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1.
iScience ; JOUR: 105544,
Article in English | ScienceDirect | ID: covidwho-2105156

ABSTRACT

Summary Umbilical cord blood (UCB) is an irreplaceable source for hematopoietic stem progenitor cells (HSPCs). However, the effects of SARS-CoV-2 infection and COVID-19 vaccination on UCB phenotype, specifically the HSPCs therein, are currently unknow. We thus evaluated any effects of SARS-CoV-2 infection and/or COVID-19 vaccination from the mother on the fate and functionalities of HSPCs in the UCB. The numbers and frequencies of HSPCs in the UCB decreased significantly in donors with previous SARS-CoV-2 infection and more so with COVID-19 vaccination via the induction of apoptosis, likely mediated by IFN-γ-dependent pathways. Two independent hematopoiesis assays, a colony forming unit assay and a mouse humanization assay, revealed skewed hematopoiesis of HSPCs obtained from donors delivered from mothers with SARS-CoV-2 infection history. These results indicate that SARS-CoV-2 infection and COVID-19 vaccination impair the functionalities and survivability of HSPCs in the UCB, which would make unprecedented concerns on the future of HSPC-based therapies.

2.
Industrial Crops and Products ; JOUR: 115944,
Article in English | ScienceDirect | ID: covidwho-2105136

ABSTRACT

Due to the pandemics of COVID-19, herbal medicine has recently been explored for possible antiviral treatment and prevention via novel platform of microbial fuel cells. It was revealed that Coffea arabica leaves was very appropriate for anti-COVID-19 drug development. Antioxidant and anti-inflammatory tests exhibited the most promising activities for C. arabica ethanol extracts and drying approaches were implemented on the leaf samples prior to ethanol extraction. Ethanol extracts of C. arabica leaves were applied to bioenergy evaluation via DC-MFCs, clearly revealing that air-dried leaves (CA-A-EtOH) exhibited the highest bioenergy-stimulating capabilities (ca. 2.72 fold of power amplification to the blank). Furthermore, molecular docking analysis was implemented to decipher the potential of C. arabica leaves metabolites. Chlorogenic acid (-6.5kcal/mol) owned the highest binding affinity with RdRp of SARS-CoV-2, showing a much lower average RMSF value than an apoprotein. This study suggested C. arabica leaves as an encouraging medicinal herb against SARS-CoV-2.

3.
Membrane Proteins, Vol. 128 ; CHAP: 289-324,
Article in English | Web of Science | ID: covidwho-2101587

ABSTRACT

Gangliosides are anionic lipids that form condensed membrane clusters (lipid rafts) and exert major regulatory functions on a wide range of proteins. In this review, we propose a new view of the structural features of gangliosides with special emphasis on emerging properties associated with protein binding modes. We analyze the different possibilities of molecular associations of gangliosides in lipid rafts and the role of cholesterol in this organization. We are particularly interested in amide groups of N-acetylated sugars which make it possible to neutralize the negative charge of the carboxylate group of sialic acids. We refer to this effect as "NH trick" and we demonstrate that it is operative in GM1, GD1a, GD1b and GT1b gangliosides. The NH trick is key to understand the different topologies adopted by gangliosides (chalice-like at the edge of lipid rafts, condensed clusters in central areas) and their impact on protein binding. We define three major types of ganglioside-binding domains (GBDs): alpha-helical, loop shaped, and large flat surface. We describe the mode of interaction of each GBD with typical reference proteins: synaptotagmin, 5HT1A receptor, cholera and botulinum toxins, HIV-1 surface envelope glycoprotein gp120, SARS-CoV-2 spike protein, cellular prion protein, Alzheimer's beta-amyloid peptide and Parkinson's disease associated alpha-synuclein. We discuss the common mechanisms and peculiarities of protein binding to gangliosides in the light of physiological and pathological conditions. We anticipate that innovative ganglioside-based therapies will soon show an exponential growth for the treatment of cancer, microbial infections, and neurodegenerative diseases.

4.
Am J Respir Crit Care Med ; 205(12): 1403-1418, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-2098104

ABSTRACT

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.


Subject(s)
COVID-19 , Lymphopenia , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Cytokines , Humans , Infliximab , Leukocytes, Mononuclear , Receptors, Tumor Necrosis Factor , SARS-CoV-2 , Tumor Necrosis Factor Inhibitors , Tumor Necrosis Factor-alpha
5.
Immunol Rev ; 310(1): 27-46, 2022 09.
Article in English | MEDLINE | ID: covidwho-2097774

ABSTRACT

Immunological memory is the basis of protective immunity provided by vaccines and previous infections. Immunological memory can develop from multiple branches of the adaptive immune system, including CD4 T cells, CD8 T cells, B cells, and long-lasting antibody responses. Extraordinary progress has been made in understanding memory to SARS-CoV-2 infection and COVID-19 vaccines, addressing development; quantitative and qualitative features of different cellular and anatomical compartments; and durability of each cellular component and antibodies. Given the sophistication of the measurements; the size of the human studies; the use of longitudinal samples and cross-sectional studies; and head-to-head comparisons between infection and vaccines or between multiple vaccines, the understanding of immune memory for 1 year to SARS-CoV-2 infection and vaccines already supersedes that of any other acute infectious disease. This knowledge may help inform public policies regarding COVID-19 and COVID-19 vaccines, as well as the scientific development of future vaccines against SARS-CoV-2 and other diseases.


Subject(s)
COVID-19 Vaccines , COVID-19 , Antibodies, Viral , COVID-19/prevention & control , Cross-Sectional Studies , Humans , Immunologic Memory , SARS-CoV-2
6.
Clin Infect Dis ; 75(9): 1652-1654, 2022 Oct 29.
Article in English | MEDLINE | ID: covidwho-2097327

ABSTRACT

We compared antibody and T-cell responses against the severe acute respiratory syndrome coronavirus 2 vaccine strain spike protein to responses against the Omicron variant in 15 messenger RNA vaccine recipients. While these individuals had significantly lower levels of antibodies that inhibited Omicron spike protein binding to ACE2, there was no difference in T-cell responses.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2/genetics , RNA, Messenger/genetics , T-Lymphocytes , Antibodies, Viral , Antibodies, Neutralizing
7.
Tromboz, Gemostaz i Reologiya ; JOUR(3):32-42, 2022.
Article in Russian | Scopus | ID: covidwho-2091446

ABSTRACT

Background. Identification of easily accessible and most accurate predictors of favorable and fatal outcomes in COVID-19 is of great importance, as it allows timely correction of the patient’s treatment tactics. Objective: to develop predictors based on a general blood test that allow to predict COVID-19 outcome at relatively early stages. Patients/Methods. We examined 125 patients with severe and extremely severe course of COVID-19, in whom the number of platelets, leukocytes, their fractions and ratios were determined on days 1, 5, 7, 10, 14 and 21 of hospital stay. ROC-analysis was performed to calculate survival and lethality thresholds having predictive value. Results. It was found that the most accurate predictive parameters of COVID-19 outcome were leukocyte total number and ratios platelets/leukocytes, platelets/neutrophils, neutrophils/lymphocytes, neutrophils/monocytes. At the same time neutrophils/lymphocytes ratio can be considered the most accurate test for predicting COVID-19 outcome, that according to the expert scale with a “good” rating already at days 5 and 7, and with an “excellent” rating at days 10, 14 and 21 allow to conclude about the possible outcome of the pathological process. However, clinically valuable is the coincidence of predic-tions of COVID-19 outcome for 2–3 or more parameters. Conclusions. Neutrophils/lymphocytes ratio is the most accurate predictor of COVID-19 outcome. Total leukocyte count and platelet/leukocyte, platelet/neutrophil, neutrophil/lymphocyte, and neutrophil/ monocyte ratios are additional predictors of COVID-19 outcome. Timely correction of the identified shifts in the content of platelets, leukocytes and their fractions, as well as their ratios, seems to be a perspective direction in the pathogenetic therapy of COVID-19. © 2022, Hemostasis and Rheology LLC.

8.
Mol Med ; 28(1): 40, 2022 04 09.
Article in English | MEDLINE | ID: covidwho-2089157

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused 6 million deaths worldwide. While asymptomatic individuals are responsible of many potential transmissions, the difficulty to identify and isolate them at the high peak of infection constitutes still a real challenge. Moreover, SARS-CoV-2 provokes severe vascular damage and thromboembolic events in critical COVID-19 patients, deriving in many related deaths and long-hauler symptoms. Understanding how these processes are triggered as well as the potential long-term sequelae, even in asymptomatic individuals, becomes essential. METHODS: We have evaluated, by application of a proteomics-based quantitative approach, the effect of serum from COVID-19 asymptomatic individuals over circulating angiogenic cells (CACs). Healthy CACs were incubated ex-vivo with the serum of either COVID-19 negative (PCR -/IgG -, n:8) or COVID-19 positive asymptomatic donors, at different infective stages: PCR +/IgG - (n:8) and PCR -/IgG + (n:8). Also, a label free quantitative approach was applied to identify and quantify protein differences between these serums. Finally, machine learning algorithms were applied to validate the differential protein patterns in CACs. RESULTS: Our results confirmed that SARS-CoV-2 promotes changes at the protein level in the serum of infected asymptomatic individuals, mainly correlated with altered coagulation and inflammatory processes (Fibrinogen, Von Willebrand Factor, Thrombospondin-1). At the cellular level, proteins like ICAM-1, TLR2 or Ezrin/Radixin were only up-regulated in CACs treated with the serum of asymptomatic patients at the highest peak of infection (PCR + /IgG -), but not with the serum of PCR -/IgG + individuals. Several proteins stood out as significantly discriminating markers in CACs in response to PCR or IgG + serums. Many of these proteins particiArticle title: Kindly check and confirm the edit made in the article title.pate in the initial endothelial response against the virus. CONCLUSIONS: The ex vivo incubation of CACs with the serum of asymptomatic COVID-19 donors at different stages of infection promoted protein changes representative of the endothelial dysfunction and inflammatory response after viral infection, together with activation of the coagulation process. The current approach constitutes an optimal model to study the response of vascular cells to SARS-CoV-2 infection, and an alternative platform to test potential inhibitors targeting either the virus entry pathway or the immune responses following SARS-CoV-2 infection.


Subject(s)
COVID-19 , Humans , Immunoglobulin G , Nucleic Acid Amplification Techniques , SARS-CoV-2
9.
J Clin Invest ; 2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-2089018

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

10.
Pediatr Allergy Immunol ; 33(10): e13863, 2022 10.
Article in English | MEDLINE | ID: covidwho-2088299

ABSTRACT

BACKGROUND: Studies of anti-SARS-CoV-2 humoral and adaptive response in COVID-19 non-vaccinated pediatric convalescents are controversial and further evidence from the pediatric population are needed. OBJECTIVES: To elucidate SARS-CoV-2 humoral and memory B- and T-cells responses in pediatric convalescents as compared with the adult. METHODS: Blood samples were obtained from 80 non-vaccinated, IgG-positive, COVID-19 convalescents (age 8.0-61.0 years), 4.0 months from onset. Frequency of responders and magnitudes of SARS-COV-2 IgG, memory B-cells (MBC) and IFNg- and IL2-secreting memory T-cells (MTC) in response to immuno-dominant peptide pools in pediatric, young adults and middle-aged adults with onset age 8-18 years (N = 20), 19-39 years (N = 30) and 40-61 years (N = 30), respectively, were analyzed. SARS-CoV-2 IgG were detected by ELISA (Euroimmun, Germany). MBC, IFNg-, IL2- and IFNg+IL2-secreting MTC (IFNg-MTC, IL2-MTC and IFNg+IL2-MTC) were detected using FluoroSpot (Mabtech, Sweden). RESULTS: MBC level was lower in pediatric as compared with the middle-aged adults (median 12.75 interquartile range [IQR] 4.27-33.7 and 32.0 IQR 6.0-124.2, respectively, p = .003). MBC level in young adults was lower than in middle-aged adults (median 18.5 IQR 1.7-43.8 and 32.0 IQR 6.0-124.2, respectively, p = .006). The level of IL2-MTC was lower in the pediatric group as compared with middle aged-adults (median 2.1 IQR 0-16.9 and 28.6 IQR 11-49.6, respectively, p < .03) and in young adults lower than in middle-aged adults (median 1.45 IQR 0-18.6 and 28.6 IQR 11-49.6, respectively, p = .02). In addition, the level of IFNg-MTC was lower in pediatric as compared with young adults (median 4.25 IQR 0.0-15.0 and 20.9 IQR 0-75.2, respectively, p = .05). The level of IgG was comparable between pediatric and both young and middle-aged adult groups (4.82 ± 2.95, 3.70 ± 2.65 and 4.9 ± 2.94, respectively, p > .34). CONCLUSION: Non-vaccinated COVID-19 pediatric convalescents have lower adaptive immune responses than adults sustaining the recommendation for vaccination of the pediatric population.


Subject(s)
COVID-19 , SARS-CoV-2 , Adolescent , Adult , Child , Humans , Middle Aged , Young Adult , Antibodies, Viral , Immunoglobulin G , Interleukin-2 , B-Lymphocytes , T-Lymphocytes
11.
Mycoses ; 2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2088289

ABSTRACT

BACKGROUND: The second wave of COVID-19 in India was followed by large number of mucormycosis cases. Indiscriminate use of immunosuppressive drugs, underlying diseases such as diabetes, cancers, or autoimmune diseases was thought to be the cause. However, the mortality was not as high as that seen in non-COVID mucormycosis. OBJECTIVE: To study the detailed characteristics of T-cells for evaluating the underlying differences in the T-cell immune dysfunction in post-COVID and non-COVID mucor patients. MATERIAL AND METHOD: The study included histopathologically confirmed cases of mucor (13 post-COVID, 13 non-COVID) and 15 healthy individuals (HI). Expression of T-cell activation (CD44, HLADR, CD69, CD38) and exhaustion (CTLA, PD-1, LAG-3 and TIM-3) markers was evaluated by flow cytometry. RESULTS: All cases showed significant depletion of T-cells compared to HI. Both post-COVID and non-COVID groups showed increased activation and exhaustion as compared to HI. Non-COVID mucor group showed significant activation of CD4+ T cells for HLADR and CD38 (p = .025, p = .054) and marked T-cell exhaustion in form of expression of LAG-3 on both CD4+ T and CD8+ T cells in comparison with post-COVID patients (p = .011, p = .036). Additionally, co-expression of PD-1 & LAG-3 and LAG-3 & TIM-3 on CD8+ T cells was statistically significant in non-COVID mucor patients (p = .016, p = .027). CONCLUSION: Immunosuppression in non-COVID mucor showed pronounced exhaustion of T-cells in comparison to post-COVID mucor cases implicating T-cell immune dysfunction is much more severe in non-COVID mucor which are in a state of continuous activation followed by extreme exhaustion leading to poorer outcome.

12.
Immunobiology ; 227(6): 152296, 2022 Oct 27.
Article in English | MEDLINE | ID: covidwho-2086308

ABSTRACT

Aerobic exercise is well recognized to be beneficial to physical and mental health. Many studies have shown that aerobic exercise can improve the human immune system, but whether it could affect lung regeneration and inflammation remained unclear. Bronchioloalveolar stem cells (BASCs) play a key role in lung regeneration and repair, but it is unclear whether aerobic exercise affects BASCs. Here, we randomly divided 8 weeks old male mice into three groups: the control group without any aerobic exercise; the rest group which received 2 weeks of aerobic exercise (running wheel training) plus 5 days' rest, and the exercise group which received 2 weeks of aerobic exercise without any rest. Our data indicated that mice in the exercise group had significantly increased BASCs compared to the control group, such difference did not exist in the rest group. Furthermore, the immune profiling suggested that lung inflammation was slightly up-regulated in the exercise group, particularly the inflammatory monocytes and IL-17A+ T cells. In conclusion, we provide direct evidence showing that aerobic exercise can facilitate lung regeneration with mild inflammatory effect, this finding is of great importance in the current COVID-19 pandemic.

13.
Curr Cardiol Rep ; 2022 Oct 22.
Article in English | MEDLINE | ID: covidwho-2085560

ABSTRACT

Although SARS-CoV-2, the causative virus of the global COVID-19 pandemic, primarily affects the respiratory tract, it is now recognized to have broad multi-organ tropism and systemic effects. Early reports indicated that SARS-CoV-2 infection could lead to cardiac damage, suggesting the virus may directly impact the heart. Cardiac cell types derived from human pluripotent stem cells (hPSCs) enable mechanistic interrogation of SARS-CoV-2 infection in human cardiac tissue. PURPOSE OF REVIEW: To review the studies published since the emergence of the COVID-19 pandemic which utilize hPSCs and their cardiovascular derivative cell types to interrogate the tropism and effects of SARS-CoV-2 infection in the heart, as well as explore potential therapies. RECENT FINDINGS: Recent studies reveal that SARS-CoV-2 is capable of infecting and replicating within hPSC-derived cardiomyocytes and sinoatrial nodal cells, but not as extensively in their non-parenchymal counterparts. Additionally, they show striking viral effects on cardiomyocyte structure, transcriptional activity, and survival, along with potential mechanisms and therapeutic targets. Cardiac models derived from hPSCs are a viable platform to study the impact of SARS-CoV-2 on cardiac tissue and may lead to novel mechanistic insight as well as therapeutic interventions.

14.
European Review for Medical and Pharmacological Sciences ; JOUR(16):5963-5970, 26.
Article in English | Web of Science | ID: covidwho-2081709

ABSTRACT

OBJECTIVE: SARS-CoV-2 might present with multisystem involvement due to its entry into many cells with ACE2 receptors on their surfaces, such as heart, endothelial, and lung al-veoli cells. Studies have indicated that COVID-19 infection causes a severe clinical presentation in diabetic patients due to dysregulation of the meta-bolic and immune systems. The hematological ef-fects of COVID-19 and the relationship of lympho-penia with the severity of the disease have been reported previously. The parameter of percent-age of large unstained cells (LUCs) reflects active lymphocytes and peroxidase-negative cells. The neutrophil-to-lymphocyte ratio (NLR) is another reliable marker of inflammation in cases of cardi-ac diseases, solid tumors, and sepsis. The pres-ent study aimed to evaluate whether the parame-ters of LUCs and NLR differed between diabetic and nondiabetic individuals with COVID-19. Asso-ciations with disease severity were also sought.MATERIALS AND METHODS: In our retro-spective study, the data of 1,053 patients [230 diabetic patients (21.83%) and 823 nondiabetic patients (78.15%)] were reviewed. The white blood cell (WBC) count, neutrophil count, neutrophil%, lymphocyte count, lymphocyte%, LUC count, %LUCs, NLR, platelet count, hemoglobin level, HbA1c, history of diabetes, surveillance during hospitalization, and pulmonary infiltration status within the first 24 hours after admission to the hospital were analyzed from the records.RESULTS: When diabetic patients were com-pared with nondiabetics, the age [65 (20-90) vs. 42 (18-94) years], WBC count [6.72 (2.6-24.04) vs. 5.91 (1.35-52.68)], neutrophil count [4.29 (1.28-65) vs. 3.68 (0.02-50.47)], neutrophil% [67.53 +/- 12.3 vs. 64.08 +/- 13.28], NLR [3.35 (0.83-38.11) vs. 2.48 (0.01-68.58)], and LUC count [0.11 (0.03-0.98) vs. 0.1 (0.02-3.06)] of the diabetic group were found to be higher and these differences were statistically significant (p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, and p=0.015, respectively).CONCLUSIONS: We determined that LUC counts and NLR values in COVID-19-positive pa-tients with diabetes were statistically significant-ly higher compared to nondiabetic patients.

15.
J Allergy Clin Immunol Pract ; 2022 Oct 21.
Article in English | MEDLINE | ID: covidwho-2083126

ABSTRACT

BACKGROUND: The contemporaneous presence of immune-defects and heart diseases in patients with 22q11.2 deletion syndrome might represent risk factors for severe COVID-19. OBJECTIVE: To analyze SARS-CoV-2 outcome in 22q11.2DS patients and immunogenicity of different doses of mRNA SARS-CoV-2 vaccine. METHODS: Longitudinal observational study on SARS-Cov-2 outcome in 60 adults with 22q11.2DS (March 2020-June 2022). Anti-Spike, and anti-receptor binding domain antibody responses, generation of Spike-specific memory B-cells and Spike-specific T-cells at different time points before and after the mRNA BNT162b2 vaccination were evaluated in sixteen 22q11.2DS patients. RESULTS: We recorded a 95% rate of vaccination, with almost all patients being immunized with the booster dose. Twenty-one patients had SARS-CoV-2 infection. Three patients were infected before vaccine availability, six after receiving two doses of vaccine and twelve after the booster dose. SARS-CoV-2- infection had a mild course, except one unvaccinated patient with several comorbidities who died from acute respiratory distress syndrome (fatality-rate: 5%). Infected patients had more frequently moderate/severe intellectual disability, lymphopenia and lower CD4+ count. Despite major congenital heart diseases, COVID-19 did not impact cardiological conditions. The BNT162b2 vaccine induced S1-IgG responses, low serum S1-IgA, and slightly impaired specific memory B-response. Specific T-cell responses observed were related to lymphocytes and CD4+ T cell counts. CONCLUSION: SARS-CoV-2 infection had a mild course in most patients with 22q11.2DS, even in patients with major cardiovascular diseases. Immunization induced Spike-specific IgG responses and generated specific memory B and T cells. The weaker memory responses in patients with lymphopenia suggested the need for additional doses.

16.
Int J Mol Sci ; 23(20)2022 Oct 19.
Article in English | MEDLINE | ID: covidwho-2082150

ABSTRACT

The serious clinical course of SARS-CoV-2 infection is usually accompanied by acute kidney injury (AKI), worsening prognosis and increasing mortality. AKI in COVID-19 is above all a consequence of systemic dysregulations leading to inflammation, thrombosis, vascular endothelial damage and necrosis. All these processes rely on the interactions between innate immunity elements, including circulating blood cells, resident renal cells, their cytokine products, complement systems, coagulation cascades and contact systems. Numerous simultaneous pathways of innate immunity should secure an effective host defense. Since they all form a network of cross-linked auto-amplification loops, uncontrolled activation is possible. When the actions of selected pathways amplify, cascade activation evades control and the propagation of inflammation and necrosis worsens, accompanied by complement overactivity and immunothrombosis. The systemic activation of innate immunity reaches the kidney, where the damage affecting single tubular cells spreads through tissue collateral damage and triggers AKI. This review is an attempt to synthetize the connections between innate immunity components engaged in COVID-19-related AKI and to summarize the knowledge on the pathophysiological background of processes responsible for renal damage.


Subject(s)
Acute Kidney Injury , COVID-19 , Humans , SARS-CoV-2 , Acute Kidney Injury/complications , Immunity, Innate , Inflammation , Complement System Proteins , Necrosis , Cytokines
17.
SSRN;
Preprint in English | SSRN | ID: ppcovidwho-346244

ABSTRACT

SARS-CoV-2 vaccination is the leading strategy to prevent severe courses after SARS-CoV-2 infection. In our study, we analyzed humoral and cellular immune responses in detail to three consecutive homologous or heterologous SARS-CoV-2 vaccinations and breakthrough infections. All individuals (n=20) responded to vaccination with increasing S1-/RBD-/S2-specific IgG levels, whereas specific plasma IgA displayed individual variability. The third dose increased antibody inhibitory capacity (AIC) against immune-escape variants Beta and Omicron independently from age. The mRNA-primed vaccination induced IgG and IgA immunity more efficiently, whereas vector-primed individuals displayed higher levels of memory T and B cells. Vaccinees showed a SARS-CoV-2-specific T cell responses, which were further improved and specified after Omicron breakthrough infections in parallel to appearance of new variant-specific antibodies. In conclusion, the third vaccination was essential to increase IgG levels, mandatory to boost AIC against immune-escape variants and induced SARS-CoV-2-specific T cells. Breakthrough infection with Omicron generates additional spike specificities covering all known variants.

18.
Front Immunol ; 13: 1025495, 2022.
Article in English | MEDLINE | ID: covidwho-2080158

ABSTRACT

Disorders of systemic metabolism can influence immunity. Individuals with obesity are known to have increased inflammation, increased risk to select autoimmune diseases, impaired response to several infections, and impaired vaccine response. For example, over the last decade, it has become clear that individuals with obesity have increased risk of morbidity and mortality from influenza infection. Unsurprisingly, this finding is also observed in the current COVID-19 pandemic: individuals with obesity, particularly severe obesity, have increased risk of poor outcomes from SARS-CoV-2 infection, including increased rates of hospitalization, ICU admission, mechanical ventilation, and death. Several studies have now demonstrated a critical role for T cells in the context of obesity-associated immune dysfunction in response to viral infection, and one mechanism for this may be altered T cell metabolism. Indeed, recent studies have shown that activated T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, both in vitro and in vivo following viral infection. For that reason, treatments that target abnormal immune cell metabolism in obesity may improve outcomes to viral infection. To that end, several recent studies have shown that use of the metabolic drug, metformin, can reverse abnormal T cell metabolism and restore T cell immunity, as well as survival, in response to viral infection. These findings will be discussed in detail here.


Subject(s)
COVID-19 , Metformin , Animals , Mice , Humans , Pandemics , SARS-CoV-2 , T-Lymphocytes , Obesity/complications , Metformin/therapeutic use , Oxidative Stress , Glucose
19.
Front Immunol ; 13: 942192, 2022.
Article in English | MEDLINE | ID: covidwho-2080137

ABSTRACT

The cellular immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in response to full mRNA COVID-19 vaccination could be variable among healthy individuals. Studies based only in specific antibody levels could show an erroneous immune protection at long times. For that, we analyze the antibody levels specific to the S protein and the presence of SARS-CoV-2-specific T cells by ELISpot and AIM assays in intensive care unit (ICU) workers with no antecedents of COVID-19 and vaccinated with two doses of mRNA COVID-19 vaccines. All individuals were seronegative for the SARS-CoV-2 protein S before vaccination (Pre-v), but 34.1% (14/41) of them showed pre-existing T lymphocytes specific for some viral proteins (S, M and N). One month after receiving two doses of COVID-19 mRNA vaccine (Post-v1), all cases showed seroconversion with high levels of total and neutralizing antibodies to the spike protein, but six of them (14.6%) had no T cells reactive to the S protein. Specifically, they lack of specific CD8+ T cells, but maintain the contribution of CD4+ T cells. Analysis of the immune response against SARS-CoV-2 at 10 months after full vaccination (Post-v10), exhibited a significant reduction in the antibody levels (p<0.0001) and protein S-reactive T cells (p=0.0073) in all analyzed individuals, although none of the individuals become seronegative and 77% of them maintained a competent immune response. Thus, we can suggest that the immune response to SARS-CoV-2 elicited by the mRNA vaccines was highly variable among ICU workers. A non-negligible proportion of individuals did not develop a specific T cell response mediated by CD8+ T cells after vaccination, that may condition the susceptibility to further viral infections with SARS-CoV-2. By contrast, around 77% of individuals developed strong humoral and cellular immune responses to SARS-CoV-2 that persisted even after 10 months. Analysis of the cellular immune response is highly recommended for providing exact information about immune protection against SARS-CoV-2.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Antibodies, Neutralizing , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , Intensive Care Units , RNA, Messenger/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination , T-Lymphocytes
20.
Front Immunol ; 13: 861251, 2022.
Article in English | MEDLINE | ID: covidwho-2080128

ABSTRACT

COVID-19 is characterised by a broad spectrum of clinical and pathological features. Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we analysed the phenotype and activity of NK cells in the blood of COVID-19 patients using flow cytometry, single-cell RNA-sequencing (scRNA-seq), and a cytotoxic killing assay. In the plasma of patients, we quantified the main cytokines and chemokines. Our cohort comprises COVID-19 patients hospitalised in a low-care ward unit (WARD), patients with severe COVID-19 disease symptoms hospitalised in intensive care units (ICU), and post-COVID-19 patients, who were discharged from hospital six weeks earlier. NK cells from hospitalised COVID-19 patients displayed an activated phenotype with substantial differences between WARD and ICU patients and the timing when samples were taken post-onset of symptoms. While NK cells from COVID-19 patients at an early stage of infection showed increased expression of the cytotoxic molecules perforin and granzyme A and B, NK cells from patients at later stages of COVID-19 presented enhanced levels of IFN-γ and TNF-α which were measured ex vivo in the absence of usual in vitro stimulation. These activated NK cells were phenotyped as CD49a+CD69a+CD107a+ cells, and their emergence in patients correlated to the number of neutrophils, and plasma IL-15, a key cytokine in NK cell activation. Despite lower amounts of cytotoxic molecules in NK cells of patients with severe symptoms, majority of COVID-19 patients displayed a normal cytotoxic killing of Raji tumour target cells. In vitro stimulation of patients blood cells by IL-12+IL-18 revealed a defective IFN-γ production in NK cells of ICU patients only, indicative of an exhausted phenotype. ScRNA-seq revealed, predominantly in patients with severe COVID-19 disease symptoms, the emergence of an NK cell subset with a platelet gene signature that we identified by flow and imaging cytometry as aggregates of NK cells with CD42a+CD62P+ activated platelets. Post-COVID-19 patients show slow recovery of NK cell frequencies and phenotype. Our study points to substantial changes in NK cell phenotype during COVID-19 disease and forms a basis to explore the contribution of platelet-NK cell aggregates to antiviral immunity against SARS-CoV-2 and disease pathology.


Subject(s)
COVID-19 , Humans , Granzymes/metabolism , Perforin/metabolism , Interleukin-15/metabolism , Interleukin-18/metabolism , SARS-CoV-2 , Tumor Necrosis Factor-alpha/metabolism , Blood Platelets/metabolism , Integrin alpha1/metabolism , Killer Cells, Natural , Cytokines/metabolism , Chemokines/metabolism , Interleukin-12/metabolism , Antiviral Agents/metabolism , RNA/metabolism
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