bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of cross-reactive immunity following coronavirus vaccination or natural infection
Authors: Dangi Tanushree , Palacio Nicole M , Sanchez Sarah , Penaloza-MacMaster Pablo 
Published: February 2023

Abstract
SARS-CoV-2 has infected more than 100 million people worldwide. Several vaccine candidates have been deployed under emergency use authorization, but it is unclear whether a coronavirus (CoV) vaccine can protect against other CoV. To investigate this proof-of-concept, we evaluated cross-reactive immunity following vaccination with a modified vaccinia Ankara expressing SARS-CoV-1 spike protein. We first vaccinated C57BL/6 mice intramuscularly and then measured heterologous antibodies (SARS-CoV-2, OC43 and mouse hepatitis virus, MHV) by ELISA. Interestingly, the SARS-CoV-1 vaccine elicited cross-reactive antibodies that recognize these other CoV. Sera from mice immunized with the SARS-CoV-1 vaccine neutralized SARS-CoV-2 pseudovirus in vitro (5-fold greater than control naïve sera; p=0.007), and transfer of these immune sera into naïve mice provided partial protection after heterologous challenges. Similar cross-reactivity was observed following immunization with a SARS-CoV-2 vaccine, and we mapped a conserved CD8 T cell epitope in both SARS-CoV-1 and CoV-2 spike protein, allowing us to develop an MHC tetramer to track this cross-reactive response. Finally, we interrogated whether a CoV infection could elicit cross-reactive immunity. We show that an OC43 infection generated cross-reactive antibodies against SARS-CoV-2, OC43 and MHV, and conferred partial protection against MHV challenge. In summary, our findings demonstrate that cross-reactive immunity can be elicited by vaccination, providing a framework for the rational design of universal CoV vaccines. Moreover, these data suggest that prior infection with endemic CoV may provide partial protection against other CoVs.
CD8 co-receptor links T cell avidity and metabolism
Authors: Clutton Genevieve Tyndale , Weideman Ann Marie , Kallon Sallay , Xu Yinyan , Warren Joanna , Lenarcic Erik , Lin Lin , Council Olivia , Muehlbauer Michael , Mincey Adam , Hill Demitrius , Moorman Nathaniel , RolTisch  , Newgard Christopher , Bain James , Armistead Paul , Hudgens Michael , Goonetilleke Nilu 
Published: February 2023

Abstract
This study investigated the mechanistic basis behind the reported superior efficacy of high-avidity CD8 T cells. CMV and HIV are both chronic viral infections, but while CMV-specific CD8 T cells can mediate lifelong viral control, in untreated HIV infection HIV-specific CD8 T cells progressively lose function. Using in vitro studies of human cells, we show that avidity-dependent downregulation of the CD8 co-receptor directly programs metabolism, due to a novel association between CD8 and the glucose transporter GLUT1. We used flow cytometry to profile ex vivo and virus-specific CD8 T cells from HIV-infected individuals on antiretroviral therapy. Ex vivo, cells expressing low levels of CD8 (CD8dim) expressed more CD69 but less cell surface GLUT1, and took up less glucose (2-NBDG) than CD8bright T cells. Following antigen stimulation, CD3, CD8, and GLUT1 were downregulated from the cell surface in an avidity-dependent manner. CMV-specific CD8 T cells, which were of higher avidity, downregulated these proteins to a greater extent than lower-avidity HIV-specific CD8 T cells. GLUT1 downregulation strongly correlated with CD8 but not CD3 downregulation. Antibody-mediated downregulation of CD8 from the cell surface resulted in reduced glucose uptake and increased fatty acid (Bodipy) uptake, independent of CD3. Finally, CD3, CD8, and GLUT1 downregulation by HIV-specific CD8 T cells was impaired following viral escape mutations that reduced CD8 T cell avidity. We confirmed this finding in a transduction setting with a single clonal TCR. Our data reveal a novel function of the CD8 co-receptor, linking the avidity and metabolism of CD8 T cells.
Characterization of hepatitis C virus-specific Th1 and Th1-biased circulating T follicular helper CD4+ T cells that arise following pregnancy
Authors: Phelps Christopher , Walker Christopher M. , Honegger Jonathan R. 
Published: February 2023

Abstract
Chronic hepatitis C virus (HCV) infection is marked by a loss of HCV-specific CD4+ T cells and CD8+ T cell exhaustion. However, recovery of antiviral CD4+ T cells and decreased viremia occurs in some women after pregnancy. We hypothesize that recovery of HCV-specific Th1 and Tfh biased CD4+ T cell populations contributes to viral control postpartum. Here we undertook a detailed phenotypic analysis of lineage-defining chemokine receptor expression on recovering HCV-specific CD4+ T cells using tetramer staining and flow cytometry of PBMCs from 14 women with chronic HCV infection. Seven women had &gt;10-fold decreases in viremia by 3 months postpartum (3PP) (controllers) and the remaining half did not (non-controllers). At 3PP, tetramer+CD4+T cells were predominantly CXCR5+/CXCR3+/CCR6− (cTfh1) with most of the remaining HCV-specific CD4+ T cells being CXCR5−/CXCR3+/CCR6−(Th1). The proportions of cTfh1 cells within tetramer+CD4+ T cell populations were higher in controllers compared to non-controllers (median 74.3% vs. 52.8%, p=0.0262, Mann-Whitney), while the proportions of Th1 cells were higher in non-controllers (p=0.007, Mann-Whitney). Higher cTfh1 frequencies correlated with viral control (p=0.0072, Spearman). In all mothers, over 85% of HCV-specific cTfh1 cells were PD-1+. ICOS expression correlated with reduced viral control. Together, these data suggest that a shift of HCV-specific CD4+ T cell responses towards a cTfh1 phenotype contributes to the unique viral control that occurs in some women after pregnancy.
Viral and tumor immunity is enhanced in mice expressing the pro-autoimmune allele of tyrosine phosphatase Ptpn22
Authors: Orozco Robin C , Marquardt Kristi , Mowen Kerri A , Pratumchai Isaraphorn , Teijaro John R , Sherman Linda A 
Published: February 2023

Abstract
The 1858C&gt;T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W) is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases. Specifically, this alternative allele affects lymphocyte activation, toll-like receptor signaling, and cytokine production in various autoimmune contexts. Despite the importance of these inflammatory networks in pathogen and tumor clearance, the influence of PTPN22 and its pro-autoimmune allele have on viral and tumorigenic conditions is poorly defined. To interrogate these roles, we used CRISPR/Cas9 to generate mice expressing the Ptpn22 R619W molecule, which is the ortholog of R620W in humans. Using LCMV-cl13 infection and B16 tumor models, we tested the hypothesis that pleiotropic effects of Ptpn22 R619W enhances anti-viral and anti-tumor immunity. Importantly, R619W bearing mice have less tumor burden and clear chronic viral infection faster than wildtype mice. Consistent with these results, R619W mice have enhanced antigen-specific T cell activation during viral infection and more tumor infiltrating activated T cells. Also, R619W bearing mice have a more immunostimulatory cDC phenotype during disease. As this gene is expressed in all immune cells, we interrogated the role that the R619W molecule has on T cell intrinsic versus extrinsic mechanisms of T cell activation. We show an additive mechanism in which both T cell and non-T cell compartments expressing the R619W molecule cause the most T cell activation. Our results suggest that a pro-autoimmune allele can be beneficial by promoting anti-viral and anti-tumor immune responses through multiple immune cell types, and may have a protective effect in these diseases.
Age-dependent differences in the immune response to human metapneumovirus
Authors: Parks Olivia Bartlett , Lan Jie , Zhang Yu , Williams John V 
Published: February 2023

Abstract

Objective:
Human metapneumovirus (HMPV) is a leading cause of serious respiratory infection in older adults, but pathophysiology in this population is incompletely understood.

Methods:
We developed an elderly mouse model of HMPV using 72-week-old mice. Aged mice and 6-week-old mice were infected intratracheally with HMPV and euthanized at different time points to measure viral titer and cellular immune response. We also infected young v. aged macrophages in vitro to determine cytokine response.

Results:
Aged HMPV-infected mice demonstrated increased weight loss, higher clinical disease scores, increased lung histopathology, and delayed viral clearance with virus persisting in the lung through day 9 post-infection while 6-week young mice cleared infection completely by day 7. Aged mice showed a significant increase in absolute number of CD8+ T cells in bronchoalveolar lavage (BAL) and lung; however, CD8+ T cells in aged mice exhibited fewer HMPV-specific tetramer+ CD8+ cells in both BAL and lung. Most aged cells expressed two or more impairment receptors (PD1, LAG3, or TIM3). Luminex analysis of lung homogenate and BAL revealed increased Th2 and inflammatory cytokine expression in aged mice. Aged HMPV-infected peritoneal macrophages in vitro had significantly increased expression of IFNb and decreased IFNg, while bone marrow-derived macrophages had decreased IFNl expression.

Conclusions:
These findings suggest that aged mice have a dysregulated CD8+ T cell response to HMPV, increasing disease but delaying viral clearance. Altered cytokine production by aged macrophages may skew CD8+ T cell response. Future studies will investigate the specific mechanisms surrounding impaired immune response in the aged host.
Female obese mice have a higher mortality rate and altered immune responses following viral infection in comparison to wild type mice
Authors: Geerling Elizabeth , Hassert Mariah , Stone E Taylor , Steffen Tara L , Pinto Amelia K 
Published: February 2023

Abstract
A rise in adiposity in the United States has resulted in &gt;70% of adults being overweight or obese. Globally, areas that have seen a rise in obesity also have an increase in viral pathogens, resulting in a double disease burden. Studies done using influenza, hepatitis C, West Nile and dengue viruses have shown that excessive adiposity alters immune responses to vaccination. Similarly, obese individuals have a greater risk for developing COVID-19 following SARS-CoV-2 infection and a higher mortality rate than non-obese individuals. However, limited studies have been done to identify mechanisms responsible for obesity-induced impaired immune function. Based on published studies and our preliminary data, we hypothesized that obesity-associated chronic inflammation alters the immune system, enhancing susceptibility to viral diseases and hindering vaccine efficacy. To study this, we are using West Nile virus and SARS-CoV-2 in murine models of obesity. By infecting regular chow-fed (wt) and high fat diet-induced obese (ob) mice, we compared virus-specific immune responses at varying time points post infection. Results from these studies indicate that female ob mice have a higher mortality rate, dysfunctional virus-specific T cell responses and lowered efficacy of neutralizing antibodies. However, ob males do not show these differences when compared to wt males. These results demonstrate that obesity can enhance disease severity following viral infection which may have long term consequences for the generation of protective immune responses to vaccination, and sex appears to play a role in this phenomenon. Our ongoing studies are focused on determining how sex and chronic inflammation alter immune responses to these viral pathogens.
Reducing the priming dose of a SARS CoV-2 vaccine improves vaccine-elicited immunity
Authors: Sanchez Sarah , Palacio-Betancur Nicole , Dangi Tanushree , Penaloza-MacMaster Pablo 
Published: February 2023

Abstract
SARS-CoV-2 caused a global pandemic that has killed over 2 million people. While several vaccine candidates have received emergency use authorization, there is still limited vaccine availability and lack of knowledge on optimal vaccine dosing. A recent AstraZeneca vaccine study with an adenovirus vector suggested that priming with a low dose (LD) is superior than priming with a standard dose (SD). We extended these results to a murine vaccination model to further understand the mechanism of how limiting the priming dose affects vaccine-elicited immunity. We first primed C57BL/6 mice intramuscularly with an adenovirus-based vaccine expressing SARS CoV-2 spike (Ad5-spike), either with a LD (106 PFU) or a SD (109 PFU), followed by a SD boost three weeks later. An initial priming with a SD resulted in a higher magnitude of adaptive immune responses relative to an initial priming with a LD, consistent with the notion that adaptive responses are proportional to the priming antigen dose. However, T cell responses generated by a LD prime exhibited more rapid central memory differentiation, suggesting that they could display improved recall expansion following subsequent booster immunization. Interestingly, mice that were primed with a LD exhibited significantly more potent anamnestic T cell responses upon boosting, relative to mice that were primed and boosted with a SD. Antibody responses were also significantly improved in the LD/SD vaccine regimen. Overall, our data suggest that limiting the priming dose may offer a substantial long-term benefit for SARS CoV-2 vaccines. These findings may be useful for improving vaccine availability and also for the rational design of prime-boost vaccine regimens for SARS CoV-2 and other diseases.
Immune profiling of COVID-19 infection in pediatric solid organ transplantation
Authors: Ekong Udeme D , Paul Saikat , Royal Scott , Chahine Joeffrey , Yazigi Nada , Kaufman Stuart , Khan Khalid , Matsumoto Cal , Kroemer Alexander , Fishbein Thomas 
Published: February 2023

Abstract

Background:
We describe the clinical presentation & immune response to COVID-19 infection in pediatric SOT.

Method:
Medical records of COVID-19 PCR+ & seropositive patients (SP) were reviewed for details of their disease course. Blood was obtained during PCR or seropositivity for immunophenotyping. Controls were pediatric solid organ transplant (SOT) patients with negative COVID-19 (NCs) status. As induction of immunological memory is central to anti-pathogen adaptive immunity induced by infection, immunohistochemistry of liver tissue for tissue resident memory cells (TRM) was performed.

Results:
15 patients had COVID positive status (7 PCR+ & 8 SP) between March 2020 & January 2021. 4 symptomatic PCR+ patients were hospitalized for 24–72-hours & 1 symptomatic SP patient had a prolonged PICU stay. Infrequent TRM were seen in liver biopsies of PCR+ & SP patients vs. biopsies from same patients that pre-date a COVID-19+ status. Patients with COVID + status appeared to segregate into 2 groups: 1 group with activated CD4+ response, & the 2nd group lacking obvious activated CD4+ response, similar to NC patients (n=16). The PCR+ patients expressed significantly less CD4+ & CD8+ IFN-γ compared to the SP patients (p=0.009; p=0.01 respectively). Similarly, activated CD8 “EMRAs” was significantly lower in PCR+ patients compared to SP patients (p=0.01).

Conclusion:
COVID-19 infection in pediatric SOT patients is generally mild with notable increased frequency of CD8+ “EMRAs” & IFN-γ in SP patients, presumably a result of antigen-experienced cells.
Role of IL-17-EGFR axis in alleviated lung inflammation and recovery during the late phase of acute influenza virus infection
Authors: Huang William , Huang Ching-Tai , Hung Chen-Yiu , Chen Tse-Ching , Chang Chia-Shiang , Huang Yu-Lin , Chen Ting-An , Lin Yung-Chang , Lin Chun-Yen , Dutta Avijit 
Published: February 2023

Abstract
Influenza hemagglutinin (HA)-specific T-Cell-Receptor (TCR) transgenic mice sustain the influenza virus infection of an inoculum size which is fatal in wild type mice. There is a prominent IL-17 response of the HA-specific TCR transgenic CD4+ T cells in late phase of infection in the transgenic mice. We have demonstrated that the late phase IL-17 response is a de novo response of naïve T cells under guidance of the Th1 cells with influenza viral neuraminidase-activated TGF-β. There is also a late phase up-regulation of epidermal growth factor receptor (EGFR) on the transgenic CD4+ T cells in the lungs. EGFR inhibition with Gefitinib resulted in impaired sustainability of the infection of the transgenic mice. They suffered from profound body weight loss and severe disease with significant mortality. IL-17-induced EGFR-mediated signaling cascade has been documented in skin stem cells that are involved in wound healing. We will further dissect the role of this cascade in alleviation of lung inflammation and recovery from the disease during the late phase of acute influenza virus infection.
ILC1 and TRM occupy the same mucosal barrier niche and provide non-overlapping protection against infection
Authors: Vrba Sophia , Wynne-Jones Erica , Reynoso Glennys , Malo Courtney , Shannon John , Hickman Heather 
Published: February 2023

Abstract
Tissue-resident memory T cells (TRM) occupy front-line niches in barrier tissues where they are poised to rapidly respond to secondary infection. Intriguingly, even though new infections result in new populations of TRM, there appears to be enough space in the tissue to accommodate new TRM without displacing older cells. We have recently been investigating how the oral mucosa is protected against infection using a newly developed model of viral infection of the inner lip with vaccinia virus (VACV). Many orthopoxviruses including variola (the causative agent of smallpox), are thought to have invaded through the oropharyngeal mucosa. We have previously shown that group 1 innate lymphoid cells (ILCs) are the major force protecting the oral mucosa during VACV infection. ILC1s serve as the primary source for IFN-γ, which is critical to restrict viral replication. In a tissue heavily populated with ILC1s, however, it is unclear what, if any, role other tissue resident memory cells (including TRM) play during infection. We have used a combination of static and intravital imaging of Rag−/− Il12rg−/− mice and Ncr1-gfp+ reporter mice to spatially map ILC1 and TRM locations in the oral mucosa. Using Rag−/−Il12rg−/− mice and Rag− /− T-bet-ZsGreen reporter mice and adoptive transfer of virus-specific T cells, we plan to examine the function of ILC1s and TRM in the absence of the other cell population as well as when both are present. We are further exploring whether competition for local cytokines could be regulating niche occupancy. Together, these data will expand our understanding on the complex interplay between innate and adaptive immune cells during viral infection of a critical but often overlooked barrier tissue.
Activated peripheral TFH cells and MAIT cells together with increased plasma TNF-α levels mark the pathogenesis of acute dengue virus infection
Authors: Murugesan Amudhan , Anbalagan Annai Meena , Sathappan Usha Preeyaa , manickan Elanchezhiyan , Larsson Marie , Yong Yean K , Shankar Esaki M , Velu Vijayakumar 
Published: February 2023

Abstract
Dengue virus (DENV) infection has become an increasingly common public health concern in tropical and subtropical regions. Dengue infection appears to cause immune activation in a wide array of immune cells. Here, we estimated Th1 and Th2 cytokines and correlated their levels with primary and secondary dengue. We also investigated the signatures of immune activation of circulating Tfh cells and mucosal-associated invariant T (MAIT) cells in adults with confirmed acute clinical dengue virus infection. We found that IL-2, TNF-α, IL-4, and IL-10 levels were significantly elevated in patients with secondary DENV infection, whereas the level of IL-13 remained unaltered during both primary and secondary infections. No statistically significant difference was noticed with IL-12p70, IL-5, IFN-γ, and GM-CSF between the healthy controls and the primary and secondary dengue. Increase of 1 unit of TNF-α was associated with a decrease of 160 units of blood platelets. We found a higher frequency of activated Tfh cells and pTfh cells in clinical DENV infection. We also found similar activated and expanding phenotypes of MAIT cells. Our study suggests that TNF-α could play a key role in the pathogenesis of dengue along with activated pTfh cells and circulating MAIT cells in acute DENV infection.
HLA class II binding analysis for SARS-CoV-2 Spike through cell-surface MHC density assay
Authors: Miyadera Hiroko , Jiang Nian 
Published: February 2023

Abstract
Introduction: We developed MHC-peptide interaction assay that measures cell-surface expression of covalently linked peptide-MHC II complex. The utility of the assay has been validated for known CD4+ T-cell epitopes of Mycobacterium tuberculosis antigens (Miyadera et al. submitted). Using this assay (named “delta MHC (ΔMHC) assay”), we screened HLA II-binding regions in SARS-CoV-2 Spike protein to identify potential T-cell epitopes.

Method:
ΔMHC assay uses engineered fibroblast cell line that stably expresses DPA1. The cell line is transduced with pMXs-IG (Kitamura et al. 2003 Exp Hematol) that carries DPB1*05:01-peptide fusion. The assay measures cell-surface HLA expression through flow cytometry and calculates the expression levels normalized to the internal control GFP and control peptide. The peptides (15-mer) that covered the entire Spike protein were analyzed in this study.

Results:
We performed the assay for HLA-DP5 (DPA1*02:02-DPB1*05:01), which is present at high frequency in East Asian populations. Among the 211 Spike peptides analyzed, we found &gt; 8 peptides that showed strong binding to DP5, indicating that these regions might act as T-cell epitopes. Additional &gt;10 regions showed intermediate binding. Part of binding regions were overlapped with DR-restricted T-cell epitopes reported for SARS-CoV (Yang et al. 2009, Int Imm). Some of the DP5-binding regions were also overlapped with viral mutation sites of contagious variants (VOC 2020 12/01 (UK), 501Y.V2 (South Africa), B1.1.24B (Brazil)). The binding analyses of the variants for DP5 and DP0401 are underway.
Novel potent IFN-γ-inducing CD8+ T cell epitopes conserved among diverse Bovine Viral Diarrhea Virus strains
Authors: SANGEWAR NEHA Sangewar , Waghela Suryakant D , Yao Jianxiu , Sang Huldah , Bray Jocelyne M , Mwangi Waithaka 
Published: February 2023

Abstract
Studies of immune responses elicited by Bovine Viral Diarrhea Virus (BVDV) vaccines have primarily focused on the characterization of neutralizing B cell and CD4+ T cell epitopes. Despite availability of vaccines for decades, BVDV prevalence in cattle remains largely unaffected. There is limited knowledge regarding the role of BVDV-specific CD8+ T cells in immune protection and indirect evidence suggests that they play a crucial role during BVDV infection. In this study, presence of BVDV-specific CD8+ T cells that are highly cross-reactive in cattle was demonstrated. Most importantly, novel potent IFN-γ-inducing CD8+ T cell epitopes were identified from different regions of BVDV polyprotein. Eight CD8+ T cell epitopes were identified from structural BVDV antigens: Erns, E1, and E2 glycoproteins. In addition, from nonstructural BVDV antigens: Npro, NS2-3, NS4A-B, and NS5A-B, twenty CD8+ T cell epitopes were identified. Majority of these IFN-γ-inducing CD8+ T cell epitopes were found to be highly conserved among more than two hundred strains from BVDV-1 and -2 genotypes. These conserved epitopes were also validated as cross-reactive since they induced high recall IFN-γ+ CD8+ T cell responses, ex vivo, in purified CD8+ T cells from BVDV-1- and -2-immunized cattle. Altogether, twenty-eight bovine MHC I-binding epitopes were identified from key BVDV antigens that can elicit broadly reactive CD8+ T cells against diverse BVDV strains. The data presented here will lay the groundwork for the development of a contemporary CD8+ T cell-based BVDV vaccine capable of addressing BVDV heterogeneity more effectively than current vaccines.