bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixed origins: HIV vaccine induced Env-specific antibodies arise from naive and cross-reactive memory B cells
Authors: Kobie James , Piepenbrink Michael , Fucile Christopher , Rosenberg Alexander F. , Basu Madhubanti 
Published: January 2023

Abstract
The most potent and broad HIV envelope (Env)-specific antibodies (Abs) often when reverted to their inferred germline versions representing the naïve B cell receptor, usually fail to bind Env. This may suggest that the primary B cell population that responds to the initial Env exposure is not exclusively comprised of a naïve population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated 66 gp120 reactive mAbs from participants from HVTN105, a phase I trial testing AIDSVAX B/E (gp120 protein) combined with a DNA immunogen. In order to determine the origin of these mAb producing B cells, we used Miseq-based VH lineage tracking approach and identified several of these mAb lineages in peripheral blood prior to vaccination (pre-immune). Further, several of these pre-immune lineages also persist in the bone marrow ~8 months after the final vaccination, including within in the CD138+ long-lived plasma cell compartment. When tested by ELISA, pre-immune mAbs bound to HIV Env, with relatively lower ability than their post-vaccination forms, but showed higher reactivity than their germline form. The majority of the pre-immune lineage members were IgM, however IgG and IgA members were predominant prior to vaccination and the majority of the pre-immune lineage members exhibited somatic hypermutation. These results may indicate that the vaccine-induced Env-specific antibody lineages originated from a mixed ancestor population of naïve and cross-reactive memory cells.
A CXCR5−PD1+ T helper subset triggers excessive plasma cell differentiation and antibody responses in dengue
Authors: Gupta Nimesh , Ansari Asgar , Sachan Shilpa , Kumar Vinod , Coshic Poonam , Sood Rita , Sette Alessandro , Wig Naveet , Weiskopf Daniela , Soneja Manish , Gupta Nimesh 
Published: January 2023

Abstract
Understanding the underlying determinants of cross-reactive and weakly neutralizing antibody response in dengue virus infection will facilitate the rational development of vaccines and therapeutics. Accordingly, we investigated CD4 T cell subsets in promoting the antibody development in dengue. In longitudinal and antigen-specific analysis we demonstrate the existence of a CXCR5−PD1+ T helper (Th)-subset that co-expresses PD1/ICOS and expands robustly in dengue with warning sign and severe dengue. The magnitude of CXCR5− PD1+ Th-subset is significantly higher than the frequency of activated Tfh cells in dengue. Interestingly, this PD1+/ICOS+ phenotype is exclusively enriched in the DENV-specific CXCR3 expressing Th population. Moreover, the CXCR5−PD1+ Th-subset harbors the potential of B-cell help in terms of expressing key help factors; IL21, CD40L, IL10 and IFNγ. We further demonstrate that IgG responses to NS1 are independent of germinal center (GC) reaction and that CXCR5−PD1+ Th-subset is superior to Tfh subset in inducing plasma cell differentiation and NS1-specific IgG in autologous T-B co-cultures. The targeted gene expression analysis and antigen stimulation assay confirms unique traits in CXCR5−PD1+ Th-subset over the conventional Tfh cells in dengue. Targeting this unique CXCR5−PD1+ Th-subset might limit the excessive differentiation of plasma cells and shape the optimal antibody responses in dengue virus infection.
The Pro-autoimmune allele of tyrosine phosphatase PTPN22 enhances anti-viral and anti-tumor immunity
Authors: Orozco Robin C , Marquardt Kristi , Mowen Kerri A , Pratumchai Isaraphorn , Teijaro John R , Sherman Linda A 
Published: January 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 to clear pathogens and tumors, the influence of PTPN22, and its pro-autoimmune allele, have on viral and tumorigenic conditions is still being 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 wild-type mice. Consistent with these results, R619W mice have enhanced antigen-specific T cell activation during viral infection and increased tumor-infiltrating Th1 CD4 T cells. Additionally, we define an underlying mechanism by which Ptpn22 promotes PD-L1 expression on conventional dendritic cells (cDCs) in wild-type mice, but is abrogated in R619W mice during disease. Lastly, R619W expression in lymphocytes alone can enhance T cell activation; however, the combination of R619W expressing lymphocytes and DCs enhances T cell activation even more. 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.
Chronic viral infection promotes efficient germinal center B cell responses
Authors: Pinschewer Daniel D. , Fallet Bénédict , Hao Yi , Florova Marianna , Cornille Karen , de los Aires Alba Verge , Zubani Giulia Girelli , Ertuna Yusuf , Greiff Victor , Menzel Ulrike , Hammad Karim , Merkler Doron , Reddy Sai T. , Weill Jean-Claude , Reynaud Claude-Agnès 
Published: January 2023

Abstract
Persistent viral infections subvert key elements of adaptive immunity. To compare germinal center (GC) B cell responses in chronic and acute lymphocytic choriomeningitis virus infection we exploit activation-induced deaminase (AID) fate-reporter mice and perform adoptive B cell transfer experiments. Chronic infection yields GC B cell responses of higher cellularity than acute infection, higher memory B cell and antibody secreting cell output for longer periods of time, a better representation of the late B cell repertoire in serum immunoglobulin and higher titers of protective neutralizing antibodies. GC B cells of chronically infected mice are similarly hypermutated as those emerging from acute infection. They efficiently adapt to viral escape variants and even in hypermutation-impaired AID-mutant mice, chronic infection selects for GC B cells with hypermutated BCRs and neutralizing antibody formation. These findings demonstrate that, unlike for CD8+ T cells, chronic viral infection drives a functional, productive and protective GC B cell response.
T cell-derived XCL1 induces protective immunity against West Nile virus within the CNS
Authors: Durrant Douglas M. , Cortes Alejandro , Alvarado Marina 
Published: January 2023

Abstract
West Nile Virus (WNV) is a leading cause of mosquito-borne neuroinvasive disease in the US. Following infection, WNV can cause neuronal injury and disease. Previous studies have shown that the proper activation of virus-specific T cells results in protection from WNV infection and any associated disease. Dendritic cells (DCs) are often defined as pivotal inducers of immunity due to their role in activating immune defense mechanisms against invading pathogens. XCR1, a chemokine receptor expressed predominantly by a subset of DCs, has been shown to be essential in cross-presenting antigen and in activating anti-viral immunity. However, DCs are not readily present within the CNS and it remains unknown how DCs are recruited to the CNS during WNV encephalitis to fully activate antiviral immunity. XCL1, the ligand for XCR1, is expressed by activated T cells, DCs, macrophages, and NK cells. We hypothesize that following WNV infection, virus-specific T cells within the CNS produce XCL1 in order to recruit and stabilize their interaction with XCR1+ DCs thus ensuring their proper activation and subsequent protection against WNV encephalitis. Here we demonstrate that mice lacking XCR1+ DCs are more susceptible to WNV encephalitis, display increased neuronal cell death, as well as increased viral burden compared to control animals. In addition, in the absence of XCR1+ DCs, WNV-infected animals displayed decreased parenchymal localization of T cells within the brain compared to controls. These data indicate that XCL1-XCR1 interactions are crucial in the development of efficient anti-viral immunity. The knowledge gained from this work may then be applicable to other viral diseases of the CNS.
Characterization of platelet signature on monocytes isolated from HIV infected individuals
Authors: Suwunnakorn Sumanun , Singh Meera V. , Singh Vir B. , Palshikar Mukta , Thakar Juilee , Weber Emily A. , Maggirwar Sanjay B. 
Published: January 2023

Abstract

Background
Higher levels of platelet-monocyte complexes (PMCs) are detected in human immunodeficiency virus (HIV)-infected individuals. Such complexes are implicated in expansion of monocytes exhibiting inflammatory phenotype, and their translocation into tissues, thus promoting development of cerebrovascular and cardiovascular disorders. Here we have recruited small sub-set of HIV-infected individuals to investigate how platelets cause epigenetic changes in monocytes of HIV-infected individuals. We posit that the formation of PMCs facilitates monocyte differentiation via exchange of biomaterial between activated platelets and monocytes during HIV-infection.

Methods
We performed ATAC-seq to measure changes in chromatin accessibility from two types of monocytes, PMC-derived or non-PMC-derived, isolated from HIV-infected persons.

Results
Using ATAC-Seq data, we were able to detect distinct changes in chromatin accessibility patterns within the genomic regions of proinflammatory mediators in PMC-derived monocytes. Chromatin accessibility of inflammatory genes was dramatically increased in PMC-derived monocytes. This suggested to us a possibility of active exchange of molecules that causes such alterations in monocytes.

Conclusions
Increases in chromatin accessibility of pro-inflammatory genes occur in the PMC-derived monocytes in persons with HIV. This change is likely due to the transfer of platelet antigens to monocytes via cell-cell interaction, suggesting a novel mechanism through which platelets trigger inflammatory response in monocytes. Thus, our initial findings pave a way that has a strong diagnostic as well as therapeutic value.
Viral vaccines improve PD-1 therapy against cancer
Authors: Penaloza-MacMaster Pablo A , Chung Young Rock , Dangi Tanushree , Penaloza-MacMaster Pablo 
Published: January 2023

Abstract
Programmed cell death-1 (PD-1) therapy is effective against various types of cancer. However, only 30% of cancers respond to PD-1 therapy, highlighting the need to further improve its efficacy. In this study, we interrogated whether one could exploit the immunostimulatory properties of viral vaccines to enhance PD-1 therapy in a B16 melanoma model that is poorly responsive to PD-1 therapy. Immunization of tumor-bearing mice with clinically approved viral vaccines, such as the smallpox virus vaccine and the yellow fever virus vaccine (YFV-17D), resulted in an unprecedented improvement of PD-1 therapy. This synergistic effect on PD-1 therapy was more potent upon a secondary immunization, suggesting a positive effect of recruiting pre-existent immune memory to the tumor microenvironment. Interestingly, co-administration of viral vaccines together with PD-1 therapy did not increase tumor-specific CD8 T cell responses relative to PD-1 therapy alone. Mechanistically, the adjuvant effect of viral vaccines on PD-1 therapy seems to be dependent on innate immune responses. These findings may be important for improving the efficacy of checkpoint-based immunotherapies by exploiting the immunogenicity of viral vaccines. Altogether, our data suggest that viral vaccines could be repurposed as immunotherapy adjuvants, and that the beneficial effects of viral vaccines on PD-1 therapy can be further improved by repetitive boosting of bystander immunity.
R21 AI132848-01A1 (NIAID); IRG-15-173-21 (ACS), and the Lurie Cancer Center.
STAT1-dependent tolerance of intestinal viral infection
Authors: Sharon Andrew J , Filyk Heather A , Fonseca Nicolette M , Simister Rachel L , Yuen Wallace , Hardman Blair K , Robinson Hannah G , Seo Jung Hee , Rocha-Pereira Joana , Welch Ian , Neyts Johan , Crowe Sean A , Osborne Lisa C 
Published: January 2023

Abstract
The diverse commensal ecosystem present in the mammalian intestine requires the host immune system to maintain a tolerogenic environment. The virome is an understudied component of the microbiota which promotes intestinal homeostasis and protection from injury, but the host mechanisms that regulate tolerance to viral commensals are poorly described. The antiviral signal transducer STAT1 has previously been shown to mediate tolerance to systemic viral pathogens by suppressing adaptive immune responses and protecting the host from immunopathology, but we sought to characterize its role in the context of a commensal intestinal viral infection.
We used a persistent strain of murine norovirus (MNV CR6) to interrogate host mechanisms of viral tolerance and commensalism, as CR6 has previously been shown to promote intestinal homeostasis. While CR6 infections of wildtype mice were asymptomatic and limited to the colon, STAT1-deficient mice exhibited virus-induced weight loss and mortality accompanied by systemic viral spread, colonic bacterial dysbiosis, CD4+ T cell dysfunction and hyperaccumulation of CD8+ T cells. However, clinical manifestation of virus-induced disease in STAT1-deficient mice was independent of T cells and the bacterial microbiota. Instead, therapeutic control of viral replication was sufficient to prevent virus-induced disease despite ongoing T cell dysregulation. Collectively, our data indicate that STAT1 maintains tolerance to a viral component of the intestinal microbiota by control of viral replication rather than immunopathology, suggesting that STAT1 uses distinct strategies to tolerate pathogenic and commensal viruses.
Zika Virus Infects Primary Human Glial Cells and Results in Neuroinflammation and Cell Death
Authors: Sun Jiaren , Liang Yuejin , Hu Haitao , Zhang Biao 
Published: January 2023

Abstract
Zika virus (ZIKV) infection in humans has been linked to serious birth defects, including abnormalities of the brain and eyes. Here, we used two lines of primary human glial cells from the brain and found both are susceptible to ZIKV infection. Viral RNA abundance increased from 6 to 36 h post-infection (hpi). Both cells showed cytopathic effects with cell shedding, suspension and death at 48 hpi. We found increased mRNA levels of IL-6, IL-1b, CXCL10 (IP-10), IL-8 and CCL2 in ZIKV-infected microglial cells, as well as those of TNF-a in astrocytes. Elevated levels of CXCL10 protein were also observed in microglial cells at 48 hpi. These results suggested that glial cells may directly contribute to neuroinflammation by releasing pro-inflammatory cytokines. ZIKV infection can also activate ISGs, as evidenced by increased mRNA levels of IFN-b, OAS1, Mx1 and IFITM1 in infected microglia at 48 hpi. In addition, ZIKV can induce levels of caspase-1 and caspase-3 expression in microglia and astrocytes, respectively. These findings suggest that activation of glial cells contributes to neuroinflammation and induces distinct cell death pathways in different glial cells. Finally, we examined the antiviral effect of azithromycin in infected glial cells and found a dose-dependent effect (0, 10 and 20 uM) on viral reduction. Azithromycin treatment significantly decreased gene expression of TNF-a. Moreover, the antiviral effect of azithromycin was confirmed in mouse models of ZIKV infection. Collectively, our study demonstrated that ZIKV can infect primary human glial cells, leading to inflammatory responses and cell death. Azithromycin treatment inhibits viral load in glial cells and alleviate neuroinflammation during ZIKV infection.
LncRNA HOTAIRM1 promotes the immunosuppressive functions of MDSCs through upregulating HOXA1 expression during chronic HCV infection
Authors: Yao Zhi Q , Thakuri Bal Krishan Chand , Zhang Jinyu 
Published: January 2023

Abstract
HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that is critical for the myeloid cell development by targeting HOXA1. We have previously shown that myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that have immunosuppressive functions. However, the role and mechanisms of HOTAIRM1 in the differentiation and function of MDSCs in the setting of viral infection remain elusive. In this study, we demonstrated that HOTAIRM1 and its target gene HOXA1 were upregulated and closely associated with the expression of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and signal transducer and activator of transcription 3 (STAT3) in myeloid cells derived from individuals with chronic hepatitis C virus (HCV) infection. We further revealed that HCV-associated exosomes could induce HATAIRM1 and HOXA1 expression via the miRNA-mediated signaling pathway. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy myeloid cells promoted MDSC differentiation and suppressive functions, evidenced by an increased frequency of MDSCs, expression of immunosuppressive molecules, and inhibition of co-cultured CD4 T cells to produce IFN-γ. Conversely, silencing HOTAIRM1 or HOXA1 expression in HCV myeloid cells partially restored the frequencies of MDSCs, the expressions of their suppressive molecule, and the IFN-γ production in co-cultured T cells. Taken together, this study reveals that HOTAIRM1-HOXA1 enhances the immunosuppressive function of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.
MicroRNA-92a controls the balance between inflammatory and regulatory T cells in CNS autoimmunity
Authors: Fujiwara Mai , Raheja Radhika , Garo Lucien P , Ajay Amrendra K , Saxena Shrishti , Gandhi Roopali , Weiner Howard L , Gopal Murugaiyan 
Published: January 2023

Abstract
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are mediated by dysregulated autoreactive T cell responses in the central nervous system (CNS). This dysregulation consists of an imbalance between inflammatory T helper cells, such as Th17 cells, and Foxp3+ T regulatory cells (Tregs). MicroRNAs (miRNAs), a class of small non-coding RNAs, are known to play a key role in immune function, and to be dysregulated in EAE and MS. However, identifying specific miRNA pathways that directly connect clinical activity with immune mechanisms in CNS autoimmunity has been a challenge. Previous work has identified miR-92a as one of the most significantly elevated miRNAs in the sera of MS patients, which positively correlates with neurological symptoms and brain atrophy. We now report a major functional role for miR-92a in CNS autoimmunity. MiR-92a is increased during EAE, and its loss strikingly attenuates clinical disease. This attenuation is accompanied by reduced Th17 and increased Treg cells in the CNS. Mechanistically, we found that T cell-intrinsic miR-92a inhibits the development and function of Treg cells while promoting those of Th17 cells by targeting Foxo1, a key transcription factor in T helper cell biology. Preclinical administration of miR-92a inhibitor phenocopies miR-92a loss and ameliorates EAE. Analogous to mice, miR-92a is significantly elevated in MS patient T cells, and reciprocally regulates human Treg and Th17 differentiation. These findings suggest miR-92a skews the Treg/Th17 balance to promote CNS autoimmunity, and that miR-92a silencing may be of therapeutic benefit for MS patients.
Elevated levels of pentraxin 3 correlate with neutrophil counts and coronary artery dilation during acute Kawasaki disease, as a predictor of coronary artery lesions
Authors: Ching Lauren Lei , Nerurkar Vivek R , Lim Eunjung , Shohet Ralph V , Melish Marian E , Bratincsak Andras 
Published: January 2023

Abstract
Kawasaki disease (KD) is the leading cause of acquired heart disease in the developed world. 25–30% of untreated patients will develop irreversible coronary artery lesions (CAL). Pentraxin-3 (PTX-3), has been well studied in inflammatory diseases, in particular vascular endothelial dysfunction associated with cardiovascular disease. We hypothesized that PTX-3 played an important role in the development of KD associated CAL, and investigated circulating levels of PTX-3 in KD patients serum. Children with acute KD were followed from diagnosis through normalization of the clinical markers of inflammation. Blood draws and echocardiograms were conducted at several timepoints, acute (prior to IVIG treatment), sub-acute (5–10 days after IVIG treatment), and convalescent (1–4 months after KD diagnosis) phases. In this study we enrolled 70 children with KD, which included 26 (37%) who presented with CAL. Patients included in this study came from a diverse ethnic background. We observed a significant increase in PTX-3 levels during acute KD phase, compared to sub-acute and convalescent phases. PTX-3 levels during acute KD were significantly higher among KD patients with CAL. Further, PTX-3 levels were significantly correlated to coronary artery diameter size during acute KD and neutrophil counts throughout KD progression regardless of coronary artery diameter. We observed PTX-3 levels highly correlated to neutrophil counts, a known source of PTX-3 in acute inflammation and an important player in the development of KD vasculitis. Therefore, we propose PTX-3 as a novel factor associated with acute KD and in the development of KD associated CAL, and neutrophil derived PTX-3 as an important player of KD vascular dysfunction.
Laying Siege to the Castle: The Role of Sepsis Related Cytokines and Inflammation in Bringing Down the Barriers
Authors: Campbell Carmen Elaine , Boisvert William A 
Published: January 2023

Abstract
The endothelium plays a critical role in the progression from sepsis to organ failure. The endothelium lines all blood vessels and organs in the body. As such, it provides a protective barrier against pathologic micro-organisms. The endothelium is also responsible for dynamically regulating the passage of small molecules, fluid, and cells between the bloodstream and tissues. In sepsis, many factors play a role in compromising the endothelium. Dysfunctional endothelium often results in development of capillary leak, tissue hypoperfusion, hypoxia, edema, and shock. This study evaluates the individual contributions of sepsis-related immunomodulatory cytokines as well as a potential synergistic effect of cytokine combinations on vascular endothelial permeability. The Electric Cell-substrate Impedance Sensor was employed to evaluate the barrier function (Rb) and cell membrane capacitance (CMC) of endothelial cell monolayers treated with an array of cytokines including TNF-α IFN-γ, TGF-β, IL1-β, IL-6, IL-8, IL-10, and IL-12. The ECIS results revealed significant differences in the Rb of cell monolayers exposed to sepsis related cytokines compared to cytokine-free control samples. Components of intercellular tight junctions and associated cell adhesion molecules also revealed differences in the endothelial cell monolayer under immunofluorescence microscopy. Thus, cytokines as individual entities or in combinations that may be produced during episodes of sepsis significantly alter the endothelial morphology and permeability.