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1.
Front Immunol ; 13: 820250, 2022.
Article in English | MEDLINE | ID: covidwho-1775664

ABSTRACT

Background: SARS-CoV-2 transmission mainly occurs through exposure of the upper airway mucosa to infected secretions such as saliva, which are excreted by an infected person. Thus, oral mucosal immunity plays a central role in the prevention of and early defense against SARS-CoV-2 infection. Although virus-specific antibody response has been extensively investigated in blood samples of SARS-CoV-2-infected patients and vaccinees, local humoral immunity in the oral cavity and its relationship to systemic antibody levels needs to be further addressed. Material and Methods: We fine-tuned a virus neutralization assay (vNTA) to measure the neutralizing activity (NA) of plasma and saliva samples from 20 SARS-CoV-2-infected (SI), 40 SARS-CoV-2-vaccinated (SV), and 28 SARS-CoV-2-vaccinated subjects with a history of infection (SIV) using the "wild type" SARS-CoV-2 lineage B.1 (EU) and the Delta (B.1.617.2) strains. To validate the vNTA results, the presence of neutralizing antibodies (NAbs) to the spike receptor binding domain (RBD) was evaluated with an ELISA assay. Results: NA to SARS-CoV-2 lineage B.1 (EU) was present in plasma samples from all the tested subjects, with higher titers in SIV compared to both SI and SV. Conversely, NA was detected in saliva samples from 10.3% SV, 45% SI, and 92.6% SIV, with significantly lower titers in SV compared to both SI and SIV. The detection of NAbs in saliva reflected its reduced NA in SV. Discussion: The difference in NA of plasma vs. saliva was confirmed in a vNTA where the SARS-CoV-2 B.1 and Delta strains were tested head-to-head, which also revealed a reduced NA of both specimens compared to the B.1 variant. Conclusions: The administration of SARS-CoV-2 vaccines was associated with limited virus NA in the oral cavity, as measured in saliva and in comparison to plasma. This difference was more evident in vaccinees without a history of SARS-CoV-2 infection, possibly highlighting the importance of local exposure at the site of virus acquisition to effectively prevent the infection and block its spread. Nevertheless, the presence of immune escape mutations as possibly represented by the SARS-CoV-2 Delta variant negatively affects both local and systemic efficacy of NA associated with vaccination.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , COVID-19 Vaccines , Humans , Saliva , Spike Glycoprotein, Coronavirus
2.
Front Immunol ; 13: 827889, 2022.
Article in English | MEDLINE | ID: covidwho-1731779

ABSTRACT

It is well established that pregnancy induces deep changes in the immune system. This is part of the physiological adaptation of the female organism to the pregnancy and the immunological tolerance toward the fetus. Indeed, over the three trimesters, the suppressive T regulatory lymphocytes are progressively more represented, while the expression of co-stimulatory molecules decreases overtime. Such adaptations relate to an increased risk of infections and progression to severe disease in pregnant women, potentially resulting in an altered generation of long-lived specific immunological memory of infection contracted during pregnancy. How potent is the immune response against SARS-CoV-2 in infected pregnant women and how long the specific SARS-CoV-2 immunity might last need to be urgently addressed, especially considering the current vaccinal campaign. To address these questions, we analyzed the long-term immunological response upon SARS-CoV-2 infection in pregnant women from delivery to a six-months follow-up. In particular, we investigated the specific antibody production, T cell memory subsets, and inflammation profile. Results show that 80% developed an anti-SARS-CoV-2-specific IgG response, comparable with the general population. While IgG were present only in 50% of the asymptomatic subjects, the antibody production was elicited by infection in all the mild-to-critical patients. The specific T-cell memory subsets rebalanced over-time, and the pro-inflammatory profile triggered by specific SARS-CoV-2 stimulation faded away. These results shed light on SARS-CoV-2-specific immunity in pregnant women; understanding the immunological dynamics of the immune system in response to SARS-CoV-2 is essential for defining proper obstetric management of pregnant women and fine tune gender-specific vaccinal plans.


Subject(s)
COVID-19/immunology , Immunologic Memory/immunology , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/immunology , Adult , Animals , Antibodies, Viral/immunology , Antibody Formation/immunology , B-Lymphocytes/immunology , Cell Line , Chlorocebus aethiops , Female , Humans , Pregnancy , Pregnant Women , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , Vero Cells , Young Adult
3.
J Virol ; 94(12)2020 06 01.
Article in English | MEDLINE | ID: covidwho-1723543

ABSTRACT

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that recently emerged in China is thought to have a bat origin, as its closest known relative (BatCoV RaTG13) was described previously in horseshoe bats. We analyzed the selective events that accompanied the divergence of SARS-CoV-2 from BatCoV RaTG13. To this end, we applied a population genetics-phylogenetics approach, which leverages within-population variation and divergence from an outgroup. Results indicated that most sites in the viral open reading frames (ORFs) evolved under conditions of strong to moderate purifying selection. The most highly constrained sequences corresponded to some nonstructural proteins (nsps) and to the M protein. Conversely, nsp1 and accessory ORFs, particularly ORF8, had a nonnegligible proportion of codons evolving under conditions of very weak purifying selection or close to selective neutrality. Overall, limited evidence of positive selection was detected. The 6 bona fide positively selected sites were located in the N protein, in ORF8, and in nsp1. A signal of positive selection was also detected in the receptor-binding motif (RBM) of the spike protein but most likely resulted from a recombination event that involved the BatCoV RaTG13 sequence. In line with previous data, we suggest that the common ancestor of SARS-CoV-2 and BatCoV RaTG13 encoded/encodes an RBM similar to that observed in SARS-CoV-2 itself and in some pangolin viruses. It is presently unknown whether the common ancestor still exists and, if so, which animals it infects. Our data, however, indicate that divergence of SARS-CoV-2 from BatCoV RaTG13 was accompanied by limited episodes of positive selection, suggesting that the common ancestor of the two viruses was poised for human infection.IMPORTANCE Coronaviruses are dangerous zoonotic pathogens; in the last 2 decades, three coronaviruses have crossed the species barrier and caused human epidemics. One of these is the recently emerged SARS-CoV-2. We investigated how, since its divergence from a closely related bat virus, natural selection shaped the genome of SARS-CoV-2. We found that distinct coding regions in the SARS-CoV-2 genome evolved under conditions of different degrees of constraint and are consequently more or less prone to tolerate amino acid substitutions. In practical terms, the level of constraint provides indications about which proteins/protein regions are better suited as possible targets for the development of antivirals or vaccines. We also detected limited signals of positive selection in three viral ORFs. However, we warn that, in the absence of knowledge about the chain of events that determined the human spillover, these signals should not be necessarily interpreted as evidence of an adaptation to our species.


Subject(s)
Betacoronavirus/genetics , Evolution, Molecular , Selection, Genetic , Amino Acid Sequence , Animals , Betacoronavirus/classification , COVID-19 , Chiroptera/virology , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Models, Molecular , Open Reading Frames/genetics , Pandemics , Phylogeny , Pneumonia, Viral/virology , SARS-CoV-2 , Viral Proteins/chemistry , Viral Proteins/genetics
4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320772

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic of coronavirus disease (COVID-19). Whereas in most cases COVID-19 is asymptomatic or pauci symptomatic, extremely severe clinical forms are observed. In this case complex immune dysregulations and an excessive inflammatory response are observed and are the main cause of morbidity and mortality. Natural Killer cells are key players in the control of viral infection and their activity is regulated by a tight balance between activating and inhibitory receptors;an alteration of NK activity was suggested to be associated with the development of severe forms of COVID-19. In this study we analyzed peripheral NK cell subpopulations and the expression of activating and inhibitory receptors in 30 in-patients suffering from chronic neurological conditions who recovered from mild, moderate or severe SARS-CoV-2 infection comparing the results to those of 10 SARS-CoV-2-uninfected patients. Results showed that an expansion of NK subset with lower cytolytic activity and an augmented expression of the 2DL1 inhibitory receptor, particularly when in association with the C2 ligand (KIR2DL1-C2), characterized the immunological scenario of severe COVID-19 infection;an increase of NK expressing the ILT2 inhibitory receptor was instead seen in patients recovering from mild or moderate infection compared to controls. Results herein suggest that the KIR2DL1-C2 NK inhibitory complex is a risk factor toward the development of severe form of COVID-19. Our results confirm that a complex alteration of NK activity is present in COVID-19 infection and offer a molecular explanation for this observation.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315899

ABSTRACT

Background: UltraViolet-C (UV-C) lamps may be used to supplement current hospital cleaning and disinfection of surfaces contaminated by SARS-CoV-2. Our aim is to provide some practical indications for the correct use of UV-C lamps. Methods We studied three UV-C lamps, measuring their spatial irradiance and emission over time. We quantify the error that is committed by calculating the irradiation time based exclusively on the technical data of the lamps or by making direct irradiance measurements. Finally, we tested specific dosimeters for UV-C. Results Our results show that the spatial emission of UV-C lamps is strongly dependent on the power of the lamps and on the design of their reflectors. Only by optimizing the positioning and calculating the exposure time correctly, is it possible to dispense the dose necessary to obtain SARS-CoV-2 inactivation. In the absence of suitable equipment for measuring irradiance, the calculated irradiation time can be underestimated. We therefore consider it precautionary to increase the calculated times by at least 20%. Conclusion To use UV-C lamps effectively, it is necessary to follow a few simple precepts when choosing, positioning and verifying the lamps. In the absence of instruments dedicated to direct verification of irradiance, photochromic UV-C dosimeters may represent a useful tool for easily verifying that a proper UV-C dose has been delivered.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310600

ABSTRACT

Understanding the evolutionary dynamics of the four human endemic coronaviruses might provide insight into the future trajectories of SARS-CoV-2 evolution. We re-assessed the timing of endemic coronavirus emergence and we show that all viruses entered human populations in a time-frame ranging from ~500 to 55 years ago. Because the three highly pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) spilled-over in tight temporal succession, the pattern of coronavirus emergence, in analogy to that of influenza pandemics, is highly irregular. To contextualize this observation in a wider perspective of viral diseases emergence since 1945, we mined epidemiology database information. After controlling for reporting bias, we find that, contrary to widespread beliefs, the occurrence of viral diseases (either zoonotic or not) has not increased over the last decades. Analysis of the recent and ongoing evolution of HCoV-229E and HCoV-OC43 indicated that positive selection most likely contributed to fine-tune the interaction with the human interferon/inflammatory response. Conversely, integration of evolutionary inference and molecular dating provided evidence that these viruses are not undergoing antigenic drift and the temporal emergence of spike protein variants is best explained by optimization of receptor binding affinity. These data provide a fresh look on viral disease emergence and on coronavirus evolution.

7.
J Photochem Photobiol ; 10: 100107, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1611878

ABSTRACT

We performed an in-depth analysis of the virucidal effect of discrete wavelengths: UV-C (278 nm), UV-B (308 nm), UV-A (366 nm) and violet (405 nm) on SARS-CoV-2. By using a highly infectious titer of SARS-CoV-2 we observed that the violet light-dose resulting in a 2-log viral inactivation is only 104 times less efficient than UV-C light. Moreover, by qPCR (quantitative Polymerase chain reaction) and fluorescence in situ hybridization (FISH) approach we verified that the viral titer typically found in the sputum of COVID-19 patients can be completely inactivated by the long UV-wavelengths corresponding to UV-A and UV-B solar irradiation. The comparison of the UV action spectrum on SARS-CoV-2 to previous results obtained on other pathogens suggests that RNA viruses might be particularly sensitive to long UV wavelengths. Our data extend previous results showing that SARS-CoV-2 is highly susceptible to UV light and offer an explanation to the reduced incidence of SARS-CoV-2 infection seen in the summer season.

8.
Microbiol Spectr ; 10(1): e0150421, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1604818

ABSTRACT

In December 2019, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started spreading worldwide causing the coronavirus disease 2019 (COVID-19) pandemic. The hyperactivation of the immune system has been proposed to account for disease severity and death in COVID-19 patients. Despite several approaches having been tested, no therapeutic protocol has been approved. Given that Cyclosporine A (CsA) is well-known to exert a strong antiviral activity on several viral strains and an anti-inflammatory role in different organs with relevant benefits in diverse pathological contexts, we tested its effects on SARS-CoV-2 infection of lung cells. We found that treatment with CsA either before or after infection of CaLu3 cells by three SARS-CoV-2 variants: (i) reduces the expression of both viral RNA and proteins in infected cells; (ii) decreases the number of progeny virions released by infected cells; (iii) dampens the virus-triggered synthesis of cytokines (including IL-6, IL-8, IL1α and TNF-α) that are involved in cytokine storm in patients. Altogether, these data provide a rationale for CsA repositioning for the treatment of severe COVID-19 patients. IMPORTANCE SARS-CoV-2 is the most recently identified member of the betacoronavirus genus responsible for the COVID-19 pandemic. Repurposing of available drugs has been a "quick and dirty" approach to try to reduce mortality and severe symptoms in affected patients initially, and can still represent an undeniable and valuable approach to face COVID-19 as the continuous appearance and rapid diffusion of more "aggressive"/transmissible variants, capable of eluding antibody neutralization, challenges the effectiveness of some anti-SARS-CoV-2 vaccines. Here, we tested a known antiviral and anti-inflammatory drug, Cyclosporine A (CsA), and found that it dampens viral infection and cytokine release from lung cells upon exposure to three different SARS-CoV-2 variants. Knock down of the main intracellular target of CsA, Cyclophilin A, does not phenocopy the drug inhibition of viral infection. Altogether, these findings shed new light on the cellular mechanisms of SARS-CoV-2 infection and provide the rationale for CsA repositioning to treat severe COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/virology , Cyclosporine/pharmacology , Cytokines/immunology , Lung/virology , SARS-CoV-2/drug effects , Virus Release/drug effects , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome , Cytokines/genetics , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology
9.
J Clin Med ; 10(24)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1572519

ABSTRACT

BACKGROUND: The effects of immunomodulators in patients with Coronavirus Disease 2019 (COVID-19) pneumonia are still unknown. We investigated the cellular inflammatory and molecular changes in response to standard-of-care + pidotimod (PDT) and explored the possible association with blood biomarkers of disease severity. METHODS: Clinical characteristics and outcomes, neutrophil-to-lymphocyte ratio (NLR), plasma and cell supernatant chemokines, and gene expression patterns after SARS-CoV-2 and influenza (FLU) virus in vitro stimulation were assessed in 16 patients with mild-moderate COVID-19 pneumonia, treated with standard of care and PDT 800 mg twice daily (PDT group), and measured at admission, 7 (T1), and 12 (T2) days after therapy initiation. Clinical outcomes and NLR were compared with age-matched historical controls not exposed to PDT. RESULTS: Hospital stay, in-hospital mortality, and intubation rate did not differ between groups. At T1, NLR was 2.9 (1.7-4.6) in the PDT group and 5.5 (3.4-7.1) in controls (p = 0.037). In the PDT group, eotaxin and IL-4 plasma concentrations progressively increased (p < 0.05). Upon SARS-CoV-2 and FLU-specific stimulation, IFN-γ was upregulated (p < 0.05), while at genetic transcription level, Pathogen Recognition Receptors (TRLs) were upregulated, especially in FLU-stimulated conditions. CONCLUSIONS: Immunomodulation exerted by PDT and systemic corticosteroids may foster a restoration in the innate response to the viral infection. These results should be confirmed in larger RCTs.

10.
Cells ; 10(11)2021 11 16.
Article in English | MEDLINE | ID: covidwho-1523883

ABSTRACT

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population.


Subject(s)
COVID-19/immunology , Coinfection/immunology , HIV Infections/immunology , Adolescent , Adult , COVID-19/virology , Child , Child, Preschool , Coinfection/virology , HIV Infections/virology , Humans , Infant , Inflammation , Interleukin-10/blood , Interleukin-10/genetics , Male , RNA, Messenger/blood , SARS-CoV-2/immunology , Young Adult
11.
Lancet Rheumatol ; 3(10): e690-e697, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1486375

ABSTRACT

BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2/FiO2. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

12.
Virus Evol ; 7(2): veab061, 2021.
Article in English | MEDLINE | ID: covidwho-1467407

ABSTRACT

Four coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E) are endemic in human populations. All these viruses are seasonal and generate short-term immunity. Like the highly pathogenic coronaviruses, the endemic coronaviruses have zoonotic origins. Thus, understanding the evolutionary dynamics of these human viruses might provide insight into the future trajectories of SARS-CoV-2 evolution. Because the zoonotic sources of HCoV-OC43 and HCoV-229E are known, we applied a population genetics-phylogenetic approach to investigate which selective events accompanied the divergence of these viruses from the animal ones. Results indicated that positive selection drove the evolution of some accessory proteins, as well as of the membrane proteins. However, the spike proteins of both viruses and the hemagglutinin-esterase (HE) of HCoV-OC43 represented the major selection targets. Specifically, for both viruses, most positively selected sites map to the receptor-binding domains (RBDs) and are polymorphic. Molecular dating for the HCoV-229E spike protein indicated that RBD Classes I, II, III, and IV emerged 3-9 years apart. However, since the appearance of Class V (with much higher binding affinity), around 25 years ago, limited genetic diversity accumulated in the RBD. These different time intervals are not fully consistent with the hypothesis that HCoV-229E spike evolution was driven by antigenic drift. An alternative, not mutually exclusive possibility is that strains with higher affinity for the cellular receptor have out-competed strains with lower affinity. The evolution of the HCoV-OC43 spike protein was also suggested to undergo antigenic drift. However, we also found abundant signals of positive selection in HE. Whereas such signals might result from antigenic drift, as well, previous data showing co-evolution of the spike protein with HE suggest that optimization for human cell infection also drove the evolution of this virus. These data provide insight into the possible trajectories of SARS-CoV-2 evolution, especially in case the virus should become endemic.

13.
Int J Mol Sci ; 22(19)2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1438628

ABSTRACT

The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient's outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and targeted mass spectrometry and ELISA. Results indicated a progressive increase in dihydrosphingosine, dihydroceramides, ceramides, sphingosine, and a decrease in sphingosine-1-phosphate. These changes are associated with a serine palmitoyltransferase long chain base subunit 1 (SPTLC1) increase in relation to COVID-19 severity. Severe patients showed a decrease in sphingomyelins and a high level of acid sphingomyelinase (aSMase) that influences monosialodihexosyl ganglioside (GM3) C16:0 levels. Critical patients are characterized by high levels of dihydrosphingosine and dihydroceramide but not of glycosphingolipids. In severe and critical patients, unbalanced lipid metabolism induces lipid raft remodeling, leads to cell apoptosis and immunoescape, suggesting active sphingolipid participation in viral infection. Furthermore, results indicated that the sphingolipid and glycosphingolipid metabolic rewiring promoted by aSMase and GM3 is age-dependent but also characteristic of severe and critical patients influencing prognosis and increasing viral load. AUCs calculated from ROC curves indicated ceramides C16:0, C18:0, C24:1, sphingosine and SPTLC1 as putative biomarkers of disease evolution.


Subject(s)
COVID-19/blood , Sphingolipids/blood , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , Female , Humans , Lipidomics , Male , Middle Aged , Prognosis , SARS-CoV-2/isolation & purification , Severity of Illness Index , Sphingolipids/analysis , Sphingomyelins/analysis , Sphingomyelins/blood , Young Adult
14.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1406466

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has triggered an unprecedented international effort to sequence complete viral genomes. We leveraged this wealth of information to characterize the substitution spectrum of SARS-CoV-2 and to compare it with those of other human and animal coronaviruses. We show that, once nucleotide composition is taken into account, human and most animal coronaviruses display a mutation spectrum dominated by C to U and G to U substitutions, a feature that is not shared by other positive-sense RNA viruses. However, the proportions of C to U and G to U substitutions tend to decrease as divergence increases, suggesting that, whatever their origin, a proportion of these changes is subsequently eliminated by purifying selection. Analysis of the sequence context of C to U substitutions showed little evidence of apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-mediated editing and such contexts were similar for SARS-CoV-2 and Middle East respiratory syndrome coronavirus sampled from different hosts, despite different repertoires of APOBEC3 proteins in distinct species. Conversely, we found evidence that C to U and G to U changes affect CpG dinucleotides at a frequency higher than expected. Whereas this suggests ongoing selective reduction of CpGs, this effect alone cannot account for the substitution spectra. Finally, we show that, during the first months of SARS-CoV-2 pandemic spread, the frequency of both G to U and C to U substitutions increased. Our data suggest that the substitution spectrum of SARS-CoV-2 is determined by an interplay of factors, including intrinsic biases of the replication process, avoidance of CpG dinucleotides and other constraints exerted by the new host.


Subject(s)
COVID-19/genetics , Evolution, Molecular , Genome, Viral , Mutation , Pandemics , SARS-CoV-2/genetics , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , Animals , COVID-19/epidemiology , Humans , Phylogeny , SARS-CoV-2/metabolism
15.
Mol Neurobiol ; 58(12): 6111-6120, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1375838

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic of coronavirus disease (COVID-19). Whereas in most cases COVID-19 is asymptomatic or pauci-symptomatic, extremely severe clinical forms are observed. In this case, complex immune dysregulations and an excessive inflammatory response are reported and are the main cause of morbidity and mortality. Natural killer cells are key players in the control of viral infection, and their activity is regulated by a tight balance between activating and inhibitory receptors; an alteration of NK activity was suggested to be associated with the development of severe forms of COVID-19. In this study, we analyzed peripheral NK cell subpopulations and the expression of activating and inhibitory receptors in 30 patients suffering from neurological conditions who recovered from mild, moderate, or severe SARS-CoV-2 infection, comparing the results to those of 10 SARS-CoV-2-uninfected patients. Results showed that an expansion of NK subset with lower cytolytic activity and an augmented expression of the 2DL1 inhibitory receptor, particularly when in association with the C2 ligand (KIR2DL1-C2), characterized the immunological scenario of severe COVID-19 infection. An increase of NK expressing the ILT2 inhibitory receptor was instead seen in patients recovering from mild or moderate infection compared to controls. Results herein suggest that the KIR2DL1-C2 NK inhibitory complex is a risk factor toward the development of severe form of COVID-19. Our results confirm that a complex alteration of NK activity is present in COVID-19 infection and offer a molecular explanation for this observation.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , Receptors, KIR/metabolism , B-Lymphocytes/immunology , COVID-19/physiopathology , Histocompatibility Antigens/immunology , Humans , Ligands , Lymphocyte Subsets/immunology , T-Lymphocytes/immunology
16.
Sci Rep ; 11(1): 14805, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1319047

ABSTRACT

Solar UV-C photons do not reach Earth's surface, but are known to be endowed with germicidal properties that are also effective on viruses. The effect of softer UV-B and UV-A photons, which copiously reach the Earth's surface, on viruses are instead little studied, particularly on single-stranded RNA viruses. Here we combine our measurements of the action spectrum of Covid-19 in response to UV light, Solar irradiation measurements on Earth during the SARS-CoV-2 pandemics, worldwide recorded Covid-19 mortality data and our "Solar-Pump" diffusive model of epidemics to show that (a) UV-B/A photons have a powerful virucidal effect on the single-stranded RNA virus Covid-19 and that (b) the Solar radiation that reaches temperate regions of the Earth at noon during summers, is sufficient to inactivate 63% of virions in open-space concentrations (1.5 × 103 TCID50/mL, higher than typical aerosol) in less than 2 min. We conclude that the characteristic seasonality imprint displayed world-wide by the SARS-Cov-2 mortality time-series throughout the diffusion of the outbreak (with temperate regions showing clear seasonal trends and equatorial regions suffering, on average, a systematically lower mortality), might have been efficiently set by the different intensity of UV-B/A Solar radiation hitting different Earth's locations at different times of the year. Our results suggest that Solar UV-B/A play an important role in planning strategies of confinement of the epidemics, which should be worked out and set up during spring/summer months and fully implemented during low-solar-irradiation periods.


Subject(s)
COVID-19/epidemiology , SARS-CoV-2/radiation effects , Sunlight , Humans , Seasons
17.
Cells ; 10(7)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1314589

ABSTRACT

MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at both systemic and placental levels, is missing. To fill this gap, blood and placenta biopsies collected at delivery from 15 asymptomatic SIPW were immediately analysed for: miRNA expression (n = 84) (QPCR array), antiviral/immune mRNA target expression (n = 74) (QGene) and cytokine/chemokines production (n = 27) (Multiplex ELISA). By comparing these results with those obtained from six uninfected pregnant women (UPW), we observed that, following SARS-CoV-2 infection, the transcriptomic profile of pregnant women is significantly altered in different anatomical districts, even in the absence of clinical symptoms and vertical transmission. This characteristic combination of miRNA and antiviral/immune factors seems to control both the infection and the dysfunctional immune reaction, thus representing a positive correlate of protection and a potential therapeutic target against SARS-CoV-2.


Subject(s)
COVID-19/genetics , MicroRNAs/genetics , Pregnancy Complications, Infectious/genetics , Adult , COVID-19/blood , COVID-19/diagnosis , Female , Humans , MicroRNAs/analysis , MicroRNAs/blood , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/diagnosis , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult
18.
BMC Infect Dis ; 21(1): 594, 2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1277920

ABSTRACT

BACKGROUND: UltraViolet-C (UV-C) lamps may be used to supplement current hospital cleaning and disinfection of surfaces contaminated by SARS-CoV-2. Our aim is to provide some practical indications for the correct use of UV-C lamps. METHODS: We studied three UV-C lamps, measuring their spatial irradiance and emission over time. We quantify the error that is committed by calculating the irradiation time based exclusively on the technical data of the lamps or by making direct irradiance measurements. Finally, we tested specific dosimeters for UV-C. RESULTS: Our results show that the spatial emission of UV-C lamps is strongly dependent on the power of the lamps and on the design of their reflectors. Only by optimizing the positioning and calculating the exposure time correctly, is it possible to dispense the dose necessary to obtain SARS-CoV-2 inactivation. In the absence of suitable equipment for measuring irradiance, the calculated irradiation time can be underestimated. We therefore consider it precautionary to increase the calculated times by at least 20%. CONCLUSION: To use UV-C lamps effectively, it is necessary to follow a few simple precepts when choosing, positioning and verifying the lamps. In the absence of instruments dedicated to direct verification of irradiance, photochromic UV-C dosimeters may represent a useful tool for easily verifying that a proper UV-C dose has been delivered.


Subject(s)
COVID-19/prevention & control , Disinfection/methods , SARS-CoV-2/drug effects , Ultraviolet Rays , Hospitals , Humans , Virus Inactivation/radiation effects
19.
Hum Immunol ; 82(8): 551-560, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1265675

ABSTRACT

Given the highly polymorphic nature of Human Leukocyte Antigen (HLA) molecules, it is not surprising that they function as key regulators of the host immune response to almost all invading pathogens, including SARS-CoV-2, the etiological agent responsible for the recent COVID-19 pandemic. Several correlations have already been established between the expression of a specific HLA allele/haplotype and susceptibility/progression of SARS-CoV-2 infection and new ones are continuously emerging. Protective and harmful HLA variants have been described in both mild and severe forms of the disease, but considering the huge amount of existing variants, the data gathered in such a brief span of time are to some extent confusing and contradictory. The aim of this mini-review is to provide a snap-shot of the main findings so far collected on the HLA-SARS-CoV-2 interaction, so as to partially untangle this intricate yarn. As key factors in the generation of antigenic peptides to be presented by HLA molecules, ERAP1 and ERAP2 role in SARS-CoV-2 infection will be revised as well.


Subject(s)
Aminopeptidases/genetics , Antigen Presentation , Antigens, Viral/immunology , COVID-19/genetics , HLA Antigens/genetics , Minor Histocompatibility Antigens/genetics , Polymorphism, Genetic , SARS-CoV-2/immunology , Aminopeptidases/immunology , Animals , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Epitopes , HLA Antigens/immunology , Host-Pathogen Interactions , Humans , Minor Histocompatibility Antigens/immunology , SARS-CoV-2/pathogenicity
20.
Cells ; 10(6)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1264419

ABSTRACT

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , Basigin/physiology , SARS-CoV-2/physiology , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basigin/antagonists & inhibitors , Basigin/genetics , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Hep G2 Cells , Host-Pathogen Interactions , Humans , Molecular Targeted Therapy , RNA Interference/physiology , RNA, Small Interfering/pharmacology , RNA, Small Interfering/therapeutic use , Receptors, Virus/metabolism , Receptors, Virus/physiology , SARS-CoV-2/metabolism , Vero Cells , Viral Tropism/physiology
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