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1.
Commun Biol ; 4(1): 1317, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34811480

RESUMO

As Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to spread, characterization of its antibody epitopes, emerging strains, related coronaviruses, and even the human proteome in naturally infected patients can guide the development of effective vaccines and therapies. Since traditional epitope identification tools are dependent upon pre-defined peptide sequences, they are not readily adaptable to diverse viral proteomes. The Serum Epitope Repertoire Analysis (SERA) platform leverages a high diversity random bacterial display library to identify proteome-independent epitope binding specificities which are then analyzed in the context of organisms of interest. When evaluating immune response in the context of SARS-CoV-2, we identify dominant epitope regions and motifs which demonstrate potential to classify mild from severe disease and relate to neutralization activity. We highlight SARS-CoV-2 epitopes that are cross-reactive with other coronaviruses and demonstrate decreased epitope signal for mutant SARS-CoV-2 strains. Collectively, the evolution of SARS-CoV-2 mutants towards reduced antibody response highlight the importance of data-driven development of the vaccines and therapies to treat COVID-19.

2.
Environ Sci Technol ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34767339

RESUMO

Leptospirosis is an environmentally transmitted zoonotic disease caused by pathogenic Leptospira spp. that affects poor communities worldwide. In urban slums, leptospirosis is associated with deficient sanitary infrastructure. Yet, the role of sewerage in the reduction of the environmental contamination with pathogenic Leptospira has not been explored. Here, we conducted a survey of the pathogen in soils surrounding open and closed sewer sections in six urban slums in Brazil. We found that soils surrounding conventionally closed sewers (governmental interventions) were 3 times less likely to contain pathogenic Leptospira (inverse OR 3.44, 95% CI = 1.66-8.33; p < 0.001) and contained a 6 times lower load of the pathogen (0.82 log10 units difference, p < 0.01) when compared to their open counterparts. However, no differences were observed in community-closed sewers (poor-quality closings performed by the slum dwellers). Human fecal markers (BacHum) were positively associated with pathogenic Leptospira even in closed sewers, and rat presence was not predictive of the presence of the pathogen in soils, suggesting that site-specific rodent control may not be sufficient to reduce the environmental contamination with Leptospira. Overall, our results indicate that sewerage expansion to urban slums may help reduce the environmental contamination with the pathogen and therefore reduce the risk of human leptospirosis.

3.
J Infect Dis ; 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34718647

RESUMO

BACKGROUND: The underlying immunologic deficiencies enabling SARS-CoV-2 reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for COVID-19. METHODS: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigation were performed on samples from the primary and secondary infections. RESULTS: Whole viral genome sequencing and phylogenic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection. DISCUSSION: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naïve CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients.

5.
Res Sq ; 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34341786

RESUMO

The microbial populations in the gut microbiome have recently been associated with COVID-19 disease severity. However, a causal impact of the gut microbiome on COVID-19 patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. Antibiotics and other treatments during COVID-19 can potentially confound microbiome associations. We therefore first demonstrate that the gut microbiome is directly affected by SARS-CoV-2 infection in a dose-dependent manner in a mouse model, causally linking viral infection and gut microbiome dysbiosis. Comparison with stool samples collected from 97 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, paralleling our observations in the animal model. Specifically, we observed blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species in hospitalized COVID-19 patients. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data obtained from these patients suggest that bacteria translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID 19.

6.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230210

RESUMO

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Assuntos
COVID-19/imunologia , Ácido Cinurênico/imunologia , SARS-CoV-2 , Adulto , Idoso , COVID-19/sangue , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Ácido Cinurênico/sangue , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/imunologia , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/imunologia , Triptofano/metabolismo
8.
J Infect Dis ; 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34139761

RESUMO

In this study, we genotyped samples from environmental reservoirs (surface water and soil), colonized rat specimens and cases of human severe leptospirosis from an endemic urban slum in Brazil, to determine the molecular epidemiology of pathogenic Leptospira and identify pathways of leptospirosis infection. We identified a well-stablished population of Leptospira interrogans serovar Copenhageni common to human leptospirosis cases, and animal and environmental reservoirs. This finding provides genetic evidence for a potential environmental spillover pathway for rat-borne leptospirosis through the environment in this urban community and highlights the importance of environmental and social interventions to reduce spillover infections.

9.
Nat Med ; 27(7): 1178-1186, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33953384

RESUMO

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.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/mortalidade , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Portador Sadio/imunologia , Feminino , Humanos , Imunidade Humoral , Cinética , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Fatores de Tempo
10.
Med (N Y) ; 2(5): 591-610.e10, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33969332

RESUMO

Background: Pregnant women are at increased risk for severe outcomes from coronavirus disease 2019 (COVID-19), but the pathophysiology underlying this increased morbidity and its potential effect on the developing fetus is not well understood. Methods: We assessed placental histology, ACE2 expression, and viral and immune dynamics at the term placenta in pregnant women with and without respiratory severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Findings: The majority (13 of 15) of placentas analyzed had no detectable viral RNA. ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term, suggesting that low ACE2 expression may protect the term placenta from viral infection. Using immortalized cell lines and primary isolated placental cells, we found that cytotrophoblasts, the trophoblast stem cells and precursors to syncytiotrophoblasts, rather than syncytiotrophoblasts or Hofbauer cells, are most vulnerable to SARS-CoV-2 infection in vitro. To better understand potential immune mechanisms shielding placental cells from infection in vivo, we performed bulk and single-cell transcriptomics analyses and found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited robust immune responses, including increased activation of natural killer (NK) and T cells, increased expression of interferon-related genes, as well as markers associated with pregnancy complications such as preeclampsia. Conclusions: SARS-CoV-2 infection in late pregnancy is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. Funding: NIH (T32GM007205, F30HD093350, K23MH118999, R01AI157488, U01DA040588) and Fast Grant funding support from Emergent Ventures at the Mercatus Center.

11.
medRxiv ; 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34013301

RESUMO

Individuals with acute malaria infection generated high levels of antibodies that cross-react with the SARS-CoV-2 Spike protein. Cross-reactive antibodies specifically recognized the sialic acid moiety on N-linked glycans of the Spike protein and do not neutralize in vitro SARS-CoV-2. Sero-surveillance is critical for monitoring and projecting disease burden and risk during the pandemic; however, routine use of Spike protein-based assays may overestimate SARS-CoV-2 exposure and population-level immunity in malaria-endemic countries.

12.
Res Sq ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34013255

RESUMO

The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal-transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection 7 months after primary infection. To elucidate the immunological mechanisms responsible for reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses that was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we identified the development of neutralizing antibodies and humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation.

13.
Cell Rep Med ; 2(5): 100288, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33969321

RESUMO

Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.

14.
medRxiv ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33791729

RESUMO

Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient's immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.

15.
PLoS One ; 16(3): e0248025, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33657167

RESUMO

INTRODUCTION: Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW. METHODS AND FINDINGS: We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV-2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P < .01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P < .01). CONCLUSIONS: In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms.


Assuntos
Anosmia/epidemiologia , COVID-19/diagnóstico , Pessoal de Saúde/tendências , Adulto , Anosmia/diagnóstico , Anosmia/virologia , Infecções Assintomáticas/epidemiologia , COVID-19/epidemiologia , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/patogenicidade , Autorrelato , Olfato/fisiologia , Estados Unidos/epidemiologia
17.
Emerg Infect Dis ; 27(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33755009

RESUMO

We analyzed feasibility of pooling saliva samples for severe acute respiratory syndrome coronavirus 2 testing and found that sensitivity decreased according to pool size: 5 samples/pool, 7.4% reduction; 10 samples/pool, 11.1%; and 20 samples/pool, 14.8%. When virus prevalence is >2.6%, pools of 5 require fewer tests; when <0.6%, pools of 20 support screening strategies.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , COVID-19 , SARS-CoV-2/isolamento & purificação , Saliva/virologia , Manejo de Espécimes/métodos , COVID-19/diagnóstico , COVID-19/epidemiologia , Fortalecimento Institucional/métodos , Alocação de Recursos para a Atenção à Saúde , Humanos , Limite de Detecção , Alocação de Recursos/métodos , Sensibilidade e Especificidade , Estados Unidos
18.
Med (N Y) ; 2(3): 263-280.e6, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33521748

RESUMO

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.

19.
medRxiv ; 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33532791

RESUMO

Pregnant women appear to be at increased risk for severe outcomes associated with COVID-19, but the pathophysiology underlying this increased morbidity and its potential impact on the developing fetus is not well understood. In this study of pregnant women with and without COVID-19, we assessed viral and immune dynamics at the placenta during maternal SARS-CoV-2 infection. Amongst uninfected women, ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term. Term placentas from women infected with SARS-CoV-2, however, displayed a significant increase in ACE2 levels. Using immortalized cell lines and primary isolated placental cells, we determined the vulnerability of various placental cell types to direct infection by SARS-CoV-2 in vitro . Yet, despite the susceptibility of placental cells to SARS-CoV-2 infection, viral RNA was detected in the placentas of only a subset (∼13%) of women in this cohort. Through single cell transcriptomic analyses, we found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited markers associated with pregnancy complications, such as preeclampsia, and robust immune responses, including increased activation of placental NK and T cells and increased expression of interferon-related genes. Overall, this study suggests that SARS-CoV-2 is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. While this likely represents a protective mechanism shielding the placenta from infection, inflammatory changes in the placenta may also contribute to poor pregnancy outcomes and thus warrant further investigation.

20.
Am J Trop Med Hyg ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33534768

RESUMO

Leptospirosis is a zoonotic disease and a worldwide public health problem that affects mainly high-risk groups. Characterizing knowledge, attitude, and practice (KAP) among high-risk groups is important to develop appropriate prevention programs. Here, we performed a cross-sectional study among 300 visitors of a recreational forest in Malaysia to examine leptospirosis KAP and demographics. These variables were integrated to create knowledge and practice scores for each respondent. All respondents had heard about leptospirosis, and 87% of them correctly identified it as a disease. The majority of respondents had high knowledge (63%), positive attitude, and good practice (68%) toward prevention of the disease. However, there were gaps in knowledge, with 78% of the respondents indicating eating without washing hands as the major cause of leptospirosis transmission. Our final model identified that higher knowledge score was associated with higher practice score. Our results indicate that it is important to increase knowledge, especially on transmission routes of leptospirosis, among visitors in recreational areas. Moreover, more attention needs to be paid to promote good practice habits among visitors, targeting those at higher risk of being infected by leptospirosis to prevent potential outbreaks in the recreational areas.

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