Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 123
Filtrar
1.
Adv Mater Technol ; : 2100602, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34514084

RESUMO

CRISPR (Clustered regularly interspaced short palindromic repeats)-based diagnostic technologies have emerged as a promising alternative to accelerate delivery of SARS-CoV-2 molecular detection at the point of need. However, efficient translation of CRISPR-diagnostic technologies to field application is still hampered by dependence on target amplification and by reliance on fluorescence-based results readout. Herein, an amplification-free CRISPR/Cas12a-based diagnostic technology for SARS-CoV-2 RNA detection is presented using a smartphone camera for results readout. This method, termed Cellphone-based amplification-free system with CRISPR/CAS-dependent enzymatic (CASCADE) assay, relies on mobile phone imaging of a catalase-generated gas bubble signal within a microfluidic channel and does not require any external hardware optical attachments. Upon specific detection of a SARS-CoV-2 reverse-transcribed DNA/RNA heteroduplex target (orf1ab) by the ribonucleoprotein complex, the transcleavage collateral activity of the Cas12a protein on a Catalase:ssDNA probe triggers the bubble signal on the system. High analytical sensitivity in signal detection without previous target amplification (down to 50 copies µL-1) is observed in spiked samples, in ≈71 min from sample input to results readout. With the aid of a smartphone vision tool, high accuracy (AUC = 1.0; CI: 0.715 - 1.00) is achieved when the CASCADE system is tested with nasopharyngeal swab samples of PCR-positive COVID-19 patients.

2.
Hepatol Commun ; 5(3): 434-445, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34553511

RESUMO

Coronavirus disease 2019 (COVID-19) is associated with adverse outcomes, including need for invasive mechanical ventilation and death in people with risk factors. Liver enzyme elevation is commonly seen in this group, but its clinical significance remains elusive. In this study, we calculated the Fibrosis-4 (FIB-4) score for a cohort of hospitalized patients with COVID-19 and assessed its association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, inflammatory cytokine levels, and clinical outcome. A total of 202 hospitalized participants who tested positive for SARS-CoV-2 by nasopharyngeal sampling were included in this analysis. FIB-4 was calculated for each participant using the alanine aminotransferase, aspartate aminotransferase, age, and platelet count. We evaluated the association between FIB-4 and mortality using both multivariate logistic regression and Cox proportional hazards model. Correlations between FIB-4 and SARS-CoV-2 RNA and cytokine levels were evaluated using the Spearman test. Among the 202 participants, 22 died. The median FIB-4 in participants who survived and died were 1.91 and 3.98 (P < 0.001 by Mann-Whitney U test), respectively. Each one-unit increment in FIB-4 was associated with an increased odds of death (odds ratio, 1.79; 95% confidence interval, 1.36, 2.35; P < 0.001) after adjusting for baseline characteristics including sex, body mass index, hypertension, diabetes, and history of liver diseases. During hospitalization, FIB-4 peaked and then normalized in the survival group but failed to normalize in the death group. FIB-4 was positively correlated with the level of SARS-CoV-2 viral load and monocyte-associated cytokines, especially interleukin-6 and interferon gamma-induced protein 10. Conclusion: FIB-4 is associated with mortality in COVID-19, independent of underlying conditions including liver diseases. FIB-4 may be a simple and inexpensive approach to risk-stratify individuals with COVID-19.

3.
Kidney Int Rep ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34541422

RESUMO

Introduction: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19-associated AKI. Methods: This is a case-control study among two independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. Cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes criteria; controls had no AKI. Metabolites were measured by liquid chromatography - mass spectrometry. Results: Fourteen cases and 14 controls were included from Boston, and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio, seen with impaired NAD+ biosynthesis, was present in cases at each location and pooled across locations (median [IQR]: 1.34 [0.59-2.96] in cases, 0.31 [0.13-1.63] in controls, p=0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2/28 in Boston, 0/18 in Birmingham). Conclusion: Urinary metabolites spanning multiple biochemical pathways differentiate AKI vs. non-AKI in patients hospitalized with COVID-19, and suggest a conserved impairment in NAD+ biosynthesis which may present a novel therapeutic target to mitigate COVID-19-associated AKI.

4.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467988

RESUMO

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Assuntos
COVID-19/imunologia , Interferon Tipo I/imunologia , Interferon gama/imunologia , Interferons/imunologia , COVID-19/sangue , Quimiocinas/sangue , Citocinas/sangue , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Interferon gama/sangue , Interferon gama/genética , Interferons/sangue , Leucócitos Mononucleares/imunologia , SARS-CoV-2/isolamento & purificação
5.
Clin Infect Dis ; 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34363462

RESUMO

The impact of COVID19 vaccination on viral characteristics of breakthrough infections is unknown. In this prospective cohort study, incidence of SARS-CoV-2 infection decreased following vaccination. Although asymptomatic positive tests were observed following vaccination, higher cycle thresholds, repeat negative tests and inability to culture virus raises questions about their clinical significance.

6.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34433692

RESUMO

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.


Assuntos
COVID-19/etiologia , Linfócitos T Reguladores/fisiologia , Adulto , Idoso , Linfócitos T CD4-Positivos/virologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/virologia , Interleucina-18/genética , Interleucina-18/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Linfócitos do Interstício Tumoral/fisiologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/virologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Clin Infect Dis ; 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34245255

RESUMO

The clinical significance of SARS CoV-2 RNA in stool remains uncertain. We found that extrapulmonary dissemination of infection to the gastrointestinal (GI) tract, assessed by the presence of SARS-CoV-2 RNA in stool, is associated with decreased COVID-19 survival. Measurement of SARS-CoV-2 RNA in stool may have utility for clinical risk assessment.

9.
J Infect Dis ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34293137

RESUMO

BACKGROUND: Sex differences in vulnerability to and severity of SARS-CoV-2 infection have been described in non-pregnant populations. ACE2 and TMPRSS2, host molecules required for viral entry, are regulated by sex steroids and expressed in the placenta. We sought to investigate whether placental ACE2 and TMPRSS2 expression vary by fetal sex and in the presence of maternal SARS-CoV-2 infection. METHODS: Placental ACE2 and TMPRSS2 were quantified in 68 pregnant individuals (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. Maternal SARS-CoV-2 status was determined by nasopharyngeal RT-PCR. Placental SARS-CoV-2 viral load was quantified. RTqPCR was performed to quantify expression of ACE2 and TMPRSS2 relative to the reference gene YWHAZ. Western blots were performed on placental homogenates to quantify protein levels. The impact of fetal sex and SARS-CoV-2 exposure on ACE2 and TMPRSS2 expression was analyzed by 2-way ANOVA. RESULTS: SARS-CoV-2 virus was undetectable in all placentas. Maternal SARS-CoV-2 infection impacted TMPRSS2 placental gene and protein expression in a sexually dimorphic fashion (2-way ANOVA interaction p-value: 0.002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on placental ACE2 gene or protein expression. Placental TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman's ρ=0.54, p=0.02) but not females (ρ=0.23, p=0.34) exposed to maternal SARS-CoV-2. CONCLUSIONS: Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection. These findings may have implications for offspring vulnerability to placental infection.

10.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196300

RESUMO

BACKGROUNDSARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive.METHODSWe evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR-based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform.RESULTSThis study included 300 participants with nucleic acid test-confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4-25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5-10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways.CONCLUSIONThese results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.FUNDINGMark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).


Assuntos
COVID-19/sangue , COVID-19/virologia , SARS-CoV-2 , Viremia/sangue , Viremia/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Pandemias , Prognóstico , Proteoma/metabolismo , Proteômica , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Internalização do Vírus
11.
Clin Infect Dis ; 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34117753

RESUMO

BACKGROUND: Development of HIV remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern ART regimens and timing of ART initiation may impact this outcome. METHODS: ACTG A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon two successive viral loads ≥1,000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies. RESULTS: Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of chronic-treated and none of early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens while 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at post-treatment interruption week 12 (chronic vs early: 2% vs 9%, P=0.0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants re-suppressed after ART re-initiation. CONCLUSIONS: Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.

12.
AIDS ; 35(13): 2225-2227, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34127579

RESUMO

Clinical trials including an analytical treatment interruption (ATI) are vital for evaluating the efficacy of novel strategies for HIV remissions. We briefly describe an interactive tool for predicting viral rebound timing in ATI trials and the impact of posttreatment controller (PTC) definitions on PTC frequency estimates. A 4-week viral load threshold of 1000 cps/ml provides both high specificity and sensitivity for PTC detection. PTC frequency varies greatly based on the definition of a PTC.

13.
Genet Epidemiol ; 45(7): 685-693, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34159627

RESUMO

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome-wide association studies (GWAS), we looked at the association between whole-genome sequencing (WGS) data of the virus and COVID-19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single-stranded SARS-CoV-2 genomes of COVID-19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome-wide significance (p values of 4.09e-09 and 4.41e-23, respectively), though only 25,088 bp remained significant in follow-up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e-13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow-up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real-time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Brasil , Estudo de Associação Genômica Ampla , Humanos , Mutação , Filogenia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética
14.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060478

RESUMO

A small percentage of people living with HIV-1 can control viral replication without antiretroviral therapy (ART). These patients are called elite controllers (ECs) if they are able to maintain viral suppression without initiating ART and posttreatment controllers (PTCs) if they control HIV replication after ART has been discontinued. Both types of controllers may serve as a model of a functional cure for HIV-1 but the mechanisms responsible for viral control have not been fully elucidated. In this review, we highlight key lessons that have been learned so far in the study of ECs and PTCs and their implications for HIV cure research.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/metabolismo , Humanos
15.
Nat Commun ; 12(1): 3922, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188039

RESUMO

Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the host pathways involved in post-ART HIV control. Here we report plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-remission using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. These signatures remain significant after adjusting for key demographic and clinical confounders. We also report mechanistic links between some of these biomarkers and HIV latency reactivation and/or myeloid inflammation in vitro. Finally, machine learning algorithms, based on selected sets of these biomarkers, predict time-to-viral-rebound with 74% capacity and probability-of-viral-remission with 97.5% capacity. In summary, we report non-invasive plasma biomarkers, with potential functional significance, that predict both the duration and probability of HIV remission after treatment interruption.


Assuntos
Biomarcadores/sangue , Infecções por HIV/sangue , Suspensão de Tratamento , Adulto , Antirretrovirais/administração & dosagem , Estudos de Coortes , DNA Viral/sangue , Feminino , Glicômica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Inflamação , Macrófagos/imunologia , Masculino , Metabolômica , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , RNA Viral/sangue , Ativação Viral
16.
medRxiv ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34124714

RESUMO

Background: Data on pediatric COVID-19 has lagged behind adults throughout the pandemic. An understanding of SARS-CoV-2 viral dynamics in children would enable data-driven public health guidance. Methods: Respiratory swabs were collected from children with COVID-19. Viral load was quantified by RT-PCR; viral culture was assessed by direct observation of cytopathic effects and semiquantitative viral titers. Correlations with age, symptom duration, and disease severity were analyzed. SARS-CoV-2 whole genome sequences were compared with contemporaneous sequences. Results: 110 children with COVID-19 (median age 10 years, range 2 weeks-21 years) were included in this study. Age did not impact SARS-CoV-2 viral load. Children were most infectious within the first five days of illness, and severe disease did not correlate with increased viral loads. Pediatric SARS-CoV-2 sequences were representative of those in the community and novel variants were identified. Conclusions: Symptomatic and asymptomatic children can carry high quantities of live, replicating SARS-CoV-2, creating a potential reservoir for transmission and evolution of genetic variants. As guidance around social distancing and masking evolves following vaccine uptake in older populations, a clear understanding of SARS-CoV-2 infection dynamics in children is critical for rational development of public health policies and vaccination strategies to mitigate the impact of COVID-19.

17.
Ann Intern Med ; 174(8): 1151-1158, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34125574

RESUMO

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.


Assuntos
COVID-19/terapia , Pandemias , Guias de Prática Clínica como Assunto , Comitês Consultivos , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Criança , Interpretação Estatística de Dados , Aprovação de Drogas , Medicina Baseada em Evidências , Feminino , Humanos , Relações Interprofissionais , National Institutes of Health (U.S.) , Gravidez , SARS-CoV-2 , Participação dos Interessados , Estados Unidos
18.
J Infect Dis ; 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34036353

RESUMO

We analyzed the plasma levels of interferons and cytokines, and the expression of interferon-stimulated genes in peripheral blood mononuclear cells in COVID-19 patients with different disease severity. Mild patients exhibited transient type I interferon responses, while ICU patients had prolonged type I interferon responses with hyper-inflammation mediated by interferon regulatory factor 1. Type II interferon responses were compromised in ICU patients. Type III interferon responses were induced in the early phase of SARS-CoV-2 infection, even in convalescent patients. These results highlight the importance of type I and III interferon responses during the early phase of infection in controlling COVID-19 progression.

19.
J R Soc Interface ; 18(177): 20201015, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33849338

RESUMO

Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. Typically suspension of therapy is rapidly followed by rebound of viral loads to high, pre-therapy levels. Indeed, a recent study showed that approximately 90% of treatment interruption study participants show viral rebound within at most a few months of therapy suspension, but the remaining 10%, showed viral rebound some months, or years, after ART suspension. Some may even never rebound. We investigate and compare branching process models aimed at gaining insight into these viral dynamics. Specifically, we provide a theory that explains both short- and long-term viral rebounds, and post-treatment control, via a multitype branching process with time-inhomogeneous rates, validated with data from Li et al. (Li et al. 2016 AIDS 30, 343-353. (doi:10.1097/QAD.0000000000000953)). We discuss the associated biological interpretation and implications of our best-fit model. To test the effectiveness of an experimental intervention in delaying or preventing rebound, the standard practice is to suspend therapy and monitor the study participants for rebound. We close with a discussion of an important application of our modelling in the design of such clinical trials.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Humanos , Fatores de Tempo , Carga Viral
20.
Cell ; 184(10): 2605-2617.e18, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33831372

RESUMO

Many individuals mount nearly identical antibody responses to SARS-CoV-2. To gain insight into how the viral spike (S) protein receptor-binding domain (RBD) might evolve in response to common antibody responses, we studied mutations occurring during virus evolution in a persistently infected immunocompromised individual. We use antibody Fab/RBD structures to predict, and pseudotypes to confirm, that mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies we isolated from a healthy COVID-19 convalescent donor. Resistance extends to the polyclonal serum immunoglobulins of four out of four healthy convalescent donors we tested and to monoclonal antibodies in clinical use. We further show that affinity maturation is unimportant for wild-type virus neutralization but is critical to neutralization breadth. Because the mutations we studied foreshadowed emerging variants that are now circulating across the globe, our results have implications to the long-term efficacy of S-directed countermeasures.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19 , Evolução Molecular , Evasão da Resposta Imune/imunologia , Hospedeiro Imunocomprometido , Fragmentos Fab das Imunoglobulinas/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Anticorpos Neutralizantes , COVID-19/genética , COVID-19/imunologia , Feminino , Células HEK293 , Humanos , Masculino , Domínios Proteicos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...