Publications by authors named "Elana Shaw"

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

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Natural products are important precursors for antibiotic drug design. These chemical scaffolds serve as synthetic inspiration for chemists who leverage their structures to develop novel antibacterials and chemical probes. We have previously studied carolacton, a natural product macrolactone from, and discovered a simplified derivative, , that maintained apparent biofilm inhibitory activity, although the biological target was unknown.

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Article Synopsis
  • Elderly patients with severe COVID-19 showed reduced T-cell diversity and weaker immune responses compared to younger patients, highlighting age-related vulnerabilities in fighting the virus.
  • The study used advanced sequencing techniques to analyze T-cell responses in both COVID-19 patients and individuals with inborn errors of immunity who received an mRNA vaccine, revealing specific genetic associations affecting these responses.
  • Findings indicated that mRNA vaccines successfully enhanced the T-cell responses in individuals with immune deficiencies, suggesting their effectiveness even in populations that struggle to develop strong immune responses on their own.
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The Danger Model predicts that there are some molecules that no immune system can ever be fully tolerant of, namely proteins that are only transiently expressed during times of stress, infection, or injury. Among these are the danger/alarm signals themselves. Accordingly, a fleeting autoantibody response to danger signals is expected during times when they are released.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 sequentially enrolled hospitalized patients with COVID-19-associated pneumonia from Brescia, Italy using the VirScan phage-display method to characterize circulating antibodies binding to 96,179 viral peptides encoded by 1,276 strains of human viruses.

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Autoantibodies (autoAbs) that neutralize type 1 interferons (T1IFNs) are a major risk factor associated with developing critical COVID-19 disease and are most commonly found in individuals over age 70 and in patients with genetic or acquired thymic defects. Swift identification of autoAb-positive individuals may allow targeted interventions to prevent critical COVID-19 disease. Herein, we provide a workflow and protocols aimed at rapidly identifying individuals who are autoAb positive from a large cohort.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers.

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Article Synopsis
  • Pediatric COVID-19 (pCOVID-19) usually has mild symptoms, but some children may develop a serious condition called multisystem inflammatory syndrome in children (MIS-C), which can lead to significant health problems.
  • A study analyzed 110 children with COVID-19, 76 with MIS-C, and 76 healthy controls using advanced techniques to understand their immune responses and genetic factors.
  • The findings revealed different immune signatures between pCOVID-19 and MIS-C, suggesting that these conditions have distinct biological pathways, which could help in developing targeted treatments.
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SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old.

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Article Synopsis
  • Anti-type 1 interferon autoantibodies showed their highest levels and neutralization activity during the acute phase of COVID-19, but these levels dropped significantly afterward.
  • Even though binding immunoglobulin G levels decreased, many patients still retained some capacity to neutralize type 1 interferon during recovery.
  • Detecting these autoantibodies in healthy people before they get severely ill from a virus could be difficult.
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Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator () gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients.

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Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.

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Type-I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID-19). Several lines of evidence suggest that impaired type-I IFN signaling may predispose to severe COVID-19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear.

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Article Synopsis
  • * A study of 22 APS-1 patients revealed that 86% were hospitalized for COVID-19 pneumonia, with many requiring intensive care and mechanical ventilation, highlighting the severity of their condition.
  • * The presence of autoantibodies in these patients significantly increases the risk of life-threatening COVID-19 pneumonia, regardless of age, indicating a serious health concern for individuals with APS-1.
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Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease.

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The World Health Organization considers the discovery of new treatments for a top priority. Virulence attenuating combination therapy (VACT) is a pragmatic strategy to improve bacterial clearance, repurpose outmoded antibiotics, improve drug efficacy at lower doses, and reduce the evolution of resistance. and studies have shown that adding a quorum sensing inhibitor or an extracellular polymeric substance repressor to classical antibiotics synergistically improves antipseudomonal activity.

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Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures.

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Article Synopsis
  • - The study analyzed 987 patients with severe COVID-19 pneumonia and found that 101 patients had neutralizing autoantibodies (auto-Abs) against interferon-ω and various types of interferon-α at the onset of the disease.
  • - These auto-Abs interfere with the ability of type I interferons to combat SARS-CoV-2 infection in laboratory tests, but they were absent in people with mild infections and very rare in healthy individuals.
  • - The presence of these auto-Abs is linked to life-threatening COVID-19 pneumonia and appears to affect 2.6% of women and 12.5% of men, indicating a significant gender difference in this autoimmune response.
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