bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex assays to determine correlation of binding and neutralizing antibodies following SARS-CoV-2 infection and vaccination
Authors: Venkateswaran Neeraja , Sarwar Jawad , Nelson William Max , Venkateswaran Kodumudi S 
Published: August 2023

Abstract
The COVID-19 pandemic has led to the rapid development of many different therapeutics and vaccines to reduce the burden of the disease. Most vaccines target the highly immunogenic spike (S) protein for generating functional immune responses to block the entry of the virus into host cells. However, the mutations in the S-protein have led to the emergence of many variants that escape the immune response. We developed two multiplex assays using Luminex® xMAP® technology to assess antibody profiles after infection and vaccination; 1) to quantify the binding antibodies against SARS-CoV2 receptor binding protein (RBD), nucleocapsid protein (NP), S1-protein (S1), and Trimer having S1, S2, and extracellular domain protein; 2) a multiplex surrogate virus neutralization antibody assay targeting CoV2 wild type and various mutant viruses. The quantitative binding assay uses the WHO standard for determining the binding antibody unit (BAU)/mL. Surrogate virus neutralization assay measures the inhibition of ACE2 protein binding to wild-type and S protein variants coupled to beads in the presence of immune or convalescent sera. We determined the negative threshold using 81 pre-pandemic serum samples collected during 2017–18. We used 116 samples collected from 45 vaccinated and 15 infected subjects for antibody quantification. Binding antibodies to RBD, S1, and trimer were higher in vaccinated individuals with minimal reactivity to NP, whereas the NP antibody response was higher in the infected individuals. We observed a direct correlation between spike protein binding and neutralizing antibodies using the two assays. We saw the most elevated neutralization antibodies against variants from individuals with breakthrough infections.
Heterologous versus homologous boosting regimens elicit qualitatively distinct, BA.5 cross reactive T cells in transplant recipients
Authors: Thompson Elizabeth A , Ngecu Wabathi , Stoddart Laila , Johnson T Scott , Chang Amy , Cascino Katherine , Alejo Jennifer , Abedon Aura T , Tobian Aaron A R , Segev Dorry , Werbel William A , Karaba Andrew H , Blankson Joel N , Cox Andrea L 
Published: August 2023

Abstract
The Omicron BA.5 subvariant of SARS-CoV-2 markedly escapes neutralizing antibodies induced by vaccination due to mutations in the Spike (S) protein. Solid organ transplant recipients (SOTRs) suffer high COVID-19 morbidity, yet show poor ancestral strain recognition after COVID-19 vaccination. CD8+ T cell responses may provide a crucial second line of defense. Therefore, it is critical to understand which vaccine regimens induce robust, conserved T cell responses. We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4 and CD8 T cell responses in SOTRs following homologous mRNA (mRNA-1273 or BNT16b2) or heterologous Ad26.COV2.S (JNJ-78436735) boosting. Homologous boosting with three mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated significantly lower pseudo-neutralization against BA.5 compared to the ancestral strain. In contrast, S-specific T cells maintained cross-reactivity against BA.5 compared to ancestral recognition. Homologous boosting induced higher polyfunctional CD4 T cells with phenotypes associated with metabolic and immunologic activation. Comparing two mRNA platforms, mRNA-1273 induced significantly higher IL-21+ peripheral T follicular helper cells and increased antibody titers compared to BNT16b2. Heterologous boosting with Ad26.COV2.S did not increase CD8 responses compared to homologous boosting, as CD8 responses were low across all individuals. These data demonstrate that boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants of concern in SOTRs, but currently available boosting strategies do not induce robust CD8 T cell responses.
U01AI138897 U54CA260491
Pre-existing immunity modulates responses to mRNA boosters
Authors: Dangi Tanushree , Sanchez Sarah , Lew Min Han , Awakoaiye Bakare , Visvabharathy Lavanya , Richner Justin , Koralnik Igor Jerome , Penaloza-MacMaster Pablo 
Published: August 2023

Abstract
mRNA vaccines have shown high efficacy in preventing severe COVID-19, but breakthrough infections, emerging variants and waning antibody levels have warranted the use of boosters. Although mRNA boosters have been widely implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we observed that lower spike-specific antibody levels before boost were associated with higher fold-increase in spike-specific antibody levels after boost, suggesting that pre-existing antibodies to SARS-CoV-2 downmodulate the immunogenicity of mRNA-based vaccines. Similar effects were observed in mice that received mRNA-based SARS-CoV-2 vaccines and HIV-1 vaccines. Our subsequent studies in mice show that pre-existing antibodies against the antigen encoded by the mRNA vaccine itself accelerate the clearance of vaccine antigen following a booster vaccination, via Fc-dependent mechanisms, limiting the amount of antigen available to prime B cell responses. These data suggest that transient downmodulation of antibody effector functions may improve the efficacy of mRNA boosters against SARS-CoV-2 and other diseases.
Start-up chart string, Northwestern University National Institute on Drug Abuse (NIDA, DP2DA051912)
Interferon-lambda modulates dendritic cell IL-10 production and CD8 T cell immunity during influenza A virus infection
Authors: Disla Lisbeth , Gong Qiaoke , Hemann Emily A 
Published: August 2023

Abstract
Influenza A virus (IAV) infection remains a major global health burden, requiring development of novel strategies to limit infection and drive durable protective immunity. Type III interferon (IFN), IFN-lambda, plays an important role in regulating IAV infection and immunity, but it’s contribution to regulating adaptive immunity remains less understood. Our previous research found mice lacking the IFN-lambda receptor (Ifnlr1−/−) are more susceptible to heterosubtypic rechallenge with influenza A virus. Ifnlr1−/− mice also have reduced effector and memory IAV-specific CD8 T cells compared to WT, highlighting a unique role for IFN-lambda in regulating protective CD8 T cell immunity against IAV. However, this defect in the CD8 T cell response was not T cell-intrinsic, but rather due to aberrant dendritic cell (DC) function in the absence of IFN-lambda signaling. RNA-Seq analysis of DC from the draining lymph nodes of mice following IAV infection revealed enhancement of an immunosuppressive network containing IL-10 in Ifnlr1−/− not present in WT. We hypothesize that IFN-lambda suppresses IL-10, playing a crucial role in regulation of protective CD8 T cell responses against IAV. Our results demonstrate IL-10 production is increased in bone marrow-derived DC (BMDC) in vitro and CD103+ DC in vivo following IAV infection in Ifnlr1−/− compared to WT. Ongoing experiments will unravel the contribution of IFN-lambda regulated IL-10 in regulation of CD8 T cell responses during IAV infection in vivo. Overall, understanding the mechanisms by which IFN-lambda signaling regulates DC function and protective CD8 T cell immunity will inform therapeutic potential of this cytokine during respiratory virus infection.
Supported by NIH grant K22 AI146141
Dissecting the role of H-2Db class I molecule in the development of brain atrophy during Theiler’s murine encephalomyelitis virus (TMEV) infection
Authors: Wininger Katheryn M , Goddery Emma , Ayasoufi Katayoun , Tritz Zachariah , Wolf Delaney , Jin Fang , Hansen Michael , Johnson Aaron J 
Published: August 2023

Abstract
Brain atrophy is a common feature of many neurological diseases as diverse as Alzheimer’s disease, cerebral palsy, Huntington’s disease, multiple sclerosis, epilepsy, encephalitis, neurosyphilis, neuroAIDS, and Covid-19 infection. We have developed a murine model of brain atrophy using the Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis. In this study, we investigated the contribution of the MHC class I molecule, H-2Db, in generating an immune response associated with the onset of brain atrophy using mice with a C57BL/6 background. The H-2DbClass I molecule not only contributed to significantly more ventricular enlargement in a T2-weighted MRI at 45 d.p.i., but this ventricular enlargement correlated to CD8 T cell infiltration. To further define the cellular and molecular mechanisms of MHC class I molecules in TMEV induced brain atrophy we investigated the cell specific contribution of brain resident antigen presenting cells (APCs) in ventricular atrophy. We developed novel bi-transgenic mouse lines with tamoxifen induced conditional ablation of the H-2Db class I molecule in Cx3CR1+ brain resident myeloid cells. Cx3CR1cre+/Db Lox P mice presented with significantly less ventricular atrophy at 45 d.p.i., compared to cre- littermates along with a decrease in CD8 T cell infiltration. These results strongly imply that antigen presentation by H-2Db on myeloid cells, at least in part is responsible for the development of brain atrophy and provided insight into the molecular mechanism of this poorly understood neuropathology.
NS103212, NS122174
Adrenergic receptors regulate T cell differentiation in viral infection and cancer
Authors: Globig Anna-Maria , Zhao Steven , Roginsky Jessica , Avina-Ochoa Natalia , Heeg Maximilian , Chaudhary Omkar , Hoffmann Filipe Araujo , Chen Dan , O’Connor Carolyn , Emu Brinda , Kaech Susan 
Published: August 2023

Abstract
CD8+ T cells are critical components of the immune reaction against viral infections and cancer and have the potential to eliminate infected or malignant cells. However, when the antigen persists, CD8+ T cells enter an exhausted state. Chronic disease can lead to increased systemic noradrenaline (NA) levels, but it is currently still unclear how NA impacts the differentiation and function of exhausted CD8+ T cells.
We here set out to characterize the effects of β adrenergic signaling on CD8+ T cells in chronic viral infection with LCMV-clone 13 and in murine cancer models. We observed that chronically infected mice had elevated systemic NA levels and CD8+ T cells expressed higher levels of the β-1 adrenergic NA receptor, Adrb1. NA impaired T cell receptor signaling of ADRB1-expressing CD8+ T cells, and reduced T cell proliferation and function. Conversely, genetic ablation of ADRB1 prevented terminal CD8+ T cell differentiation in chronic viral infection and ADRB1-blockade enhanced T cell functionality in combination with immune checkpoint blockade (ICB) in an ICB-sensitive melanoma model. Expanding these observations to an ICB-resistant model of pancreatic cancer, we found that pharmacological blockade of adrenergic receptors synergized with ICB to genetically reprogram CD8+ T cells towards a tissue resident memory T cell-like state and improved T cell functionality, resulting in decreased tumor size.
In summary, our data suggest that β adrenergic receptors represent a novel immune checkpoint that modulates CD8+ T cell differentiation and function in the context of chronic antigen exposure and that targeting adrenergic receptors may synergize with ICB in cancer patients.
AMG was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, GL 991/1-1). SZ was supported by K00CA222741. This work was supported by grants from the NIH 5 R01 CA240909 (SMK) and 5 R01 CA216101 (SMK).
Indirect IgG ELISA and serotype-specific neutralizing antibody titers are associated with protection against dengue in children in Cebu, Philippines
Authors: Odio Camila D , Daag Jedas , Crisostomo Maria Vinna , Adams Cameron , White Laura J , Deen Jacqueline , de Silva Aravinda M , Katzelnick Leah C , Ylade Michelle 
Published: August 2023

Abstract
Standard measures of dengue virus (DENV) antibodies have not been established as protective against dengue. We assess whether an indirect dengue IgG ELISA (PanBio; Brisbane, QLD, Australia) and serotype-specific neutralizing antibody titers measured by a two-dilution focus reduction neutralization test (FRNT) are associated with protection against dengue. Healthy children (n = 1,214) aged 9–14 years in Cebu, Philippines were enrolled in a prospective population-based cohort study in May – June 2017 and were tested for dengue when they reported a febrile illness through March 2020. Serum samples were collected at enrollment, and all were tested by ELISA. FRNTs were performed using the WHO DENV1–4 reference strains on a random subset to quantify serotype-specific neutralizing antibodies (nAbs). Inverse probability weighting was used to adjust for subset size. The odds of dengue as predicted by antibody measures were assessed by logistic regressions and adjusted for age, gender, and residential site. Dengue naïve children were used as the reference group in all models. The probability of dengue was 9.2% (95% CI: 4.5 – 17.9) for the naïve group, 9.5% (4.8 – 17.8) for those with ELISA &lt; 2, but 4.5% (2.8 – 7.2) for those with ELISA &gt;= 2 (p=0.04). The probability was even lower at 1.4% (0.6 – 3.1) for those with the highest DENV1–4 geometric mean titers (GMT, p = 0.0001). Pre-vaccine nAbs to DENV2 and DENV3 were protective against a homotypic dengue case (DENV2: OR 0.28, 95% CI 0.12 to 0.65; DENV3: OR 0.27, 95% CI 0.13 to 0.57), but not heterotypic dengue. We show a commercial ELISA and serotype-specific nAbs are associated with the probability of dengue, providing useful assays for use in population and vaccine trials.
This work was supported by the Philippine Department of Health, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), and NIH Extramural Grant: P01AI106695.
Identity of virus-specific and cross-reactive T cell memory to mpox
Authors: Adamo Sarah , Gao Yu , Cai Curtis , Müller Thomas R , Niessl Julia , Akhirunnesa Mily , Ljunggren Hans-Gustaf , Sällberg Matti , Bergman Peter , Ekström Anna-Mia , Grifoni Alba , Sette Alessandro , Price David A , Buggert Marcus 
Published: August 2023

Abstract
The unprecedented spread of mpox (previously known as monkeypox) in several countries worldwide has led the WHO to declare the mpox outbreak a global health emergency in 2022. T cell responses are likely to play a central role in the resolution of the mpox infection. However, the prevalence and phenotype of mpox-specific T cells have not been investigated in detail, and the extent of cross-reactive immunological memory following previous smallpox vaccination is not known. Here, we assessed T cell responses to mpox infection in n=22 convalescent patients and n=53 healthy blood donors of different age groups, using CD4- and CD8-targeted peptide pools and optimal peptides through activation-induced marker (AIM), functional, and tetramer assays. We observed considerable CD4 and CD8 T cell activation among mpox patients in response to the peptide pools. Surprisingly, we did not detect differences between age groups of non-infected donors, despite previous exposure of older individuals to smallpox vaccination. Investigation of n=3 mpox-cross-reactive immunodominant vaccinia epitopes revealed that memory cells, although present, were maintained at comparable frequencies to naïve T cell precursors in older individuals. CD8+ T cells specific for the cross-reactive epitopes were significantly expanded and acquired an effector memory phenotype of elevated T-bet and Granzyme-B levels after mpox infection. Our data demonstrate low magnitudes of cross-reactive T cells against mpox across different age groups, whereas mpox infection leads to robust induction of effector memory T cells with strong recall potential.
Supported by SNF Post-doc mobility grant (P500PB_211069)
Age upon RSV infection and epitope-specificity influence the memory differentiation of antiviral T cells
Authors: Lu Zhongyan , Turfkruyer-Husson Mathilde , DaMata Jarina , Nhan Paula , Malloy Allison M W 
Published: August 2023

Abstract

Background
Despite the high rate of respiratory syncytial virus (RSV) infection and severe symptoms in infants, subsequent infections occur, indicating impaired mucosal immune memory at early life. CD8 T cells are associated with reduced disease in human adult challenge trials and murine models, demonstrating their protective roles. However, since primary RSV infection occurs in infancy, a better understanding of the memory differentiation of RSV-specific respiratory CD8 T cells in neonates is required.

Methods
CB6F1/J mice were infected at 7, 14, 25 days of life or adulthood to characterize the RSV-specific memory T-cell development. Cells from mediastinal lymph nodes (MLN) and lungs were analyzed by flow cytometry at 7, 11, 14, and 40 days post RSV infection (dpi) after staining with fluorescent antibodies and tetramers specific for M and M2 epitopes in RSV.

Results
RSV-specific CD8 T cell responses were overall lower in neonates from peak to memory phase, but differ by epitope. At 40dpi, M-specific CD8 T cells preferentially differentiated to central-memory (CM) and resided in the MLN in both adult and neonatal mice, whereas M2-specific CD8 T cells preferentially differentiated to effector-memory (EM) and resided in the lungs in adult but not neonatal mice. Importantly, lung tissue resident memory cell differentiation was limited in early life and increased with age upon infection.

Conclusion
Our results indicate that the magnitude and memory development of RSV epitope-specific CD8 T cells differ by tissue and age at infection, suggesting that age-associated mucosal immune factors contribute to the development of RSV-specific memory T cells.

This work was supported by funding through the NIAID R01AI154619 (A.M.W.M.). Supplemental support provided by USUHS Department of Pediatrics grant PED-86-3658 (A.M.W.M.).
B cell responses to membrane-presented antigens require the function of the mechanosensitive calcium channel Piezo1
Authors: George Rachel , Sohn Haewon , Kwak Kihyuck , Torgbor Charles , Manzella-Lapeira Javier , Brzostowski Joseph , Pierce Susan K 
Published: August 2023

Abstract
It has become increasingly evident that even though B cells respond to both soluble and membrane-presented antigens in vitro, the primary mode of antigen recognition in vivo appears to be of antigens on the surfaces of antigen-presenting cells. To determine how B cells sense that an antigen is membrane associated, we investigated the role of the Piezo1 mechanosensing cation channel in human B-cell activation. We discovered that human B cells flux calcium when simply poked by a glass probe or placed on a ridged glass surface, responses that were blocked by Piezo inhibitors. Piezo1 opens in response to changes in membrane tension and we showed that B cells placed on glass but not on soft planar lipid bilayers showed increased plasma membrane tension as measured by fluorescence lifetime imaging with a membrane tension reporter. B cell calcium responses to glass surfaces and to the Piezo1 antagonist Yoda1 were independent of BCR engagement. However, critically, B cell responses to membrane-presented antigens but not to soluble anti-Ig were inhibited both by Piezo1 inhibitors and by siRNA knockdown. In the absence of Piezo-1 function B cells engaging membrane-associated anti-Ig failed to flux calcium, spread on the membrane, form an immune synapse, increase plasma membrane tension, promote actin polymerization, increase expression of CD69 or proliferate. We conclude that Piezo1 plays a pivotal role in initiation of human B cell activation to membrane antigens.
Postbaccalaureate Intramural Research Training Award - NIH OITE
Discovery of a toxin for skin immune defense in African lungfish
Authors: Salinas Irene , Posavi Marijan , Benedicenti Ottavia 
Published: August 2023

Abstract
African lungfish estivate every dry season to survive unfavorable environmental conditions. The estivation process is associated with a drastic remodeling of the skin characterized by severe inflammation, granulocyte infiltration, epithelial damage and stem cell depletion which ultimately lead to formation of a cocoon with potent antimicrobial functions. We recently identified a novel toxin molecule that can be detected in the lungfish mucus and cocoon using proteomics. There are two genes in the African lungfish genome encoding for this toxin, one with six exons and the segmented duplicated gene with five exons. The toxin is also found in the Australian lungfish genome as a single exon molecule but appears to be lost in South American lungfish. Our studies show that dermal stem cells express this toxin at the steady state. Upon estivation, toxin mRNA levels are upregulated up to 200-fold and immunofluorescence microscopy shows it co-localizes with extracellular trap markers. 3D structure modeling predicts a pore-forming delta-endotoxin with potential insecticide functions. Current experiments are trying to elucidate the biological roles of this new toxin in the lungfish skin during freshwater and estivating stages.
Elucidating the role of TCR expression in Mycosis Fungoides: A Preliminary Analysis of Skin of Color biospecimens from Howard University Department of Dermatology
Authors: James Nia , Nwade Nina , Desse Sachi , Nagarkar Akanksha , Yildiz-Altay Ummugulsum , Okoye Ginette A , Richmond Jillian M , Byrd Angel S 
Published: August 2023

Abstract
Mycosis fungoides (MF) is the most prevalent Primary Cutaneous T Cell Lymphoma, comprising up to 60% of known cases. It is primarily a disease of resident memory T-lymphocytes that undergo phenotypic changes as a result of several gene alterations including ones coding for T-cell receptor (TCR) expression. The upregulation and downregulation of TCRs may give insight into the complex etiology of MF. There is a clear discrepancy in the morbidity and mortality of MF in the skin of color (SOC) population due to a myriad of factors including delayed diagnoses, biological differences, and limited research. Differences in the physiology of skin of color can cause atypical presentations, often mimicking other pigmentary and inflammatory dermatoses, causing delays in diagnosis and higher mortality. Therefore, further investigation into the molecular physiology of MF is warranted to better understand the disease presentation, progression, and appropriate therapies for SOC patients. Previous studies have identified the most common TCRs present in predominantly White cohorts including TCRVb3, TCRVb5, TCRVb6, TCRVb7, TCRVb20 and TCRVb21. Using MF biopsies from SOC patients at Howard University Dermatology, we analyzed lesional TCR gene expression and compared it to healthy SOC patients with the goal of considering novel therapeutic targets and analyzing how these molecular findings impact the diagnosis and treatment. Preliminary data shows that TRBC1 and TRBC2 are enriched in MF SOC patients whereas TRBV7–8 was enriched in the healthy margins. Because TCRs can be used as a biomarker to identify MF, this knowledge also has the potential to aid in the early diagnosis of MF, thus improving the disparity in outcomes seen in patients of color.
Sachi Desse - recipient of the Dermatology Foundation DRSA Jillian M. Richmond - recipient of the Skin of Color Society Research Grant Angel S. Byrd - recipient of the American Skin Association Milstein Research Scholar Award for Melanoma/Non-Melanoma Skin Cancer