bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zika virus suppresses maturation of human dendritic cells
Authors: Wang Ying-Ting , Branche Emilie , Viramontes Karla M. , Cuevas Joan Valls , Carlin Aaron F. , Shresta Sujan 
Published: January 2023

Abstract
Zika virus (ZIKV) belongs to the genus Flavivirus, which includes several medically relevant viruses, including dengue, yellow fever and Japanese encephalitis viruses. ZIKV causes congenital Zika syndrome in neonates and Guillain-Barré syndrome in adults, and has emerged as a major public health problem worldwide. Dendritic cells (DCs) serve as the major cellular hosts of ZIKV, and T cell responses to flaviviruses may play a dual role in protection and pathogenesis. To decipher the precise interactions between DCs and ZIKV, we profiled the transcriptomic features of ZIKV-infected DCs versus uninfected bystander DCs in primary human blood monocyte-derived DC cultures. RNA sequencing data revealed that the expression of genes related to antigen processing/presentation pathways was reduced in ZIKV-infected DCs relative to uninfected bystander DCs that were exposed to the same environmental stimuli as ZIKV-infected DCs. Flow cytometric analysis of ZIKV-infected DCs for the expression of key DC maturation markers confirmed the RNA sequencing data. Thus, ZIKV hinders DC maturation, suggesting that ZIKV may modulate T cell responses by directly manipulating DC functions. Studies are in progress to determine how ZIKV inhibits DC maturation and influences T cell responses. Results of these studies will provide key insights towards the development of safe and effective vaccines against ZIKV and related flaviviruses.
Zika virus infection of mast cells is not associated with a degranulation response
Authors: Coish Jeremia M , Crozier Robert W. E. , Schieffelin John S. , Coorssen Jens R. , Hunter Fiona F. , MacNeil Adam J. 
Published: January 2023

Abstract
Dengue virus (DENV) infection is augmented by a process called antibody-dependent enhancement (ADE), in which pre-existing DENV immunity can render an individual more susceptible to a subsequent DENV exposure. Based on Zika virus (ZIKV) and DENV structural similarities, emerging evidence suggests anti-DENV antibodies can cross-react with ZIKV at non-neutralizing levels characteristic of ADE. Mast cells (MC), sentinel white blood cells integral in coordinating early immune defences, have been identified as a principle contributor to DENV vascular leakage. This clinical manifestation is attributed to significant histamine release caused by MC degranulation, a characteristic MC activation response. However, to our knowledge ZIKV-MC interactions remain unexplored. MC responses to virus can be modelled in vitro, including via use of the well-characterized KU812 cell line which express Fcγ receptors. Here, we sought to determine if the KU812 MC is susceptible to (1) direct ZIKV infection; and (2) ADE in the presence of anti-DENV antibodies that cross-react with ZIKV. A significant increase in viral titre (104 PFU/mL) was detected, by plaque assay, in MC directly infected with ZIKV compared to MC infected with UV-inactivated ZIKV (0 PFU/mL). Furthermore, a significant viral titre (106 PFU/mL) was detected in MC infected with ZIKV pre-incubated with anti-DENV antibodies when compared to MC infected with ZIKV pre-incubated with isotype control antibodies (104 PFU/mL). Furthermore, unlike DENV induced degranulation of MC, ZIKV did not activate a degranulation response in this model or in a primary murine model. Therefore, MC may be a contributor in ZIKV pathogenesis without the classical degranulation response seen in DENV infected MC.
Murine Ifit3 restricts West Nile virus infection and pathogenesis
Authors: Case James Brett , VanBlargan Laura A. , White James P. , Diamond Michael S. 
Published: January 2023

Abstract
The host interferon (IFN) response is the first line of defense for mammalian cells against invading pathogens. Among the most upregulated IFN-stimulated genes are members of the IFN-induced protein with tetratricopeptide repeats (IFIT) family of proteins. IFITs play a critical role in the host antiviral response by distinguishing between ‘self’ and ‘non-self’ RNA. Recent findings demonstrate that human IFIT3 binding to IFIT1 alters the viral RNA binding specificity of IFIT1. Uniquely, mice encode two copies of the Ifit3 gene, Ifit3a and Ifit3b, that differ by only five amino acids. To determine the function of mouse Ifit3 and to gain further understanding of the role of IFIT3 in antiviral immunity, we used CRISPR/Cas9 gene editing to generate Ifit3a/b DKO mice. Our results demonstrate that Ifit3 is important for survival of infection with West Nile virus (WNV, strain NY99). Whereas approximately 65% of WT C5BL/6J mice survive infection with WNV-NY99, Ifit3a/b DKO mice were more susceptible with only 20% of animals surviving infection. Virological analysis of lymphoid and CNS tissues revealed that Ifit3a/b DKO mice have increased viral loads in the brain, spinal cord, and liver compared to WT animals, and gene expression analysis of WT animals corroborated that Ifit3a and Ifit3b are highly induced in these tissues during infection. Detailed immunological analysis of Ifit3a/b DKO animals did not show a loss in the ability to generate WNV-specific antibodies, but did reveal a significant decrease in the number of CD8+ T cells in the spleen and a delayed CD8+ T cell response in the spinal cord. Altogether, our data suggest that Ifit3 restricts WNV infection and pathogenesis in distinct anatomic locations, most notably in specific regions of the CNS.
Integrated single-cell analysis of multicellular immune dynamics during hyper-acute HIV infection
Authors: Kazer Samuel W , Aicher Toby P , Muema Daniel M , Miao Vincent N , Ordovas-Montanes Jose , Ziegler Carly G K , Moodley Amber , Dong Krista L , Ndhlovu Zaza M , Ndung’u Thumbi , Walker Bruce D , Shalek Alex K 
Published: January 2023

Abstract
Development of effective vaccines and therapeutics is facilitated by understanding the earliest immune responses to infection. Here, we apply single-cell RNA-sequencing (scRNA-seq) and a novel gene module discovery-based framework to longitudinally profile peripheral multicellular immune responses in untreated hyper-acute HIV infection.
We profiled &gt;59,000 single cells from four individuals across multiple acute infection timepoints (including pre-infection), utilizing scRNA-seq data to identify transient immune responses with cell subset resolution. Onset of viremia induced interferon stimulated gene (ISG) responses integrated across multiple cell types, wherein monocytes notably contributed to the cytokine milieu. Otherwise obscured in bulk analyses, we describe a second set of responses following ISG upregulation that align in time: pro-inflammatory T cell differentiation, prolonged monocyte MHC-II upregulation, and persistent NK cytolytic killing. Leveraging our temporal, cell-type resolved data, we nominate putative cell-cell signaling networks and their key cytokines during infection. Two participants who later develop viremic control associated with elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated NK cell subset, immediately following HIV detection.
Our study reveals both cooperative and cell subset specific immune responses during untreated hyper-acute HIV infection with temporal resolution, nominating monocytes, NK cells, and pro-inflammatory signaling as perturbation targets for future vaccine studies. Moreover, our gene module discovery framework can be readily applied to other longitudinal studies in humans and other model organisms.
Plasmacytoid dendritic cells impair HIV-specific CD8 T cells to maintain HIV-1 reservoir persistence during chronic HIV infection under cART
Authors: Li Guangming , Ma Jianping , Yu Haisheng , Cheng Liang , Su Lishan 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDC) are the major type I interferon (IFN-I) producing cells and play important roles in antiviral immune responses during acute virus infection. However, sustained pDC activation and IFN-I induction has been correlated with disease progression in chronic virus infection. We have recently functionally defined the HIV-pDC-IFN axis in HIV-1 immuno-pathogenesis, and studied the mechanisms of pDC/IFN-induced immune suppression, and its role in HIV reservoir persistence. We have discovered that depleting pDC during HIV infection reverses HIV-related diseases in lymphoid organs even in the presence of higher levels of HIV replication. We further show that low levels of pDC/IFN-I signaling contribute to the immune dysfunction and foster HIV-1 persistence in cART-treated hosts. In this study, we demonstrate that pDCs-depletion during suppressive cART reversed T cell exhaustion and reduced HIV-1 reservoir cells. This control of HIV-1 reservoir induced by pDC depletion is dependent on CD8 T cells, as depletion of both pDCs and CD8 T cells failed to reduce HIV-1 reservoir cells during cART in humanized mice. Our study demonstrates a key role of pDC-dependent CD8 T cell tolerance in maintaining HIV-1 reservoir persistence during cART in vivo. We are currently characterizing the CD8 changes induced by pDC depletion from HIV-infected lymphoid organs by genomic, epigenomic and metabolomic analyses.
SIVmac239 infection dysregulates anti-mycobacterial immunity at the granuloma level and contributes to severe tuberculosis in cynomolgus macaques
Authors: Mattila Joshua T , Talukdar Priyanka , Jespersen Alyssa , Fallert Junecko Beth A , Moriarty Ryan , O’Connor Shelby , Scanga Chuck A 
Published: January 2023

Abstract
Tuberculosis (TB) is a global pandemic caused by Mycobacterium tuberculosis (Mtb) infection that is characterized by formation of lung lesions called granulomas. TB has a synergistic relationship with HIV and TB often occurs in HIV-infected individuals with near normal CD4+ T cell counts. Despite the importance of this co-infection to public health, interactions between HIV and lesion-level immunity remain poorly understood. To address this issue, we used SIVmac239-infected or SIV-negative Mauritian cynomolgus macaques with active TB to identify which cell types are infected in granulomas and how SIV modulates local immunity. Using RNAscope and immunohistochemistry, we found that CD11c+ macrophages were the most-commonly infected cell type in granulomas. To identify how viral infection changes the immune landscape in granulomas, we performed a transcriptional analysis on RNA isolated from lung granulomas. We found that SIV infection downregulated large numbers of macrophage-activating cytokines and receptors, toll-like receptors, and T cell activation markers. In contrast, anti-viral responses including type 1 interferons and receptors expressed by NK cells were upregulated. IL-10 was among the genes that were not differentially regulated. Pathway analysis indicated that many pathways were downregulated, including pathways associated with Th1-, Th2-, and NFkB-mediated responses. These data suggest that SIV infection deactivates protective responses in granulomas but activates antiviral responses that are counterproductive in TB while leaving detrimental IL-10 expression intact. We hypothesize that this disequilibrium leads to an inability to kill bacteria and restrict dissemination that exacerbates TB.
Functional MAIT cells are associated with reduced simian-human immunodeficiency virus infection
Authors: Velu Vijayakumar , Murugesan Amudhan , Ibegbu Chris , Turner Tiffany , Jones Andrew , Shanmugasundaram Uma , Reddy Pradeep , Rahman Sadia Jannath , Saha PIu , Matam Vijay-kumar , Muthu Shankar Esaki , Amara Rama Rao 
Published: January 2023

Abstract
Mucosa-associated invariant T-cells (MAITs) are recently characterized novel subset of innate-like T-cells that recognize microbial metabolites presented by MHC-1b-related protein MR1. The significance of MAIT cells in anti-bacterial defense is well understood but not clearly in viral infections such as SIV/HIV infection. Here, we studied the phenotype, distribution, function of MAITs and their association with viral levels during chronic SHIV infection in rhesus macaques (RM). Two groups of healthy and chronic SHIV-infected RM were characterized for MAITs in blood and tissues. Similar to human, we found a significant fraction of RM CD8+ T cells express markers CD161, TCRVα□7.2 with high levels of IL-18R, CCR6, CD28 and CD95 that correlates with MR1 tetramer. During chronic SHIV, the frequency of MAITs are enriched in blood but unaltered in rectum, which displayed higher proliferative and cytotoxic capacity. Blood and rectal MAITs correlated inversely with plasma viral RNA and correlated directly with CD4 T cells. They respond to LPS and correlates with serum flagellin levels. Tissue analysis of MAITs during chronic SHIV showed significant enrichment in non-lymphoid tissues (lung, rectum and liver) with higher levels of tissue resident markers CD69 and CD103 unlike spleen/LN. In vitro treatment with cytokines during SHIV infection revealed that IL-7 is key for their proliferation and IL-12, IL-18 are important for their cytotoxicity. Thus our results demonstrates that functional MAITs are enriched in blood and rectum during chronic SHIV infection that inversely correlates with plasma viral levels. Therapies such combined cytokines could be beneficial for enhancing functional MAIT cells during chronic HIV infection in vivo.
Studies of incomplete control of Epstein-Barr virus infection in association with aging by using cynomolgus macaque colony
Authors: Urano Emiko , Murakata Yoshiko , Tsujimura Yusuke , Yasutomi Yasuhiro 
Published: January 2023

Abstract
The analysis of age-related immune senescent is extremely meaningful to understand the vital homeostasis in individuals among the aging society. Epstein-Barr virus (EBV) establishes latent infection in &gt;90% of adults worldwide. In general, chronically infected EBV is controlled well for a lifelong in healthy adults. Since, EBV is reactivated by the failure of the host immune system, it can be an index to understand the hypofunction. A non-human-primate, controlled experimental animal, cynomolgus macaque (CM) has a long life span and can be used for longevity studies using aged animals that are more than 20 years old, which correspond to ≥60 years of age in humans. In this study, the state of EBV infection in the colony of CM was explored by detecting EBV in saliva as EBV reactivation, and the immunological functions were examined using PBMC from CMs concerned with the control of EBV. Age-related alteration of T cell and B cell subsets was observed in CM colony comparison with young (4–6 years) and elderly (24–26 years) group. T cell distribution was similar among young and elderly groups respectively; however, CD3 and CD28 stimulated cells from elderly EBV (+) group showed the lowest proliferation than the others. EBV-specific immune responses are under consideration. The CM colony will be a useful model of aging and the extensive study will help to elucidate the mechanisms of hypofunction through a long-life span.
The role of Virostatic genes in modulating Immune Checkpoints in Epstein-Barr Virus associated Tumors
Authors: Chakravorty Srishti , Yan Bingyu , Chauss Daniel , Wang Luopin , Canaria D. Alejandro , Jethava Krupal , Chopra Gaurav , Briggs Scott D , Zhao Bo , Olson Matthew R. , Afzali Behdad , Kazemian Majid 
Published: January 2023

Abstract
Epstein-Barr Virus (EBV) is a complex oncovirus that infects around 90% of adults. Most primary infections remain asymptomatic but result in lifelong infection. EBV can drive lethal malignancies of both lymphoid (e.g. Burkitt lymphoma) and epithelial origins (e.g. Stomach Adenocarcinoma). Despite decades of research, the exact molecular mechanisms of EBV and host immune system interactions that lead to tumorigenesis remain elusive.
Through systematic analyses of high-throughput sequencing data from &gt;1000 patients with different cancer types, we identified twelve EBV transcripts, including LMP1 and LMP2, which when overexpressed, significantly suppressed viral reactivation. These ‘virostatic genes’ had frequent missense and nonsense variations in cancer patients, disrupting their ability to restrict EBV reactivation. We also found that viral reactivation by classical chemical inducers up-regulates the expression of Programmed Death-Ligand 1 (PD-L1). Further analyses of the same RNA-seq dataset classified EBV+ tumors into two molecular subtypes based on expression pattern of upstream regulatory immune-related genes and Immune Checkpoint (IC) markers, including PD-L1. Overexpression of virostatic genes in lymphoblastic cells significantly repressed cellular PD-L1 transcription, leading us to hypothesize that a combination of IC and virostatic gene modulation may have synergistic benefits for immunotherapy of EBV-associated cancers.
Depression is more severe among females with autoimmune conditions
Authors: Ramirez Francisco E , Maghelli Giorgia , Nedley Neil 
Published: January 2023

Abstract

Rationale
We explore the relationship between severity of depression on participants with autoimmune conditions and its relationship with gender.

Methods
Participants from a non medical community educational program that finished the intervention and had an autoimmune condition were used in the study. Participants met once a week for 8 weeks for a 2-hour program, which educated them about healthy lifestyle habits like diet, exercise, control of thoughts, etc. Each patient took the Depression and Anxiety Assessment Test (DAAT registration TX 7-398-022) before and after the intervention. The questionnaire measured depression and asked about demographics, patient history and research consent.

Results
From n=5651 people that finished the intervention n=432 participants reported autoimmune disease and were used in the study, n=369 (85%) were female and n=64 (15%) were male.
At baseline regarding depression severity, female participants n=116 (32%) reported severe depression, n=130 (35%) moderate, n=60 (16%) mild, and n=62 (17%) none. Male participants on the other hand reported n=63 (22%) severe depression, n=14 (29%) moderate, n=18 (30%) mild, and n=12 (19%) none. At the end of the program, females reported the depression reported in the group was n=22 (5.9%) severe depression, moderate n=94 (26%), mild n=61 (17%), and n=191 (52%) none. For males, end group depression distribution was n=4 (6.3%) severe depression, n=11 (17%) moderate, n=15 (24%) mild, and n=33 (52%) none.

Conclusions
More women with autoimmune disease seem to have more severe depression than men, but both genders improved at the end of the program. Further follow up is being planned.
Characterizing the TCR repertoire in Neuropsychiatric Lupus
Authors: Moore Erica , Huang Michelle , Putterman Chaim 
Published: January 2023

Abstract
Approximately 40% of lupus patients experience neurological and/or psychiatric disorders. However, the mechanisms contributing to the wide range of neuropsychiatric manifestations (NPSLE) have not yet been fully elucidated. We have demonstrated that the choroid plexus (CP) in the MRL/lpr NPSLE lupus mouse model is heavily infiltrated with effector T cells. We investigated T cell receptor (TCR) usage and repertoire diversity in CP infiltrating T cells, to enhance our understanding of this T cell population and its possible contribution to neuropsychiatric disease. The CP, salivary glands, and spleens were dissected from female MRL/lpr mice (n=9, n=9, n=4 respectively) and the spleens from female MRL/MpJ (n=5) at 17–22 weeks of age, at which time MRL/lpr mice display prominent neurobehavioral deficits. The TCR repertoire was evaluated by isolating genomic DNA, amplifying the CDR3 sequence by multiplex PCR (Adaptive Technologies), and analyzing the sequences with the Adaptive Technologies immunoSeq Analyzer and the R software, LymphoSeq. MRL/lpr CP tissues had increased numbers of T cell sequences, unique productive sequences, and clonality. The top 10 productive rearrangements were more abundant in MRL/lpr CP when compared to the MRL/lpr and MRL/MpJ splenic tissues (p = 0.0673 and p = 0.0003 respectively). The MRL/lpr CP had an increased frequency of TCRBV02, TCRBV04, TCRBV12, and TCRBV26 genes compared to MRL/lpr splenic and salivary gland tissues. Despite the lymphoproliferation found in this lupus strain, the increased oligoclonal expansion and limited TCR V beta gene usage in the MRL/lpr CP T cell repertoire, as compared to other MRL/lpr tissues, implies a distinct and specific infiltration of T cells into the CP.
Modulation of treg and th17 immunity in myeloid leukemia for therapeutic intervention
Authors: Camacho Virginia , Matkins Victoria , Patel Sweta , Anderson Ashlyn , Ferrell Paul Brent , Weaver Casey Todd , Harrington Laurie E , Welner Robert S 
Published: January 2023

Abstract
Non-immune roles of Regulatory T cells (Tregs) have been described across various tissues. However, the mechanisms by which T cells regulate the bone marrow in myeloproliferative neoplasms lack resolution. Recently, we outlined how Tregs in bone marrow condition the stromal cell niche and enhance hematopoietic support via IL-10 secretion. A hallmark of leukemic progression is the increase in pro-inflammatory cytokines and cellular inflammation. In this study, we demonstrate that this inflammatory milieu promotes pathogenic skewing of both regulatory and effector T cells. We performed a comprehensive characterization of the CD4 T cell compartment in myeloproliferative neoplasms such as chronic myeloid leukemia (CML) and we found that Tregs are unstable and dysregulated the leukemic marrow. This contributes to a phenotype of immune activation as well as an increase of pathogenic inflammatory T cells. Specifically, our findings reveal that Treg Th17 ratios are disrupted in leukemia and that Th17 cells influence disease progression. Additionally, we found that Treg-secreted IL10 has beneficial effects on the functions of healthy and diseased mesenchymal stromal cells (MSCs). We demonstrate that restoring Treg function and expanding their IL10 production can be used therapeutically to delay leukemic burden. Our results support the hypothesis that Tregs are compromised during leukemic progression as a consequence of pro-inflammatory cytokines from the myeloid associated disease. These findings highlight how the Treg Th17 balance regulates disease progression. Furthermore, these studies provide an avenue by which Treg secreted IL10 can be used for therapeutic intervention in the context of heme malignancy.