Publications by authors named "Akiko Iwasaki"

251 Publications

Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity.

Nature 2021 Oct 11. Epub 2021 Oct 11.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

The emergence of SARS-CoV-2 variants with mutations in major neutralizing antibody-binding sites can affect humoral immunity induced by infection or vaccination. We analysed the development of anti-SARS-CoV-2 antibody and T cell responses in previously infected (recovered) or uninfected (naive) individuals that received mRNA vaccines to SARS-CoV-2. While previously infected individuals sustained higher antibody titres than uninfected individuals post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (e.g., B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (e.g., B.1.617.2). While both groups retained neutralization capacity against all variants, plasma from previously infected vaccinated individuals displayed overall better neutralization capacity when compared to plasma from uninfected individuals that also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the impact of emerging variants on antibody neutralizing activity.
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http://dx.doi.org/10.1038/s41586-021-04085-yDOI Listing
October 2021

Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2.

Sci Immunol 2021 10 2;6(64):eabl4509. Epub 2021 Sep 2.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/sciimmunol.abl4509DOI Listing
October 2021

Viral replication in human macrophages enhances an inflammatory cascade and interferon driven chronic COVID-19 in humanized mice.

bioRxiv 2021 Sep 27. Epub 2021 Sep 27.

Chronic COVID-19 is characterized by persistent viral RNA and sustained interferon (IFN) response which is recapitulated and required for pathology in SARS-CoV-2 infected MISTRG6-hACE2 humanized mice. As in the human disease, monocytes, and macrophages in SARS-CoV-2 infected MISTRG6-hACE2 are central to disease pathology. Here, we describe SARS-CoV-2 uptake in tissue resident human macrophages that is enhanced by virus specific antibodies. SARS-CoV-2 replicates in these human macrophages as evidenced by detection of double-stranded RNA, subgenomic viral RNA and expression of a virally encoded fluorescent reporter gene; and it is inhibited by Remdesivir, an inhibitor of viral replication. Although early IFN deficiency leads to enhanced disease, blocking either viral replication with Remdesivir or the downstream IFN stimulated cascade by injecting anti-IFNAR2 in the chronic stages of disease attenuates many aspects of the overactive immune-inflammatory response, especially the inflammatory macrophage response, and most consequentially, the chronic disease itself.
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http://dx.doi.org/10.1101/2021.09.27.461948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491846PMC
September 2021

Prevention of host-to-host transmission by SARS-CoV-2 vaccines.

Lancet Infect Dis 2021 Sep 14. Epub 2021 Sep 14.

Department of Immunobiology, New Haven, CT, USA; Yale University School of Medicine, New Haven, CT, USA; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address:

As the number of individuals vaccinated against SARS-CoV-2 rises worldwide, population-level data regarding the vaccines' ability to reduce infection are being generated. Randomised trials have shown that these vaccines dramatically reduce symptomatic COVID-19; however, less is known about their effects on transmission between individuals. The natural course of infection with SARS-CoV-2 involves infection of the respiratory epithelia and replication within the mucosa to sufficient viral titres for transmission via aerosol particles and droplets. Here we discuss the available data on the existing, approved SARS-CoV-2 vaccines' capacity to reduce transmissibility by reducing primary infection, viral replication, capacity for transmission, and symptomaticity. The potential for mucosal-targeted SARS-CoV-2 vaccine strategies to more effectively limit transmission than intramuscular vaccines is considered with regard to known immunological mechanisms. Finally, we enumerate the population-level effects of approved vaccines on transmission through observational studies following clinical trials and vaccine distribution in real-world settings.
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http://dx.doi.org/10.1016/S1473-3099(21)00472-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439617PMC
September 2021

COVID-19 vaccines: Keeping pace with SARS-CoV-2 variants.

Cell 2021 09 17;184(20):5077-5081. Epub 2021 Sep 17.

National Heart and Lung Institute, Imperial College London, London, UK.

As the SARS-CoV-2 pandemic evolves, new variants continue to emerge. Some highly transmissible variants, such as Delta, also raised concerns about the effectiveness provided by current vaccines. Understanding immunological correlates of protection and how laboratory findings correspond to clinical effectiveness is imperative to shape future vaccination strategies.
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http://dx.doi.org/10.1016/j.cell.2021.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445744PMC
September 2021

Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA.

J Mol Biol 2021 Sep 3;433(21):167227. Epub 2021 Sep 3.

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA. Electronic address:

Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5'-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds.
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http://dx.doi.org/10.1016/j.jmb.2021.167227DOI Listing
September 2021

Associations of SARS-CoV-2 serum IgG with occupation and demographics of military personnel.

PLoS One 2021 30;16(8):e0251114. Epub 2021 Aug 30.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States of America.

Background: Countries across the globe have mobilized their armed forces in response to COVID-19, placing them at increased risk for viral exposure. Humoral responses to SARS-CoV-2 among military personnel serve as biomarkers of infection and provide a basis for disease surveillance and recognition of work-related risk factors.

Methods: Enzyme-linked immunosorbent assays (ELISA) were used to measure SARS-CoV-2 spike antigen-specific IgG in serum obtained from N = 988 US National Guard soldiers between April-June 2020. Occupational information, e.g. military operating specialty (MOS) codes, and demographic data were obtained via questionnaire. Plaque assays with live SARS-CoV-2 were used to assess serum neutralizing capacity for limited subjects (N = 12).

Results: The SARS-CoV-2 IgG seropositivity rate among the study population was 10.3% and significantly associated with occupation and demographics. Odds ratios were highest for those working in MOS 2T-Transportation (3.6; 95% CI 0.7-18) and 92F-Fuel specialist/ground and aircraft (6.8; 95% CI 1.5-30), as well as black race (2.2; 95% CI 1.2-4.1), household size ≥6 (2.5; 95% CI 1.3-4.6) and known COVID-19 exposure (2.0; 95% CI 1.2-3.3). Seropositivity tracked along major interstate highways and clustered near the international airport and the New York City border. SARS-CoV-2 spike IgG+ serum exhibited low to moderate SARS-CoV-2 neutralizing capacity with IC50s ranging from 1:15 to 1:280. In limited follow-up testing SARS-CoV-2 serum IgG levels remained elevated up to 7 months.

Conclusions: The data highlight increased SARS-CoV-2 seroprevalence among National Guard vs. the local civilian population in association with transportation-related occupations and specific demographics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251114PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405017PMC
September 2021

How COVID-19 has transformed my science.

Authors:
Akiko Iwasaki

Neuron 2021 10 6;109(19):3041-3044. Epub 2021 Aug 6.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address:

The COVID-19 pandemic has caused a seismic shift in my career, including its scientific focus, research approach, and efforts to communicate with non-scientists. In this NeuroView, I recount pivotal moments that have transformed the way I do science.
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http://dx.doi.org/10.1016/j.neuron.2021.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346201PMC
October 2021

Challenges in interpreting cytokine data in COVID-19 affect patient care and management.

PLoS Biol 2021 08 6;19(8):e3001373. Epub 2021 Aug 6.

Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.

Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
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http://dx.doi.org/10.1371/journal.pbio.3001373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372945PMC
August 2021

Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation.

Res Sq 2021 Jul 27. Epub 2021 Jul 27.

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.
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http://dx.doi.org/10.21203/rs.3.rs-726620/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328072PMC
July 2021

Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma: An Adaptive Immune Evasion Strategy Most Common in Microsatellite Instable Tumors.

Am J Surg Pathol 2021 09;45(9):1213-1220

Departments of Pathology.

Immune checkpoint inhibitor therapy is effective only for a subset of patients with gastric cancer. Impaired neoantigen presentation caused by deficiency of human leukocyte antigen class I (HLA-I) has been reported as a common mechanism of immune evasion which is associated with resistance to immune checkpoint blockade. To elucidate the significance of HLA-I deficiency in gastric cancer with special focus on microsatellite instable (MSI) and Epstein-Barr virus (EBV)-positive tumors, we examined HLA-I expression on tumor cells and correlated the results with clinicopathologic features, programmed death-ligand 1 (PD-L1) expression, and degree of tumor-infiltrating immune cells. This study included 58 MSI, 44 EBV-positive, and 107 non-EBV non-MSI tumors for comparison. The frequency of HLA-I deficiency (≥1% tumor cells) was significantly higher in MSI tumors (52%) compared with EBV-positive tumors (23%) and the other tumors (28%). In contrast, PD-L1 expression levels were highest in EBV-positive tumors, followed by MSI tumors, with the lowest prevalence in the other tumors in both Tumor Proportion Score and Combined Positive Score. HLA-I deficiency was significantly more frequent in advanced tumors (pT2-4) than in early tumors (pT1) in MSI and non-EBV non-MSI subtypes. In addition, the degree of CD8-positive cells infiltration was significantly reduced in HLA-I deficient tumor areas compared with HLA-I preserved tumor area within a tumor. Based on our observations, HLA-I, as well as PD-L1, should be considered as a common mechanism of immune escape especially in the MSI subtype, and therefore could be a biomarker predicting response to immune checkpoint inhibitor therapy in gastric cancer.
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http://dx.doi.org/10.1097/PAS.0000000000001779DOI Listing
September 2021

Generating hard-to-obtain information from easy-to-obtain information: Applications in drug discovery and clinical inference.

Patterns (N Y) 2021 Jul 17;2(7):100288. Epub 2021 Jun 17.

Department of Computer Science, Yale University, New Haven, CT, USA.

Often when biological entities are measured in multiple ways, there are distinct categories of information: some information is easy-to-obtain information (EI) and can be gathered on virtually every subject of interest, while other information is hard-to-obtain information (HI) and can only be gathered on some. We propose building a model to make probabilistic predictions of HI using EI. Our feature mapping GAN (FMGAN), based on the conditional GAN framework, uses an embedding network to process conditions as part of the conditional GAN training to create manifold structure when it is not readily present in the conditions. We experiment on generating RNA sequencing of cell lines perturbed with a drug conditioned on the drug's chemical structure and generating FACS data from clinical monitoring variables on a cohort of COVID-19 patients, effectively describing their immune response in great detail.
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http://dx.doi.org/10.1016/j.patter.2021.100288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276014PMC
July 2021

Kynurenic acid may underlie sex-specific immune responses to COVID-19.

Sci Signal 2021 07 6;14(690). Epub 2021 Jul 6.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.

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.
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http://dx.doi.org/10.1126/scisignal.abf8483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432948PMC
July 2021

A stem-loop RNA RIG-I agonist confers prophylactic and therapeutic protection against acute and chronic SARS-CoV-2 infection in mice.

bioRxiv 2021 Jun 17. Epub 2021 Jun 17.

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral replication in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I) dependent manner. SLR14 demonstrated remarkable protective capacity against lethal SARS-CoV-2 infection when used prophylactically and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity by inducing IFN-I responses in the absence of the adaptive immune system. In the context of infection with variants of concern (VOC), SLR14 conferred broad protection and uncovered an IFN-I resistance gradient across emerging VOC. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and for treatment of chronically infected immunosuppressed patients.
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http://dx.doi.org/10.1101/2021.06.16.448754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219094PMC
June 2021

Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2.

bioRxiv 2021 May 19. Epub 2021 May 19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 160 million infections and more than 3 million deaths worldwide. While effective vaccines are currently being deployed, the adaptive immune determinants which promote viral clearance and confer protection remain poorly defined. Using mouse models of SARS-CoV-2, we demonstrate that both humoral and cellular adaptive immunity contributes to viral clearance in the setting of primary infection. Furthermore, we find that either convalescent mice, or mice that receive mRNA vaccination are protected from both homologous infection and infection with a variant of concern, B.1.351. Additionally, we find this protection to be largely mediated by antibody response and not cellular immunity. These results highlight the protective capacity of antibodies generated to both vaccine and natural infection.

One-sentence Summary: Defining the roles of humoral and cellular adaptive immunity in viral clearance and protection from SARS-CoV-2 and a variant of concern.
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http://dx.doi.org/10.1101/2021.05.19.444825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142653PMC
May 2021

Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus.

J Exp Med 2021 07 21;218(7). Epub 2021 May 21.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT.

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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http://dx.doi.org/10.1084/jem.20191766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144942PMC
July 2021

infection induces cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein.

medRxiv 2021 May 12. Epub 2021 May 12.

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 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.
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http://dx.doi.org/10.1101/2021.05.10.21256855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132281PMC
May 2021

Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.

Res Sq 2021 May 5. Epub 2021 May 5.

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.
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http://dx.doi.org/10.21203/rs.3.rs-405958/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132249PMC
May 2021

Diverse functional autoantibodies in patients with COVID-19.

Nature 2021 07 19;595(7866):283-288. Epub 2021 May 19.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses. Although pathological innate immune activation is well-documented in severe disease, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.
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http://dx.doi.org/10.1038/s41586-021-03631-yDOI Listing
July 2021

Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface.

Med (N Y) 2021 May 30;2(5):591-610.e10. Epub 2021 Apr 30.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.

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 . To better understand potential immune mechanisms shielding placental cells from infection , 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.
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http://dx.doi.org/10.1016/j.medj.2021.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084634PMC
May 2021

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.

Cell Rep Med 2021 May 3;2(5):100288. Epub 2021 May 3.

Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA.

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.
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http://dx.doi.org/10.1016/j.xcrm.2021.100288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091032PMC
May 2021

Delayed production of neutralizing antibodies correlates with fatal COVID-19.

Nat Med 2021 07 5;27(7):1178-1186. Epub 2021 May 5.

Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.

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.
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http://dx.doi.org/10.1038/s41591-021-01355-0DOI Listing
July 2021

B cells join T cell clusters in the host response to recurrent herpes simplex virus 2 infection.

J Clin Invest 2021 05;131(9)

Department of Dermatology and.

Recurrent genital herpes lesions are infiltrated by various leukocytes, yet the role of B cell subsets in this process is unknown. In this issue of the JCI, Ford et al. describe the presence and antibody-secreting role of local B cell populations in herpes simplex virus 2 (HSV-2) recurrent lesions. The authors analyzed a comprehensive array of sequential skin biopsy specimens from HSV-2-infected patients over time and at various stages of infection. Using immunofluorescence and in situ hybridization, the authors show the presence of rare IgD+ naive B cells and IgG-expressing antibody-secreting cells (ASCs) in recurrent HSV-2 lesions embedded in CD4+ T cell-rich dermal immune infiltrates, levels of which transiently increase during lesion reactivation and healing. Notably, local increases in HSV-2-specific antibodies in recurrent lesions were detected, whereas serum HSV-2 antibody levels remained stable. Future research is needed to understand the precise role of these tissue-visiting B cells in disease resolution.
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http://dx.doi.org/10.1172/JCI148300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087191PMC
May 2021

Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

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.
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http://dx.doi.org/10.1101/2021.03.24.21253992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010761PMC
March 2021

Clinical characteristics and outcomes for 7,995 patients with SARS-CoV-2 infection.

PLoS One 2021 31;16(3):e0243291. Epub 2021 Mar 31.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut, United States of America.

Objective: Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2.

Design: This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository.

Setting: Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas.

Populations: The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020.

Main Outcome And Performance Measures: Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support.

Results: Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 2152 (99.9%) had a discharge disposition at the end of the study period. Of these, 329 (15.3%) required invasive mechanical ventilation and 305 (14.2%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 80.7 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups.

Conclusions: This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243291PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011821PMC
April 2021

A humanized mouse model of chronic COVID-19 to evaluate disease mechanisms and treatment options.

Res Sq 2021 Mar 17. Epub 2021 Mar 17.

Coronavirus-associated acute respiratory disease, called coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More than 90 million people have been infected with SARS-CoV-2 and more than 2 million people have died of complications due to COVID-19 worldwide. COVID-19, in its severe form, presents with an uncontrolled, hyperactive immune response and severe immunological injury or organ damage that accounts for morbidity and mortality. Even in the absence of complications, COVID-19 can last for several months with lingering effects of an overactive immune system. Dysregulated myeloid and lymphocyte compartments have been implicated in lung immunopathology. Currently, there are limited clinically-tested treatments of COVID-19 with disparities in the apparent efficacy in patients. Accurate model systems are essential to rapidly evaluate promising discoveries but most currently available in mice, ferrets and hamsters do not recapitulate sustained immunopathology described in COVID19 patients. Here, we present a comprehensively humanized mouse COVID-19 model that faithfully recapitulates the innate and adaptive human immune responses during infection with SARS-CoV-2 by adapting recombinant adeno-associated virus (AAV)-driven gene therapy to deliver human ACE2 to the lungs of MISTRG6 mice. Our unique model allows for the first time the study of chronic disease due to infection with SARS-CoV-2 in the context of patient-derived antibodies to characterize in real time the potential culprits of the observed human driving immunopathology; most importantly this model provides a live view into the aberrant macrophage response that is thought to be the effector of disease morbidity and ARDS in patients. Application of therapeutics such as patient-derived antibodies and steroids to our model allowed separation of the two aspects of the immune response, infectious viral clearance and immunopathology. Inflammatory cells seeded early in infection drove immune-patholgy later, but this very same early anti-viral response was also crucial to contain infection.
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http://dx.doi.org/10.21203/rs.3.rs-279341/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987100PMC
March 2021

Increased SARS-CoV-2 Testing Capacity with Pooled Saliva Samples.

Emerg Infect Dis 2021 04;27(4)

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.
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http://dx.doi.org/10.3201/eid2704.204200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007323PMC
April 2021
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