

This letter aims to describe how Korea can improve its emergency response to the outbreak of COVID-19. The key finding is that the nation has to shift from a self-interest–oriented response to a shared-interest–oriented response. Similarly, neighboring nations could form a national framework of networks among stakeholders.     

Transient plasma cell dyscrasia in COVID-19 patients linked to IL-6 triggering

An unusual clonal gammopathy was reported in COVID-19 patient but whether this anomaly is related or not to the disease has not yet been clarified. To this aim, we selected a cohort of 35 COVID-19 patients swab positive and investigated serological levels of IL-6, immune response to major viral antigens and electrophoretic profile. Elevated levels of IL-6 were accompanied by a significative humoral response to viral Spike protein, revealing an altered electrophoretic profile in the gamma region. We can conclude that elevated levels of IL-6 triggers humoral response inducing a transient plasma cell dyscrasia in severe COVID-19 patients.     

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.     

Durability of the humoral immune response in recovered COVID-19 patients

BackgroundThe immunological factors involved in protection against the disease caused by SARS-CoV-2 are insufficiently defined and understood. However, previous knowledge pertaining to the related SARS virus and other human coronaviruses may prove useful. Population-based serosurveys measuring anti-SARS-CoV-2 antibodies may provide a pattern for estimating infection degrees and observing the development of the epidemic. In this study, we aimed to investigate the persistence of antibody against the SARS-CoV-2 in recovered patients in Al Madinah region of Saudi Arabia.Materials and methodsA total of 150 recovered COVID-19 patients participated in this study. All the patients tested positive for the presence of SARS-CoV-2 RNA, using qualitative RT-PCR. An ELISA was used to measure anti-Spike (S) IgG antibodies in serum samples and screen for their persistence at various time points post-infection.ResultsThe patients were categorized as asymptomatic (27.3%), mild (28%) and moderate (44.7%) according to the disease severity. Amongst them, 35.3% were females (n = 53) and 64.7% were males (n = 97). Significant anti-S IgG antibody levels were observed among the different groups, with the patients in moderate group exhibiting the highest levels followed by the mild group; while the lowest levels were detected among the asymptomatic. There was a significant positive correlation between the patients’ age and anti-S IgG antibody concentrations (Pearson r = 0.45; p < 0.001).ConclusionOur findings provide a solid evidence to support the use of an anti-S IgG ELISA as a diagnostic tool to indicate SARS-CoV-2 infection. IgG seropositivity was sustained in recovered patients up to a hundred days' post-infection, the latest time point for antibody measurement in our study. Ours is the first report in Saudi Arabia to investigate the durability of humoral immune response in recovered COVID-19 patients.     

Circulating cell clusters aggravate the hemorheological abnormalities in COVID-19

Microthrombi and circulating cell clusters are common microscopic findings in patients with coronavirus disease 2019 (COVID-19) at different stages in the disease course, implying that they may function as the primary drivers in disease progression. Inspired by a recent flow imaging cytometry study of the blood samples from patients with COVID-19, we perform computational simulations to investigate the dynamics of different types of circulating cell clusters, namely white blood cell (WBC) clusters, platelet clusters, and red blood cell clusters, over a range of shear flows and quantify their impact on the viscosity of the blood. Our simulation results indicate that the increased level of fibrinogen in patients with COVID-19 can promote the formation of red blood cell clusters at relatively low shear rates, thereby elevating the blood viscosity, a mechanism that also leads to an increase in viscosity in other blood diseases, such as sickle cell disease and type 2 diabetes mellitus. We further discover that the presence of WBC clusters could also aggravate the abnormalities of local blood rheology. In particular, the extent of elevation of the local blood viscosity is enlarged as the size of the WBC clusters grows. On the other hand, the impact of platelet clusters on the local rheology is found to be negligible, which is likely due to the smaller size of the platelets. The difference in the impact of WBC and platelet clusters on local hemorheology provides a compelling explanation for the clinical finding that the number of WBC clusters is significantly correlated with thrombotic events in COVID-19 whereas platelet clusters are not. Overall, our study demonstrates that our computational models based on dissipative particle dynamics can serve as a powerful tool to conduct quantitative investigation of the mechanism causing the pathological alterations of hemorheology and explore their connections to the clinical manifestations in COVID-19.     

Two classes of glutathione S-transferase genes with different response profiles to bacterial challenge in Venerupis philippinarum

Glutathione S-transferase (GST) is major cytosolic detoxification enzymes involved in many pathological and physiological processes. In the present study, two classes of GSTs (VpGST-1 and VpGST-2) were cloned from Venerupis philippinarum haemocytes by cDNA library and RACE approaches. Sequence alignments and phylogenetic analysis together supported that they belonged to a new member of sigma and pi classes GSTs protein family, respectively. The expression profiles of these two genes under Vibrio anguillarum challenge were investigated by quantitative RT-PCR. The bacterial challenge could significantly up-regulate the mRNA expression of both VpGST-1 and VpGST-2 with larger amplitude in VpGST-2, and the feedback speed for VpGST-2 was more rapid than that of VpGST-1. The differences in the response to bacterial challenge indicated that they were functional diversity and probably played cooperative roles in mediating the Vibrio challenge in clam.     

Relevance between COVID-19 and host genetics of immune response

The outbreak of coronavirus disease 2019 (COVID-19) was caused by the newly emerged corona virus (2019-nCoV alias SARS-CoV-2) that resembles the severe acute respiratory syndrome virus (SARS-CoV). SARS-CoV-2, which was first identified in Wuhan (China) has spread globally, resulting in a high mortality worldwide reaching ~4 million deaths to date. As of first week of July 2021, ~181 million cases of COVID-19 have been reported. SARS-CoV-2 infection is mediated by the binding of virus spike protein to Angiotensin Converting Enzyme 2 (ACE2). ACE2 is expressed on many human tissues; however, the major entry point is probably pneumocytes, which are responsible for synthesis of alveolar surfactant in lungs. Viral infection of pneumocytes impairs immune responses and leads to, apart from severe hypoxia resulting from gas exchange, diseases with serious complications. During viral infection, gene products (e.g. ACE2) that mediate viral entry, antigen presentation, and cellular immunity are of crucial importance. Human leukocyte antigens (HLA) I and II present antigens to the CD8⁺ and CD4⁺ T lymphocytes, which are crucial for immune defence against pathogens including viruses. HLA gene variants affect the recognition and presentation of viral antigenic peptides to T-cells, and cytokine secretion. Additionally, endoplasmic reticulum aminopeptidases (ERAP) trim antigenic precursor peptides to fit into the binding groove of MHC class I molecules. Polymorphisms in ERAP genes leading to aberrations in ERAP’s can alter antigen presentation by HLA class I molecules resulting in aberrant T-cell responses, which may affect susceptibility to infection and/or activation of immune response. Polymorphisms from these genes are associated, in global genetic association studies, with various phenotype traits/disorders many of which are related to the pathogenesis and progression of COVID-19; polymorphisms from various genes are annotated in genotype-tissue expression data as regulating the expression of ACE2, HLA’s and ERAP’s. We review such polymorphisms and illustrate variations in their allele frequencies in global populations. These reported findings highlight the roles of genetic modulators (e.g. genotype changes in ACE2, HLA’s and ERAP’s leading to aberrations in the expressed gene products or genotype changes at other genes regulating the expression levels of these genes) in the pathogenesis of viral infection.