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1.
Nat Commun ; 13(1): 5722, 2022 Sep 29.
Article in English | MEDLINE | ID: covidwho-2050376

ABSTRACT

Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in fat cells. However, susceptibility to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Visceral fat cells express more ACE2 and are more susceptible to SARS-CoV-2 infection than their subcutaneous counterparts. SARS-CoV-2 infection leads to inhibition of lipolysis in subcutaneous fat cells, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral fat cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human fat cells, replicating and altering cell function and viability in a depot- and viral lineage-dependent fashion.


Subject(s)
COVID-19 , SARS-CoV-2 , Adipose Tissue , Angiotensin-Converting Enzyme 2 , Cytokines , Humans
2.
Infect Genet Evol ; 99: 105236, 2022 04.
Article in English | MEDLINE | ID: covidwho-1670896

ABSTRACT

SARS-CoV-2 variants of concern have emerged since the COVID-19 outburst, notably the lineages detected in the UK, South Africa, and Brazil. Their increased transmissibility and higher viral load put them in the spotlight. Much has been investigated on the ability of those new variants to evade antibody recognition. However, little attention has been given to pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses by new lineages. In this work, we predicted SARS-CoV-2-specific CD8+ T cell epitopes from the main variants of concern and their potential to trigger or hinder CD8+ T cell response by using HLA binding and TCR reactivity in silico predictions. Also, we estimated the population's coverage for different lineages, which accounts for the ability to present a set of peptides based on the most frequent HLA alleles of a given population. We considered binding predictions to 110 ccClass I HLA alleles from 29 countries to investigate differences in the fraction of individuals expected to respond to a given epitope set from new and previous lineages. We observed a higher population coverage for the variant detected in the UK (B.1.1.7), and South Africa (B.1.351), as well as for the Brazilian P.1 lineage, but not P.2, compared to the reference lineage. Moreover, individual mutations such as Spike N501Y and Nucleocapsid D138Y were predicted to have an overall stronger affinity through HLA-I than the reference sequence while Spike E484K shows signs of evasion. In summary, we provided evidence for the existence of potentially immunogenic and conserved epitopes across new SARS-CoV-2 variants, but also mutant peptides exhibiting diminished or abolished HLA-I binding. It also highlights the augmented population coverage for three new lineages. Whether these changes imply more T cell reactivity or potential to evade from CD8+ T cell responses requires experimental verification.


Subject(s)
COVID-19 , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Epitopes, T-Lymphocyte/genetics , Humans , Immunity , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
3.
Frontiers in immunology ; 12, 2021.
Article in English | EuropePMC | ID: covidwho-1639763

ABSTRACT

Recently, it has been argued that obesity leads to a chronic pro-inflammatory state that can accelerate immunosenescence, predisposing to the early acquisition of an immune risk profile and health problems related to immunity in adulthood. In this sense, the present study aimed to verify, in circulating leukocytes, the gene expression of markers related to early immunosenescence associated with obesity and its possible relationships with the physical fitness in obese adults with type 2 diabetes or without associated comorbidities. The sample consisted of middle-aged obese individuals (body mass index (BMI) between 30-35 kg/m²) with type 2 diabetes mellitus (OBD;n = 17) or without associated comorbidity (OB;n = 18), and a control group of eutrophic healthy individuals (BMI: 20 - 25 kg/m²) of same ages (E;n = 18). All groups (OBD, OB and E) performed the functional analyses [muscle strength (1RM) and cardiorespiratory fitness (VO2max)], anthropometry, body composition (Air Displacement Plethysmograph), blood collections for biochemical (anti-CMV) and molecular (gene expression of leptin, IL-2, IL-4, IL-6, IL-10, TNF-α, PD-1, P16ink4a, CCR7, CD28 and CD27) analyses of markers related to immunosenescence. Increased gene expression of leptin, IL-2, IL-4, IL-10, TNF-α, PD-1, P16ink4a, CCR7 and CD27 was found for the OBD and OB groups compared to the E group. Moreover, VO2max for the OBD and OB groups was significantly lower compared to E. In conclusion, obesity, regardless of associated disease, induces increased gene expression of markers associated with inflammation and immunosenescence in circulating leukocytes in obese middle-aged individuals compared to a eutrophic group of the same age. Additionally, increased adipose tissue and markers of chronic inflammation and immunosenescence were associated to impairments in the cardiorespiratory capacity of obese middle-aged individuals.

4.
Viruses ; 13(11)2021 10 22.
Article in English | MEDLINE | ID: covidwho-1481018

ABSTRACT

A SARS-CoV-2 B.1.1.7 variant of concern (VOC) has been associated with increased transmissibility, hospitalization, and mortality. This study aimed to explore the factors associated with B.1.1.7 VOC infection in the context of vaccination. On March 2021, we detected SARS-CoV-2 RNA in nasopharyngeal samples from 14 of 22 individuals vaccinated with a single-dose of ChAdOx1 (outbreak A, n = 26), and 22 of 42 of individuals with two doses of the CoronaVac vaccine (outbreak B, n = 52) for breakthrough infection rates for ChAdOx1 of 63.6% and 52.4% for CoronaVac. The outbreaks were caused by two independent clusters of the B.1.1.7 VOC. The serum of PCR-positive symptomatic SARS-CoV-2-infected individuals had ~1.8-3.4-fold more neutralizing capacity against B.1.1.7 compared to the serum of asymptomatic individuals. These data based on exploratory analysis suggest that the B.1.1.7 variant can infect individuals partially immunized with a single dose of an adenovirus-vectored vaccine or fully immunized with two doses of an inactivated vaccine, although the vaccines were able to reduce the risk of severe disease and death caused by this VOC, even in the elderly.


Subject(s)
COVID-19 Vaccines , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/classification , SARS-CoV-2/genetics , Vaccination , Adenoviridae , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/immunology , Brazil/epidemiology , COVID-19/prevention & control , COVID-19 Serological Testing , Cohort Studies , Disease Outbreaks/statistics & numerical data , Female , Genetic Vectors , Humans , Immunoglobulin G/blood , Male , Middle Aged , RNA, Viral , Vaccines, Inactivated , Whole Genome Sequencing , Young Adult
6.
Emerg Infect Dis ; 27(6): 1737-1740, 2021.
Article in English | MEDLINE | ID: covidwho-1191601

ABSTRACT

We documented 4 cases of severe acute respiratory syndrome coronavirus 2 reinfection by non-variant of concern strains among healthcare workers in Campinas, Brazil. We isolated infectious particles from nasopharyngeal secretions during both infection episodes. Improved and continued protection measures are necessary to mitigate the risk for reinfection among healthcare workers.


Subject(s)
COVID-19/diagnosis , Health Personnel , Reinfection/diagnosis , Reinfection/virology , SARS-CoV-2/isolation & purification , Virus Shedding , Adult , Brazil/epidemiology , COVID-19/epidemiology , Female , Humans , Middle Aged , Reinfection/therapy
7.
Viruses ; 13(2)2021 02 16.
Article in English | MEDLINE | ID: covidwho-1085035

ABSTRACT

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.


Subject(s)
Bradykinin/analogs & derivatives , COVID-19/drug therapy , Complement C1 Inhibitor Protein/therapeutic use , Kallikrein-Kinin System/drug effects , Kallikreins/antagonists & inhibitors , Adult , Aged , Bradykinin/therapeutic use , Case-Control Studies , Drug Repositioning , Female , Humans , Lung/drug effects , Lung/pathology , Male , Middle Aged
8.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-670096

ABSTRACT

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Subject(s)
Betacoronavirus/physiology , Blood Glucose/metabolism , Coronavirus Infections/complications , Diabetes Complications/complications , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Monocytes/metabolism , Pneumonia, Viral/complications , Adult , COVID-19 , Cell Line , Coronavirus Infections/metabolism , Diabetes Complications/metabolism , Diabetes Mellitus/metabolism , Female , Glycolysis , Humans , Inflammation/complications , Inflammation/metabolism , Male , Middle Aged , Monocytes/virology , Pandemics , Pneumonia, Viral/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2 , Signal Transduction
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