RESUMEN
There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1-5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients' age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.
Asunto(s)
COVID-19/inmunología , Citocinas/inmunología , Inmunidad Innata/inmunología , SARS-CoV-2/inmunología , Caracteres Sexuales , Linfocitos T/inmunología , COVID-19/sangre , COVID-19/virología , Quimiocinas/sangre , Quimiocinas/inmunología , Estudios de Cohortes , Citocinas/sangre , Progresión de la Enfermedad , Femenino , Humanos , Activación de Linfocitos , Masculino , Monocitos/inmunología , Fenotipo , Pronóstico , ARN Viral/análisis , SARS-CoV-2/patogenicidad , Carga ViralRESUMEN
Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.
Asunto(s)
Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/fisiopatología , Citocinas/análisis , Neumonía Viral/inmunología , Neumonía Viral/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Análisis por Conglomerados , Citocinas/inmunología , Eosinófilos/inmunología , Femenino , Humanos , Inmunoglobulina E/análisis , Inmunoglobulina E/inmunología , Interleucina-13/análisis , Interleucina-13/inmunología , Interleucina-5/análisis , Interleucina-5/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Linfocitos T/citología , Linfocitos T/inmunología , Carga Viral , Adulto JovenRESUMEN
OBJECTIVE: To characterize the scalp microbial composition, function, and connection to dandruff severity using a metagenomics approach and to understand the impact of a Piroctone Olamine containing anti-dandruff shampoo on the scalp microbiome. METHODS: Shotgun metagenomics was used to characterize the composition of the scalp microbiomes from 94 subjects with and without clinically defined dandruff. Furthermore, the microbiome of the scalps of 100 dandruff sufferers before and after 3 weeks of treatment with either control or anti-dandruff shampoo containing 0.5% Piroctone Olamine (PO) was characterized and compared to identify microorganisms associated with the dandruff condition and the associated pathways and processes that may contribute to PO's effect on scalp microbiome. RESULTS: A higher relative abundance of Malassezia restricta and Staphylococcus capitis and a lower abundance of Cutibacterium acnes were associated with the dandruff scalps relative to the no-dandruff scalps. A 3-week PO shampoo treatment reduced the relative abundance of Malassezia species and Staphylococcus capitis and increased the relative abundance of Cutibacterium acnes. This change to the scalp microbiome composition is consistent with a return to a healthy no-dandruff microbiome and improved clinical signs and symptoms as measured by adherent scalp flaking score (ASFS) compared with the control shampoo. Functional genomics analysis showed that the PO shampoo treatment reduced oxidative stress-associated genes and decreased the abundance of protease, urease, and lipase genes. These changes correlated positively to improvements in dandruff severity. PO treatment favourably shifted scalp microbiomes in dandruff subjects toward the no-dandruff state. CONCLUSION: Our results suggest that part of the aetiology of dandruff can be attributed to dysbiosis of the scalp microbiome. PO treatment can restore a healthier microbiome, reducing oxidative stress and promoting better scalp health.
OBJECTIF: Caractériser la composition microbienne du cuir chevelu, sa fonction et son lien avec la sévérité des pellicules à l'aide d'une approche métagénomique. Comprendre l'impact d'un shampooing antipelliculaire à base de piroctone olamine sur le microbiome du cuir chevelu. MÉTHODES: La métagénomique shotgun a été utilisée pour caractériser la composition des microbiomes du cuir chevelu de 94 sujets avec et sans pellicules définies cliniquement. Par ailleurs, le microbiome des cuirs chevelus de 100 personnes ayant des pellicules avant et après trois semaines de traitement par un shampooing témoin ou un shampooing antipelliculaire contenant 0,5 % de piroctone olamine (PO) a été caractérisé et comparé pour identifier les microorganismes associés à l'état pelliculaire, et les voies et processus associés pouvant contribuer à l'effet de la PO sur le microbiome du cuir chevelu. RÉSULTATS: Une abondance relative plus élevée de Malassezia restricta et de Staphylococcus capitis, et une abondance plus faible de Cutibacterium acnes étaient associées aux cuirs chevelus avec des pellicules par rapport aux cuirs chevelus sans pellicules. Un traitement avec un shampooing contenant de la PO de 3 semaines a réduit l'abondance relative des espèces Malassezia et Staphylococcus capitis, et a augmenté l'abondance relative de Cutibacterium acnes. Cette modification de la composition du microbiome du cuir chevelu est cohérente avec un retour à un microbiome sain sans pellicules, et une amélioration des signes et symptômes cliniques mesurés par le score de desquamation du cuir chevelu adhérent (Adherent Scalp Flaking Score, ASFS) par rapport au shampooing témoin. L'analyse génomique fonctionnelle a montré que le traitement avec un shampooing contenant de la PO réduisait les gènes associés au stress oxydatif et diminuait l'abondance des gènes de la protéase, de l'uréase et de la lipase. Ces modifications étaient corrélées positivement à des améliorations de la sévérité des pellicules. Le traitement avec la PO a favorisé l'évolution des microbiomes du cuir chevelu des sujets ayant des pellicules vers un état sans pellicules. CONCLUSION: Nos résultats suggèrent qu'une partie de l'étiologie des pellicules peut être attribuée à la dysbiose du microbiome du cuir chevelu. Le traitement avec la PO peut rétablir un microbiome plus sain, en réduisant le stress oxydatif et en favorisant une meilleure santé du cuir chevelu.
Asunto(s)
Caspa , Preparaciones para el Cabello , Microbiota , Cuero Cabelludo , Humanos , Microbiota/efectos de los fármacos , Cuero Cabelludo/microbiología , Caspa/microbiología , Caspa/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Combinación de Medicamentos , Etanolaminas , PiridonasRESUMEN
The current quantitative reverse transcription PCR (RT-qPCR) assay recommended for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing in the United States requires analysis of 3 genomic targets per sample: 2 viral and 1 host. To simplify testing and reduce the volume of required reagents, we devised a multiplex RT-qPCR assay to detect SARS-CoV-2 in a single reaction. We used existing N1, N2, and RP primer and probe sets by the Centers for Disease Control and Prevention, but substituted fluorophores to allow multiplexing of the assay. The cycle threshold (Ct) values of our multiplex RT-qPCR were comparable to those obtained by the single assay adapted for research purposes. Low copy numbers (≥500 copies/reaction) of SARS-CoV-2 RNA were consistently detected by the multiplex RT-qPCR. Our novel multiplex RT-qPCR improves upon current single diagnostics by saving reagents, costs, time, and labor.
Asunto(s)
Betacoronavirus/genética , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Reacción en Cadena de la Polimerasa Multiplex/normas , Neumonía Viral/diagnóstico , ARN Viral/genética , Juego de Reactivos para Diagnóstico/normas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Betacoronavirus/patogenicidad , COVID-19 , Prueba de COVID-19 , Estudios de Casos y Controles , Técnicas de Laboratorio Clínico/normas , Infecciones por Coronavirus/virología , Cartilla de ADN/normas , Células HEK293 , Humanos , Límite de Detección , Nasofaringe/virología , Pandemias , Neumonía Viral/virología , SARS-CoV-2 , Estados UnidosRESUMEN
Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.
Asunto(s)
Ácido Fólico/metabolismo , Desnutrición/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/metabolismo , Vitamina B 12/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Carbazoles/farmacología , Anomalías Congénitas , Femenino , Deficiencia de Ácido Fólico/tratamiento farmacológico , Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias , Dibenzodioxinas Policloradas/farmacología , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/genética , Deficiencia de Vitamina B 12/tratamiento farmacológicoAsunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/diagnóstico , Nasofaringe/virología , Neumonía Viral/diagnóstico , Saliva/virología , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Humanos , Pandemias , SARS-CoV-2 , Sensibilidad y Especificidad , Manejo de Especímenes , Factores de TiempoRESUMEN
RATIONALE: Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear. OBJECTIVES: We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects. METHODS: Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38). MEASUREMENTS AND MAIN RESULTS: Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects. CONCLUSIONS: The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.
Asunto(s)
Líquido del Lavado Bronquioalveolar/microbiología , Infecciones por VIH/microbiología , Pulmón/microbiología , Microbiota , Boca/microbiología , Adulto , Terapia Antirretroviral Altamente Activa , Estudios de Cohortes , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
All animals harbor beneficial microbes. One way these microbes can benefit their animal hosts is by increasing the diversity and efficacy of communication signals available to the hosts. The fermentation hypothesis for mammalian chemical communication posits that bacteria in the scent glands of mammals generate odorous metabolites used by their hosts for communication and that variation in host chemical signals is a product of underlying variation in the bacterial communities inhabiting the scent glands. An effective test of this hypothesis would require accurate surveys of the bacterial communities in mammals' scent glands and complementary data on the odorant profiles of scent secretions--both of which have been historically lacking. Here we use next-generation sequencing to survey deeply the bacterial communities in the scent glands of wild spotted and striped hyenas. We show that these communities are dominated by fermentative bacteria and that the structures of these communities covary with the volatile fatty acid profiles of scent secretions in both hyena species. The bacterial and volatile fatty acid profiles of secretions differ between spotted and striped hyenas, and both profiles vary with sex and reproductive state among spotted hyenas within a single social group. Our results strongly support the fermentation hypothesis for chemical communication, suggesting that symbiotic bacteria underlie species-specific odors in both spotted and striped hyenas and further underlie sex and reproductive state-specific odors among spotted hyenas. We anticipate that the fermentation hypothesis for chemical communication will prove broadly applicable among scent-marking mammals as others use the technical and analytical approaches used here.
Asunto(s)
Comunicación Animal , Bacterias/metabolismo , Hyaenidae/microbiología , Microbiota/genética , Odorantes , Glándulas Odoríferas/microbiología , Simbiosis , Animales , Secuencia de Bases , Cartilla de ADN/genética , Ácidos Grasos Volátiles/metabolismo , Femenino , Fermentación , Hyaenidae/fisiología , Kenia , Masculino , Microbiota/fisiología , Datos de Secuencia Molecular , ARN Ribosómico 16S/genética , Glándulas Odoríferas/metabolismo , Análisis de Secuencia de ADNRESUMEN
RATIONALE: Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome. OBJECTIVES: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort. METHODS: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome. MEASUREMENTS AND MAIN RESULTS: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not. CONCLUSIONS: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.
Asunto(s)
Metagenoma , Sistema Respiratorio/microbiología , Fumar , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Líquido del Lavado Bronquioalveolar/microbiología , Estudios de Cohortes , Femenino , Humanos , Pulmón/microbiología , Masculino , Persona de Mediana Edad , Boca/microbiología , Estudios Prospectivos , Valores de Referencia , Análisis de Secuencia de ADN/métodos , Adulto JovenRESUMEN
OBJECTIVE: To assess antibiotics impact on outcomes in COVID-19 pneumonia patients with varying procalcitonin (PCT) levels. METHODS: This retrospective cohort study included 3665 COVID-19 pneumonia patients hospitalized at five Mayo Clinic sites (March 2020 to June 2022). PCT levels were measured at admission. Patients' antibiotics use and outcomes were collected via the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) registry. Patients were stratified into high and low PCT groups based on the first available PCT result. The distinction between high and low PCT was demarcated at both 0.25 ng/ml and 0.50 ng/ml. RESULTS: Our cohort consisted of 3665 patients admitted with COVID-19 pneumonia. The population was predominantly male, Caucasian and non-Hispanic. With the PCT cut-off of 0.25 ng/ml, 2375 (64.8 %) patients had a PCT level <0.25 ng/mL, and 1290 (35.2 %) had PCT ≥0.25 ng/ml. While when the PCT cut off of 0.50 ng/ml was used we observed 2934 (80.05 %) patients with a PCT <0.50 ng/ml while 731(19.94 %) patients had a PCT ≥0.50 ng/ml. Patients with higher PCT levels exhibited significantly higher rates of bacterial infections (0.25 ng/ml cut-off: 4.2 % vs 7.9 %; 0.50 ng/ml cut-off: 4.6 % vs 9.2 %). Antibiotics were used in 66.0 % of the cohort. Regardless of the PCT cutoffs, the antibiotics group showed increased hospital length of stay (LOS), intensive care unit (ICU) admission rate, and mortality. However, early de-escalation (<24 h) of antibiotics correlated with reduced hospital LOS, ICU LOS, and mortality. These results were consistent even after adjusting for confounders. CONCLUSION: Our study shows a substantial number of COVID-19 pneumonia patients received antibiotics despite a low incidence of bacterial infections. Therefore, antibiotics use in COVID pneumonia patients with PCT <0.5 in the absence of clinical evidence of bacterial infection has no beneficial effect.
Asunto(s)
Antibacterianos , COVID-19 , Polipéptido alfa Relacionado con Calcitonina , Humanos , Masculino , Femenino , Antibacterianos/uso terapéutico , Polipéptido alfa Relacionado con Calcitonina/sangre , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , COVID-19/mortalidad , COVID-19/complicaciones , Tratamiento Farmacológico de COVID-19 , Tiempo de Internación , Resultado del Tratamiento , SARS-CoV-2 , Hospitalización/estadística & datos numéricosRESUMEN
CONTEXT: The United States has witnessed a disproportionate rise in substance use disorders (SUD) and co-occurring mental health disorders, paired with housing instability, especially among racially minoritized communities. Traditional in-patient residential treatment programs for SUD have proven inconsistent in their effectiveness in preventing relapse and maintaining attrition among these patient populations. There is evidence showing that peer recovery programs led by individuals who have lived experience with SUD can increase social support and foster intrinsic motivation within participants to bolster their recovery. These peer recovery programs, when coupled with a standardized training program for peer recovery coaches, may be very efficacious at improving patient health outcomes, boosting performance on Substance Abuse and Mental Health Services Administration (SAMHSA) national outcome measures (NOMs), and helping participants build an overall better quality of life. OBJECTIVES: The goal of this study is to highlight the efficacy of a peer recovery program, the Minority Aids Initiative, in improving health outcomes and associated NOMs in men with SUD and/or co-occurring mental health disorder. METHODS: Participants received six months of peer recovery coaching from trained staff. Sessions were guided by the Manual for Recovery Coaching and focused on 10 different domains of recovery. Participants and coaches set long-term goals and created weekly action plans to work toward them. Standardized assessments (SAMHSA's Government Performance and Results Act [GPRA] tool, Addiction Severity Index [ASI]) were administered by recovery coaches at intake and at the 6-month time point to evaluate participant progress. Analyses of participant recovery were carried out according to SAMHSA's six NOMs and assessed the outcomes of the intervention and their significance. RESULTS: A total of 115 participants enrolled in the program over a 2-year period. Among them, 53 were eligible for 6-month follow-up interviews. In total, 321 sessions were held, with an average of three sessions per participant. Participants showed marked improvement across five of the six NOMs at the end of the 6-month course and across all ASI outcomes, with the exception of three in which participants reported an absence or few symptoms at intake. CONCLUSIONS: Our study shows that participants receive benefits across nearly all NOM categories when paired with recovery coaches who are well trained in medication-assisted treatment (MAT) and medications for opioid use disorder (MOUD) over a 6-month period. We see the following: a higher rate of abstinence; increased housing stability; lower health, behavioral, and social consequences; lower depression and anxiety; longer participant-recovery coach exposure time; and higher follow-up rates. We hope that our results can contribute to advancements and greater acceptance in the implementation of peer recovery coaching as well as an improvement in the lives of the communities affected by substance use.
Asunto(s)
Tutoría , Trastornos Relacionados con Sustancias , Humanos , Masculino , Calidad de Vida , Tratamiento Domiciliario , Trastornos Relacionados con Sustancias/terapia , Resultado del Tratamiento , Estados UnidosRESUMEN
Recent estimates for the global brain health supplement category, i.e. nootropic market size, will grow to nearly $5.8 billion by 2023. Overall, nearly one-quarter (23%) of adults currently take a supplement to maintain or improve brain health or delay and reverse dementia. Not surprisingly, the use of such supplements increases with age - more than one-third of the oldest generation (ages 74 and older) takes a supplement for brain health. This widespread use is being driven by a strong desire both in the younger and older generations to enhance cognitive performance and achieve healthy aging. The most prevalent botanicals currently dominating the nootropic marketplace include Gingko biloba, American ginseng, and Bacopa monnieri. However, other botanicals that affect stress, focus, attention, and sleep have also been procured by dietary supplement companies developing products for improving both, short and long-term brain health. This review focuses on efficacy data for neuroactive botanicals targeted at improving cognitive function, stress reduction, memory, mood, attention, concentration, focus, and alertness, including Bacopa monnieri, Ginkgo biloba, Holy basil, American ginseng, Gotu kola, Lemon balm, Common and Spanish sages and spearmint. Botanicals are discussed in terms of available clinical efficacy data and current safety profiles. Data gaps are highlighted for both efficacy and safety to bring attention to unmet needs and future research.
Asunto(s)
Bacopa , Nootrópicos , Adulto , Anciano , Encéfalo , Cognición , Suplementos Dietéticos , Humanos , Nootrópicos/efectos adversosRESUMEN
Neutrophil activation and the formation of neutrophil extracellular traps (NETs) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE). Here we report that the expression of an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and correlated with autoantibody levels and higher interferon status. Induction of ERV-K102 in SLE negatively correlated with the expression of epigenetic silencing factors. Anti-ERV-K102 IgG levels in SLE plasma correlated with higher interferon stimulated gene expression, and further promoted enhanced neutrophil phagocytosis of ERV-K102 envelope protein through immune complex formation. Finally, phagocytosis of ERV-K102 immune complexes resulted in the formation of NETs consisting of DNA, neutrophil elastase, and citrullinated histone H3. Together, we identified an immunostimulatory ERV-K envelope protein that in an immune complex with SLE IgG is capable of activating neutrophils.
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Anticuerpos/inmunología , Retrovirus Endógenos/inmunología , Lupus Eritematoso Sistémico/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Envoltura Viral/inmunología , Autoanticuerpos/inmunología , ADN/inmunología , Epigénesis Genética/inmunología , Trampas Extracelulares , Expresión Génica/inmunología , Humanos , Inmunidad Innata/inmunología , Inmunoglobulina G/inmunología , Interferones/inmunología , Lupus Eritematoso Sistémico/virología , Fagocitosis/inmunologíaRESUMEN
Background: SARS-CoV-2 infection has, as of April 2021, affected >133 million people worldwide, causing >2.5 million deaths. Because the large majority of individuals infected with SARS-CoV-2 are asymptomatic, major concerns have been raised about possible long-term consequences of the infection. Methods: Wedeveloped an antigen capture assay to detect SARS-CoV-2 spike protein in urine samples from patients with COVID-19whose diagnosis was confirmed by positive PCR results from nasopharyngeal swabs (NP-PCR+) forSARS-CoV-2. We used a collection of 233 urine samples from 132 participants from Yale New Haven Hospital and the Children's Hospital of Philadelphia that were obtained during the pandemic (106 NP-PCR+ and 26 NP-PCR-), and a collection of 20 urine samples from 20 individuals collected before the pandemic. Results: Our analysis identified 23 out of 91 (25%) NP-PCR+ adult participants with SARS-CoV-2 spike S1 protein in urine (Ur-S+). Interestingly, although all NP-PCR+ children were Ur-S-, one child who was NP-PCR- was found to be positive for spike protein in their urine. Of the 23 adults who were Ur-S+, only one individual showed detectable viral RNA in urine. Our analysis further showed that 24% and 21% of adults who were NP-PCR+ had high levels of albumin and cystatin C, respectively, in their urine. Among individuals with albuminuria (>0.3 mg/mg of creatinine), statistical correlation could be found between albumin and spike protein in urine. Conclusions: Together, our data showed that one of four individuals infected with SARS-CoV-2 develop renal abnormalities, such as albuminuria. Awareness about the long-term effect of these findings is warranted.
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COVID-19 , Glicoproteína de la Espiga del Coronavirus , Adulto , COVID-19/diagnóstico , Niño , Humanos , Pandemias , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
BACKGROUND: Scaling SARS-CoV-2 testing to meet demands of safe reopenings continues to be plagued by assay costs and supply chain shortages. In response, we developed SalivaDirect, which received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA). METHODS: We simplified our saliva-based diagnostic test by (1) not requiring collection tubes with preservatives, (2) replacing nucleic acid extraction with a simple enzymatic and heating step, and (3) testing specimens with a dualplex qRT-PCR assay. Moreover, we validated SalivaDirect with reagents and instruments from multiple vendors to minimize supply chain issues. FINDINGS: From our hospital cohort, we show a high positive agreement (94%) between saliva tested with SalivaDirect and nasopharyngeal swabs tested with a commercial qRT-PCR kit. In partnership with the National Basketball Association (NBA) and National Basketball Players Association (NBPA), we tested 3,779 saliva specimens from healthy individuals and detected low rates of invalid (0.3%) and false-positive (<0.05%) results. CONCLUSIONS: We demonstrate that saliva is a valid alternative to swabs for SARS-CoV-2 screening and that SalivaDirect can make large-scale testing more accessible and affordable. Uniquely, we can designate other laboratories to use our sensitive, flexible, and simplified platform under our EUA (https://publichealth.yale.edu/salivadirect/). FUNDING: This study was funded by the NBA and NBPA (N.D.G.), the Huffman Family Donor Advised Fund (N.D.G.), a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University (N.D.G.), the Yale Institute for Global Health (N.D.G.), and the Beatrice Kleinberg Neuwirth Fund (A.I.K.). C.B.F.V. is supported by NWO Rubicon 019.181EN.004.
Asunto(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Prueba de COVID-19 , Humanos , Laboratorios , SARS-CoV-2/genética , SalivaRESUMEN
While several clinical and immunological parameters correlate with disease severity and mortality in SARS-CoV-2 infection, work remains in identifying unifying correlates of coronavirus disease 2019 (COVID-19) that can be used to guide clinical practice. Here, we examine saliva and nasopharyngeal (NP) viral load over time and correlate them with patient demographics, and cellular and immune profiling. We found that saliva viral load was significantly higher in those with COVID-19 risk factors; that it correlated with increasing levels of disease severity and showed a superior ability over nasopharyngeal viral load as a predictor of mortality over time (AUC=0.90). A comprehensive analysis of immune factors and cell subsets revealed strong predictors of high and low saliva viral load, which were associated with increased disease severity or better overall outcomes, respectively. Saliva viral load was positively associated with many known COVID-19 inflammatory markers such as IL-6, IL-18, IL-10, and CXCL10, as well as type 1 immune response cytokines. Higher saliva viral loads strongly correlated with the progressive depletion of platelets, lymphocytes, and effector T cell subsets including circulating follicular CD4 T cells (cTfh). Anti-spike (S) and anti-receptor binding domain (RBD) IgG levels were negatively correlated with saliva viral load showing a strong temporal association that could help distinguish severity and mortality in COVID-19. Finally, patients with fatal COVID-19 exhibited higher viral loads, which correlated with the depletion of cTfh cells, and lower production of anti-RBD and anti-S IgG levels. Together these results demonstrated that viral load - as measured by saliva but not nasopharyngeal - is a dynamic unifying correlate of disease presentation, severity, and mortality over time.
RESUMEN
Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Inmunoglobulina G/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Anciano , Anciano de 80 o más Años , COVID-19/mortalidad , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Portador Sano/inmunología , Femenino , Humanos , Inmunidad Humoral , Cinética , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). Yet, the exact feature of antibody responses that governs COVID-19 disease outcomes remain unclear. Here, we analysed humoral immune responses in 209 asymptomatic, mild, moderate and severe COVID-19 patients over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-Spike (S) IgG levels, length of hospitalization and clinical parameters associated with worse clinical progression. While high anti-S IgG levels correlated with worse disease severity, such correlation was time-dependent. Deceased patients did not have higher overall humoral response than live discharged patients. However, they mounted a robust, yet delayed response, measured by anti-S, anti-RBD IgG, and neutralizing antibody (NAb) levels, compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, while sera from 89% of patients displayed some neutralization capacity during their disease course, NAb generation prior to 14 days of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se, but rather with the delayed kinetics of NAb production.
RESUMEN
The recent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exemplifies the critical need for accurate and rapid diagnostic assays to prompt clinical and public health interventions. Currently, several quantitative reverse transcription-PCR (RT-qPCR) assays are being used by clinical, research and public health laboratories. However, it is currently unclear whether results from different tests are comparable. Our goal was to make independent evaluations of primer-probe sets used in four common SARS-CoV-2 diagnostic assays. From our comparisons of RT-qPCR analytical efficiency and sensitivity, we show that all primer-probe sets can be used to detect SARS-CoV-2 at 500 viral RNA copies per reaction. The exception for this is the RdRp-SARSr (Charité) confirmatory primer-probe set which has low sensitivity, probably due to a mismatch to circulating SARS-CoV-2 in the reverse primer. We did not find evidence for background amplification with pre-COVID-19 samples or recent SARS-CoV-2 evolution decreasing sensitivity. Our recommendation for SARS-CoV-2 diagnostic testing is to select an assay with high sensitivity and that is regionally used, to ease comparability between outcomes.