bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-associated variations in anti-spike antibody responses in mild SARS-CoV-2 disease
Authors: Parsons Emily , Richard Stephanie , Laing Eric , Fries Anthony , Livezey Jeffrey , Jones Milissa , Lindholm David , Mende Katrin , Rozman Julia , Ganesan Anarudha , Lalani Tahaniyat , Mody Rupal , Bazan Samantha , Saunders David , Colombo Rhonda , Colombo Christopher , Ewers Evan , Larson Derek , Maves Ryan , Berjohn Catherine , Maldonado Carlos , Simons Mark , Tribble David , Agan Brian , Pollett Simon , Burgess Timothy , Malloy Allison 
Published: August 2023

Abstract

Background
SARS-CoV-2 most severely affects older age groups, while children experience minimal disease. We measured elements of adaptive immunity in children and adults with SARS-CoV-2 to define the age-dependent viral and host response.

Methods
Participants were enrolled in the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study. Eligibility required that individuals present with COVID-19-like symptoms between March 2020 to March 2022. Magnitude of viral RNA was determined by quantitative PCR. SARS-CoV-2-specific antibodies were measured from blood with multiplex microsphere immunoassays.

Results
Serologic responses against the spike protein were measured at early and convalescent time points and compared by age, predominant infecting SARS-CoV-2 variant, and vaccination status. In those with mild disease, the seropositivity rates did not differ based on age. The magnitude of the anti-spike IgG response differed by age at early time points. Only the oldest age group differed at convalescent time points.

Conclusions
The serologic response to SAR-CoV-2 differs with age, implicating host immunity in pathogenesis. Improved understanding of the host immune response has the potential to optimize vaccine design.
Disclaimer:The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, Department of the Navy, the Department of the Air Force, the Department of Defense or the U.S. Government and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46.

This work was supported by the Defense Health Program (grant number HU00012020067) and the National Institute of Allergy and Infectious Diseases (grant number HU00011920111).
Development and Characterization of a novel humanized ACE2 mouse model to study the pathogenesis of viral lung infection by variable SARS-CoV-2 strains
Authors: Choi Chang-Yong , Villano Jason , Pekosz Andy , Jia Hongpeng 
Published: August 2023

Abstract
Despite global efforts to end the pandemic of COVID19 which has claimed millions of lives in the past few years, there is no sign of the ending in foresee near future. One of the obstacles to end the pandemic is lack of proper animal models to better understand the pathogenesis and test preventive and therapeutic strategies. To answer this call, our group created a novel humanized ACE2 mouse line by removing mouse Ace2 exon 1–9 using CRISPR/Cas9 techinque and put full length human ACE2 cDNA into the same loci. So, the human ACE2 expression is driven by mouse Ace2 promoter. Our validation results indicate that the mice express human ACE2 in a pattern similar to that of mouse Ace2 are expressed. Moreover, inoculating young adult mice (6 weeks old) with variable strains of SARS-CoV-2 (SCV2, Washington or Delta or Omicron strain, 5 × 105 PFU/mouse) by nasal instillation resulted in differential phenotypes, including viral loads in lung, trachea and nasal turbinate, weight loss, pro-inflammatory cytokine profile, although no mortality was observed in such age grouped mice. In addition, we detected brain pathological protein related to Alzheimer’s disease, Tau protein after 6 days of the viral lung infection, indicating our mouse model has the potential to be used for preclinical studies of long COVID diseases. In summary, our novel humanized ACE2 mouse line has great potential in COVID19 related research. Our ongoing research focuses on further characterize the age and strain dependent SCV2 infection of the mouse line and understanding the pathogenesis and therapeutic strategies for long COVID diseases.
Supported by grants from NIH (1R01AI148446-01A1)
pDCs contribute to HIV persistence through depleting stem-like CD8 memory T cells
Authors: Li Guangming , Ma Jianping , Yu Haisheng , Tsahouridis Rania , Lou Yaoxian , Su Lishan 
Published: August 2023

Abstract
Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferons (IFN-I) to suppress HIV-1 replication during acute infection. However, persistent activation of pDCs during chronic HIV-1 infection contributes to HIV-1 diseases. The combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and extends the life span of HIV-infected individuals. However, the persistence of aberrant inflammation and HIV-1 reservoir cells in patients under cART leads to elevated inflammatory diseases and life-long HIV-1 persistence. We report here that pDC-depletion during suppressive cART in humanized mice resolved HIV-associated inflammatory diseases, reversed T cell immune hyper-activation and exhaustion, rescued anti-HIV T cell response. Importantly, pDC-depletion under cART reduced HIV-1 reservoirs in lymphoid tissues, associating with an increase of stem-like CD8 memory T cells (Tslc) in vivo. In vitro culture system, we confirmed that anti-HIV T cell response could also be enhanced by depleting pDC, accompanied with an increase of Tslc number. We conclude that pathogenic pDCs dysregulated anti-HIV T cell response and contributed to viral reservoir persistence via induction of persistent inflammation, immune activation and a consequent exhaustion/depletion of anti-HIV T cells. Depletion of pDCs rescued Tslc, correlated with HIV control in vivo. Targeting pDC may provide a novel strategy for treating HIV/cART-associated inflammatory diseases, controlling HIV-1 reservoirs during cART, approaching a functional cure for HIV infection.
Characterization of the cell-mediated immune response to the NIH tetravalent dengue vaccine in an endemic population
Authors: Torrey Jessica , Nadeem Iqra , Gray Lauren , Omidi Nazinin , Fernandez Stefan , Whitehead Steve , Currier Jeffrey R , Friberg Heather 
Published: August 2023

Abstract
Dengue is now endemic in more than 100 countries, with Southeast Asian and Pacific Island regions being the most seriously affected. The Department of Defense has long recognized the threat of dengue and has made great contributions to understanding it. The ideal dengue vaccine will provide long-lasting protection against all four serotypes of dengue virus (DENV1-4) and will be effective in both endemic and non-endemic populations. Several tetravalent dengue vaccines are either licensed or in advanced stages of clinical development, including the live attenuated vaccine candidate developed by the NIH. The purpose of this study is to characterize the cellular immune responses to the NIH vaccine, with particular attention to the activation and memory profiles of DENV-specific T and B cell populations. Our hypothesis is that the NIH vaccine induces a durable and tetravalent DENV-specific adaptive immune response, which varies in its magnitude and phenotype over time (3 years post-vaccination) and across age strata. To assess the magnitude, breadth, and evolution of DENV-specific T and B cells following vaccination, we use a suite of different assays, including IFNγ ELISpot, memory B cell fluorospot, and flow cytometry-based assays. This study evaluates the ability of the NIH vaccine to induce durable and balanced immune responses to all four DENV serotypes, and how that compares to naturally acquired immunity.
Innate Immune Training Enhances the Reactivation of Latently Infected HIV-1 from Monocytic Cell lines
Authors: James Heera , Forbes Greta E , John Sinu P , Fraser Iain D C 
Published: August 2023

Abstract
HIV virus can persist in a latent but activatable chronic state in resting CD4+ T-cells and macrophages that are more persistent, leading to the requirement of lifelong combination antiretroviral therapy (cART). The latency of HIV-1 in macrophage cells is associated with increased chromatin condensation induced by histone methylation at HIV-1 integration sites. Innate immune training of macrophages has been shown to relieve chromosome condensation through epigenetic rewiring. We hypothesized that training of macrophages could enhance the reactivation of HIV-1 by opening the chromatin to facilitate transcription in response to Latency Reversing Agents (LRAs). We used beta-glucan, Syk inhibitor and Rutaecarpine to train the THP89GFP cell line, which is an experimental model for latently infected HIV-1 monocytes. We found that these trained THP89GFP cells have higher transcription of HIV-1 specific genes in response to PMA stimulation. To check the epigenetic changes associated with training in the proviral HIV-1 DNA of THP89GFP, we performed a chromatin immunoprecipitation for the histone mark, H3K27Ac. Consistent with the higher induction of transcription of HIV-1 genes, we observed that multiple regions of the HIV-1 LTR had higher deposition of H3K27Ac in the trained macrophages. Our studies thus show that induction of trained innate immunity may be a viable approach to the reactivation of latently infected HIV-1. This finding supports the hypothesis that innate immune training stimuli could be developed as novel candidates for enhancing reactivation of latently infected HIV-1, which may facilitate elimination of macrophage reservoirs.
This work was supported by the Intramural Research Program of NIAID, NIH
This work was supported by the Intramural Research Program of NIAID, NIH and Office of AIDS research.
Longitudinal analysis of the LA-SPARTA cohort of high-risk individuals after SARS-CoV-2 infection and vaccination
Authors: Jenkins Meagan M , Tran Donna Phan , Flores Evelyn A , Kupferwasser Deborah , Pickering Harry , Zheng Ying , Gjertson David W , Ross Ted M , Schaenman Joanna M , Miller Loren G , Yeaman Michael R , Reed Elaine F 
Published: August 2023

Abstract
Questions remain regarding correlates of risk and immune protection against SARS-CoV-2 infection and vaccination response. Thus, we prospectively enrolled 200 participants with a high risk of SARS-CoV-2 occupational exposure. Longitudinal analysis of participant exposure risks, vaccination/infection status, and symptoms were assessed at 3, 6, and 12 months, with blood and saliva collection. Quantitative ELISA assay was used to assess the serological response to the SARS-CoV-2 spike holoprotein (S), S-receptor binding domain (RBD) and nucleocapsid protein (NP). 40 of 200 (20%) participants were found to be infected via serology. Equal incidence of infection was found in healthcare and non-healthcare occupations. In those infected, only 79.5% seroconverted for NP, and 11.5% were unaware they had been infected. The antibody response to S was greater than to RBD. Additionally, Hispanic ethnicity was associated with 2-fold greater incidence of infection despite vaccination. Booster vaccination significantly increased the avidity of RBD-specific responses to variant spike proteins. No differences in avidity were found if a participant was boosted via vaccination or natural infection. Collectively, our results indicate that antibody quality and holoprotein response may reveal meaningful determinants of protection beyond RBD antibody titer alone. Additionally, determinants of infection risk may include race/ethnicity, and remain independent of comorbidity and humoral response in this cohort.
This study received funding from Center for Influenza Vaccine Research for High Risk Populations- CIVIC 75N93019C00052 (EFR), Lundquist Institute Institutional Funds (MRY), UCLA W. M. Keck Foundation COVID 19 Research Award Program (EFR), and the Community Engagement Alliance Against COVID-19 (CEAL) (MRY, EFR). The project described was supported by the National Center for Advancing Translational Sciences through the UCLA CTSI Grant UL1TR001881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding sources. MMJ is supported by the NIH grants TL 1 DK132768 and U2C DK129496.
The Dendritic Cell Strikes Back In Coxsackievirus A10 Infection
Authors: Zhang Xin , Liu Longding 
Published: August 2023

Abstract
Coxsackievirus A10 (CV-A10) is a major causative pathogen of hand, foot, and mouth diseases (HFMDs). Currently, there is no effective vaccine for CV-A10. Dendritic cells (DCs) support antiviral immunity by linking innate and adaptive immune responses. DCs stimulated with different kinds of antigens have been used in recent vaccine studies for cancer with promising results so far. Here we examined DC dynamics during CV-A10 infection to uncover how they exert their functions and elucidate the significance and value of assessing the immunogenicity and immunoprotection of dendritic cell vaccination candidates on CV-A10-infected rhesus monkeys. We found that, dendritic cells expressing the surface marker CD11c showed an abnormal biological phenotype, including the altered transcription of various immune signaling molecules and inflammatory factors associated with innate immunity after viral replication. Furthermore, these CV-A10-infected dendritic cells have the capacity to stimulate the proliferation of T cells and to enhance the release of certain functional cytokines. An adaptive immune response induced by the back-transfusion of CV-A10-infected dendritic cells was observed in donor neonatal rhesus monkeys. Collectively, these data proposed that CV-A10 infection induced a strong innate immune response in rhesus monkey DCs, performing the function of the antigen-presenting response of this cell, which may provide helpful insights into the pathogenesis and vaccine research of CV-A10 in human.
PIM kinases are essential for CD8 T cell effector function and metabolism during chronic viral infection
Authors: Brown Ashley Kaye , Shen Jian , Volberding Peter J , Cui Weiguo 
Published: August 2023

Abstract
The production of IL-21 by CD4 T cells is one mechanism by which CD8 T cells can sustain their effector functions, including increased metabolic demand, during chronic viral infection. However, signaling cascades downstream of IL-21 that control effector function in CD8 T cells remain incompletely understood. One such set of targets are the PIM kinases. This family of serine/threonine kinases functions downstream of IL-21 via JAK-STAT signaling and are involved in diverse cellular processes. Treatment of activated CD8 T cells with IL-21 induces expression of PIM1 kinase and phosphorylation of its targets S6T372, 4EBPT37/42, and BADS112, which promote transcription and inhibit apoptosis. Using the lymphocytic choriomeningitis virus (LCMV) Clone 13 mouse model of chronic infection, we show that virus-specific effector CD8 T cells display the highest expression of Pim1 compared to exhausted and progenitor CD8 T cells at day 21 post-infection (p.i.). Infection of Pim1−/− mice with LCMV Clone 13 results in reduced virus-specific effector CD8 T cells and increased exhausted CD8 T cells at days 21–23 p.i. compared to wildtype controls. In addition, pharmacological inhibition of PIM kinases with AZD1208, a pan-PIM kinase inhibitor, in activated CD8 T cells results in compromised mitochondrial metabolism, which is essential for effector CD8 T cell function. Overall, our results suggest that PIM kinases are critical for effector CD8 T cell differentiation, function, and metabolism in the control of chronic viral infection.
Supported by grants from NIH (R01 AI148403) and by an award from the Medical College of Wisconsin Center for Immunology.
Beta cell expression of ST8Sia6 protects from autoimmune diabetes in the murine NOD model
Authors: Choe Justin , Rajcula Matthew , Hammer Brady , Mai Elissa , Shapiro Michael , Shapiro Virginia 
Published: August 2023

Abstract
In this study, we leveraged immunomodulatory Siglec-sialic acid interactions to protect beta-cells against autoimmune rejection in Type 1 Diabetes (T1D). Our lab previously demonstrated that the sialyltransferase ST8Sia6 generates ligands that bind the Siglec-E receptor expressed on murine islet-resident macrophages. Here, mice were engineered to express ST8Sia6 in beta cells (βST mice), backcrossed to the non-obese diabetic (NOD) mouse model of T1D, and followed for disease. 60% of female littermates spontaneously developed disease by 300 days, compared to only 6% in female βST mice. Histologic analysis of pancreas sections from non-diabetic βST and littermate mice suggested a similar degree of immune infiltration in early life, but drastically reduced insulitis only in βST mice at later timepoints. This was not due to an absence of autoreactive T cells, as an anti-PD-L1 challenge resulted in similarly rapid induction of disease in both βST and littermate mice. Our genetic model allows for temporal control of ST8Sia6 expression in βST mice using the tet-off system. Treating our mice with doxycycline at 20 weeks of age resulted in persistent protection compared to age matched littermates, while the same treatment at 8 weeks of age led to similar incidence of diabetes between βST mice and littermate controls. Flow cytometric analysis of islet infiltrating immune cells from euglycemic mice at 14 weeks of age demonstrated reductions in short-lived effector CD8 T cells and increased thymically derived Tregs in βST mice compared to littermate controls. These results highlight the therapeutic potential of sialyltransferase mediated immune regulation and present a potential path toward improved curative approaches for T1D.
Supported by grants from NIH (5R21AI135858-02, 1F30DK127564)
α-GalCer administration expands virtual memory CD8+ T cells through IL-4 secretion
Authors: Xie Jia-Xun , Tai Chi , Lin Jr-Shiuan 
Published: August 2023

Abstract
Virtual memory CD8+ T (CD8+ TVM) cells, a unique subset of CD8+ T cells bearing memory phenotypes, exist in naïve and even in germ-free mice. Distinct from the conventional memory T cells, TVM cells are antigen-inexperienced but able to respond quickly in a cognate antigen-independent manner, thus could provide a broad range of innate-like protective effects. Our previous study showed that TVM cells could be expanded by type 2/interleukin-4 (IL-4) responses. Thus, we used α-galactosylceramide (α-GalCer) to selectively activate invariant natural killer T (iNKT) cells and create a type 2/IL-4 response, which in turn induced robust TVM cell expansion. We further demonstrated that CD1d molecule and NKT cells were necessary for α-GalCer-induced TVM cell expansion, but the TVM cell expansion was only partially dependent on IL-4 in this scenario. It remains unclear how IL-4 induces TVM cell expansion, and what other cytokine(s) may contribute to IL-4-independent TVM cell expansion upon α-GalCer treatment.
Among multiple cytokines induced by α-GalCer treatment, we found that in addition to IL-4, IL-15 and type I interferons (IFNs), which have been reported to participate in the development and expansion of TVM cells, were elevated in response to α-GalCer treatment in vivo. We further found that IL-4 and IL-15 but not type I IFNs drove TVM cell proliferation and expansion in vitro. Thus. we speculated that one of the factors that involves in IL-4-independent α-GalCer-induced TVM cell expansion may be IL-15. We are currently testing this hypothesis. Taken together, our results suggested that the activation of iNKT cells by α-GalCer expands TVM cell pool through IL-4 production, thus may regulate the ability of TVM cells to provide broad protection.
Supported by grants from MOST (109-2320-B-002-074-MY3), NHRI (EX110/111-11033SI) and NTU (111L7829), Taiwan
Resident memory T cells in the lymph node balance localized and systemic protection
Authors: Heim Taylor , Delclaux Ines , Schultz Austin , Lund Amanda 
Published: August 2023

Abstract
The endogenous mechanisms that protect against pathogen infection in the lymph node (LN) and LN metastasis during early tumor development remain poorly understood. Resident memory T cells (Trm), which do not circulate, provide highly localized protection to both pathogens and cancer, and correlate with better clinical outcomes. Here we track LN Trm development using models of cutaneous viral infection to determine the kinetics and requirements for their differentiation. We show that after viral skin infection, Trm form in the draining LN concurrent with their establishment at the initial site of infection in skin.
LN Trm formed specifically in LNs draining infected skin expressing cognate antigen and did not form in contralateral controls. These data supported a hypothesis that T cell egress out of infected skin through lymphatic vessels was necessary for LN Trm formation. Consistent with this hypothesis, LN Trm were absent from mice lacking dermal lymphatic vessels indicating that either fluid transport or cellular transport from the skin to the LN was necessary for the establishment of LN Trm. To decouple LN priming from T cell egress we resected infected skin days 5 and 20 post infection. Ear resection at 5 days post infection impaired Trm formation but circulating memory T cell responses were unaffected. We demonstrated that LN Trm are poised for cell killing as evidenced by constitutive expression of granzymes, and were able to protect against viral rechallenge. These findings indicate that LN Trm are poised to provide rapid, localized protection specific to the draining LN. These data may suggest that LN’s harbor populations capable of controlling regional cancer metastasis and pathogenic infections.
Supported by grants from NIH (R01CA238163)
Decreased memory persistence in Piezo1 deficient T cells ameliorates disease progression in autoimmune mouse models
Authors: Aguilar Alicia Virginia , Choi Sung Hee , Myers Jay , Kingsley Daniel T , Huang Alex Y 
Published: August 2023

Abstract
To mount a successful immune response, T cells must successfully (1) migrate from the bloodstream into secondary lymphoid organs (naïve) or inflamed tissue (effector), and (2) form an effective immunological synapse for activation. Although the molecular interactions of these processes have been well described, the emergence of novel biophysical approaches has revealed that both critical processes require mechanosensing. Previously we have demonstrated that the mechanosensitive cation channel, Piezo1, forms a complex with activated integrin LFA-1, an important regulator of T cell migration and T cell receptor-triggered T cell activation. Therefore, we hypothesized that Piezo1 deficiency in T cells would diminish T cell activation and homing. To investigate Piezo1’s role on T cell function, we have generated T cell-specific Piezo1 knockout mice (P1cKO) by crossing Piezo1-floxed mice to CD4-Cre mice. Initial studies in vitro showed that under polarizing conditions P1cKO T cells produce more Th1 and Th17 inflammatory cytokines. However, when challenged with experimental autoimmune encephalomyelitis (EAE) and Graft-vs-Host Disease (GVHD), P1cKO mice showed a significant decrease in disease phenotype. Moreover, adoptive transfer mouse models of EAE show that activated P1cKO T cell transfer fails to establish disease phenotype. Upon further investigation, we found similar numbers of P1cKO T cells at sites of inflammation early in disease, but there was a decreased persistence of effector and central memory P1cKO T cells. Taken together, our data suggests that Piezo1 plays an important in role in the development and maintenance of T cell memory pools, while potentially contributing to T cell activation and migration.
This project was supported by grants from the NIH (TL1 TR002549, T32 GM007250, T32 AI089474), the St. Baldrick’s Foundation Innovation Fund, the Theresia G. & Stuart F. Kline Family Foundation, and the Karen & Alan Krause Pediatric Immunotherapy Innovation and Education Fund.