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Benaroya Research Institute (6)
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HIPC 1 (2010) (689)
HIPC 2 (2015) (464)
HIPC 3 (2022) (151)
Icahn School of Medicine at Mount Sinai (21)
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Losada A, Izquierdo-Useros N, Aviles P, Vergara-Alert J, Latino I, Segalés J, Gonzalez SF, Cuevas C, Raïch-Regué D, Muñoz-Alonso MJ, Perez-Zsolt D, Muñoz-Basagoiti J, Rodon J, Chang LA, Warang P, Singh G, Brustolin M, Cantero G, Roca N, Pérez M, Bustos-Morán E, White K, Schotsaert M, García-Sastre A
Journal of immunology (Baltimore, Md. : 1950)
2024-04-15
PMID: 38416036
Animals
Antiviral Agents
Cytokines
Depsipeptides
HIPC 3 (2022)
Humans
Icahn School of Medicine at Mount Sinai
Immunologic Factors
Influenza A Virus, H1N1 Subtype
Interleukin-6
Mice
NF-kappa B
SARS-CoV-2
Abstract:
Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because IL-6 is one of the main cytokines involved in acute respiratory distress syndrome, the effect of plitidepsin in IL-6 secretion in different in vitro and in vivo experimental models was studied. A strong plitidepsin-mediated reduction of IL-6 was found in human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand of TLR7/8)-stimulated THP1 human monocytes, plitidepsin-mediated reductions of IL-6 mRNA and IL-6 levels were also noticed. Additionally, although resiquimod-induced binding to DNA of NF-κB family members was unaffected by plitidepsin, a decrease in the regulated transcription by NF-κB (a key transcription factor involved in the inflammatory cascade) was observed. Furthermore, the phosphorylation of p65 that is required for full transcriptional NF-κB activity was significantly reduced by plitidepsin. Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines.
Caron DP, Specht WL, Chen D, Wells SB, Szabo PA, Jensen IJ, Farber DL, Sims PA
bioRxiv : the preprint server for biology
2024-04-08
PMID: 37461466
Columbia University
HIPC 3 (2022)
Abstract:
Single-cell RNA sequencing (scRNA-seq) is invaluable for profiling cellular heterogeneity and dissecting transcriptional states, but transcriptomic profiles do not always delineate subsets defined by surface proteins, as in cells of the immune system. Cellular Indexing of Transcriptomes and Epitopes (CITE-seq) enables simultaneous profiling of single-cell transcriptomes and surface proteomes; however, accurate cell type annotation requires a classifier that integrates multimodal data. Here, we describe MultiModal Classifier Hierarchy (MMoCHi), a marker-based approach for classification, reconciling gene and protein expression without reliance on reference atlases. We benchmark MMoCHi using sorted T lymphocyte subsets and annotate a cross-tissue human immune cell dataset. MMoCHi outperforms leading transcriptome-based classifiers and multimodal unsupervised clustering in its ability to identify immune cell subsets that are not readily resolved and to reveal novel subset markers. MMoCHi is designed for adaptability and can integrate annotation of cell types and developmental states across diverse lineages, samples, or modalities.
Lopez PA, Nziza N, Chen T, Shook LL, Burns MD, Demidkin S, Jasset O, Akinwunmi B, Yonker LM, Gray KJ, Elovitz MA, Lauffenburger DA, Julg BD, Edlow AG
iScience
2024-03-15
PMID: 38444609
HIPC 3 (2022)
Massachusetts Institute of technology
Abstract:
Completion of a COVID-19 vaccination series during pregnancy effectively reduces COVID-19 hospitalization among infants less than 6 months of age. The dynamics of transplacental transfer of maternal vaccine-induced antibodies, and their persistence in infants at 2, 6, 9, and 12 months, have implications for new vaccine development and optimal timing of vaccine administration in pregnancy. We evaluated anti-COVID antibody IgG subclass, Fc-receptor binding profile, and activity against wild-type Spike and RBD plus five variants of concern (VOCs) in 153 serum samples from 100 infants. Maternal IgG1 and IgG3 responses persisted in 2- and 6-month infants to a greater extent than the other IgG subclasses, with high persistence of antibodies binding placental neonatal Fc-receptor and FcγR3A. Lowest persistence was observed against the Omicron RBD-specific region. Maternal vaccine timing, placental Fc-receptor binding capabilities, antibody subclass, fetal sex, and VOC all impact the persistence of antibodies in infants through 12 months of age.
Escalera A, Rojo-Fernandez A, Rombauts A, Abelenda-Alonso G, Carratalà J, García-Sastre A, Aydillo T
iScience
2024-03-15
PMID: 38433913
HIPC 3 (2022)
Icahn School of Medicine at Mount Sinai
Abstract:
Despite multiple research efforts to characterize coronavirus disease 2019 (COVID-19) in humans, there is no clear data on the specific role of mucosal immunity on COVID-19 disease. Here, we longitudinally profile the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal HCoV-OC43 S proteins in serum and nasopharyngeal swabs from COVID-19 patients. Results showed that specific antibody responses against SARS-CoV-2 and HCoV-OC43 S proteins can be detected in the upper respiratory tract. We found that COVID-19 patients mounted a robust mucosal antibody response against SARS-CoV-2 S with specific secretory immunoglobulin A (sIgA), IgA, IgG, and IgM antibody subtypes detected in the nasal swabs. Additionally, COVID-19 patients showed IgG, IgA, and sIgA responses against HCoV-OC43 S in the local mucosa, whereas no specific IgM was detected. Interestingly, mucosal antibody titers against SARS-CoV-2 peaked at day 7, whereas HCoV-OC43 titers peaked earlier at day 3 post-recruitment, suggesting an immune memory recall to conserved epitopes of beta-HCoVs in the upper respiratory tract.
Srivastava K, Carreño JM, Gleason C, Monahan B, Singh G, Abbad A, Tcheou J, Raskin A, Kleiner G, van Bakel H, Sordillo EM, Krammer F, Simon V
Immunity
2024-03-12
PMID: 38395697
Antibodies, Viral
Antibody Formation
COVID-19
HIPC 3 (2022)
Humans
Icahn School of Medicine at Mount Sinai
Immunization, Secondary
mRNA Vaccines
SARS-CoV-2
Vaccination
Vaccines
Abstract:
It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals. Antibody kinetics were characterized by two phases: an initial rapid decay, followed by a stabilization phase with very slow decay. Booster vaccination equalized the differences in antibody concentration between participants with and without hybrid immunity, but the peak antibody titers decreased with each successive antigen exposure. Breakthrough infections increased antibodies to similar titers as an additional vaccine dose in naive individuals. Our study provides strong evidence that SARS-CoV-2 antibody responses are long lasting, with initial waning followed by stabilization.
Sarin KY, Zheng H, Chaichian Y, Arunachalam PS, Swaminathan G, Eschholz A, Gao F, Wirz OF, Lam B, Yang E, Lee LW, Feng A, Lewis MA, Lin J, Maecker HT, Boyd SD, Davis MM, Nadeau KC, Pulendran B, Khatri P, Utz PJ, Zaba LC
JCI insight
2024-03-08
PMID: 38456511
BNT162 Vaccine
COVID-19
COVID-19 Vaccines
HIPC 3 (2022)
Humans
Lupus Erythematosus, Systemic
SARS-CoV-2
Stanford
Vaccination
Abstract:
Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.
Clark J, Hoxie I, Adelsberg DC, Sapse IA, Andreata-Santos R, Yong JS, Amanat F, Tcheou J, Raskin A, Singh G, González-Domínguez I, Edgar JE, Bournazos S, Sun W, Carreño JM, Simon V, Ellebedy AH, Bajic G, Krammer F
bioRxiv : the preprint server for biology
2024-03-01
PMID: 38464151
HIPC 3 (2022)
Icahn School of Medicine at Mount Sinai
Abstract:
Neutralizing antibodies correlate with protection against SARS-CoV-2. Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection from disease progression. Non-neutralizing antibodies cannot directly protect from infection but may recruit effector cells thus contribute to the clearance of infected cells. Also, they often bind conserved epitopes across multiple variants. We characterized 42 human mAbs from COVID-19 vaccinated individuals. Most of these antibodies exhibited no neutralizing activity in vitro but several non-neutralizing antibodies protected against lethal challenge with SARS-CoV-2 in different animal models. A subset of those mAbs showed a clear dependence on Fc-mediated effector functions. We determined the structures of three non-neutralizing antibodies with two targeting the RBD, and one that targeting the SD1 region. Our data confirms the real-world observation in humans that non-neutralizing antibodies to SARS-CoV-2 can be protective.
Aggarwal C, Ahmed H, Sharma P, Reddy ES, Nayak K, Singla M, Maheshwari D, Chawla YM, Panda H, Rai RC, Gunisetty S, Priyamvada L, Bhaumik SK, Ahamed SF, Vivek R, Bhatnagar P, Singh P, Kaur M, Dixit K, Kumar S, Gottimukkala K, Saini K, Bajpai P, Sreekanth GP, Mammen S, ...
Nature medicine
2024-03-01
PMID: 38321219
Antibodies, Viral
Child
Coinfection
Dengue
Dengue Virus
Fever
HIPC 1 (2010)
HIPC 2 (2015)
Humans
Severe Dengue
Abstract:
Dengue is a global epidemic causing over 100 million cases annually. The clinical symptoms range from mild fever to severe hemorrhage and shock, including some fatalities. The current paradigm is that these severe dengue cases occur mostly during secondary infections due to antibody-dependent enhancement after infection with a different dengue virus serotype. India has the highest dengue burden worldwide, but little is known about disease severity and its association with primary and secondary dengue infections. To address this issue, we examined 619 children with febrile dengue-confirmed infection from three hospitals in different regions of India. We classified primary and secondary infections based on IgM:IgG ratios using a dengue-specific enzyme-linked immunosorbent assay according to the World Health Organization guidelines. We found that primary dengue infections accounted for more than half of total clinical cases (344 of 619), severe dengue cases (112 of 202) and fatalities (5 of 7). Consistent with the classification based on binding antibody data, dengue neutralizing antibody titers were also significantly lower in primary infections compared to secondary infections (P ≤ 0.0001). Our findings question the currently widely held belief that severe dengue is associated predominantly with secondary infections and emphasizes the importance of developing vaccines or treatments to protect dengue-naive populations.
Sumida TS, Cheru NT, Hafler DA
Nature reviews. Immunology
2024-02-19
PMID: 38374298
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Yale University
Abstract:
The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.
Van Phan H, Tsitsiklis A, Maguire CP, Haddad EK, Becker PM, Kim-Schulze S, Lee B, Chen J, Hoch A, Pickering H, Van Zalm P, Altman MC, Augustine AD, Calfee CS, Bosinger S, Cairns C, Eckalbar W, Guan L, Jayavelu ND, Kleinstein SH, Krammer F, Maecker HT, Ozonoff A, Peters B, Rouphael N, ...
medRxiv : the preprint server for health sciences
2024-02-13
PMID: 38405760
Benaroya Research Institute
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Yale University
Abstract:
Age is a major risk factor for severe coronavirus disease-2019 (COVID-19), yet the mechanisms responsible for this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host and viral dynamics in a prospective, multicenter cohort of 1,031 patients hospitalized for COVID-19, ranging from 18 to 96 years of age. We performed blood transcriptomics and nasal metatranscriptomics, and measured peripheral blood immune cell populations, inflammatory protein expression, anti-SARS-CoV-2 antibodies, and anti-interferon (IFN) autoantibodies. We found that older age correlated with an increased SARS-CoV-2 viral load at the time of admission, and with delayed viral clearance over 28 days. This contributed to an age-dependent increase in type I IFN gene expression in both the respiratory tract and blood. We also observed age-dependent transcriptional increases in peripheral blood IFN-γ, neutrophil degranulation, and Toll like receptor (TLR) signaling pathways, and decreases in T cell receptor (TCR) and B cell receptor signaling pathways. Over time, older adults exhibited a remarkably sustained induction of proinflammatory genes (e.g., CXCL6) and serum chemokines (e.g., CXCL9) compared to younger individuals, highlighting a striking age-dependent impairment in inflammation resolution. Augmented inflammatory signaling also involved the upper airway, where aging was associated with upregulation of TLR, IL17, type I IFN and IL1 pathways, and downregulation TCR and PD-1 signaling pathways. Metatranscriptomics revealed that the oldest adults exhibited disproportionate reactivation of herpes simplex virus and cytomegalovirus in the upper airway following hospitalization. Mass cytometry demonstrated that aging correlated with reduced naïve T and B cell populations, and increased monocytes and exhausted natural killer cells. Transcriptional and protein biomarkers of disease severity markedly differed with age, with the oldest adults exhibiting greater expression of TLR and inflammasome signaling genes, as well as proinflammatory proteins (e.g., IL6, CXCL8), in severe COVID-19 compared to mild/moderate disease. Anti-IFN autoantibody prevalence correlated with both age and disease severity. Taken together, this work profiles both host and microbe in the blood and airway to provide fresh insights into aging-related immune changes in a large cohort of vaccine-naïve COVID-19 patients. We observed age-dependent immune dysregulation at the transcriptional, protein and cellular levels, manifesting in an imbalance of inflammatory responses over the course of hospitalization, and suggesting potential new therapeutic targets.
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