bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage galactose-type lectin modulates host immunometabolism during Mycobacterium tuberculosis infection
Authors: Paez Reina , Chauhan Sadhana , Naqvi Kubra , Puebla-Clark Lucinda , Gelman Benjamin , Martinez-Martinez Yazmin , Prideaux Brendan , Endsley Janice 
Published: November 2024

Abstract
Macrophages (Mφ) are the primary replicative niche for Mycobacterium tuberculosis (Mtb), a prominent bacterial pathogen responsible for nearly 1.5 million deaths annually. Appropriate metabolic reprogramming and activation of these cells is a major determinant of host-pathogen interactions and control of infection. Macrophage galactose-type lectin (MGL) is an immunomodulatory CLR primarily expressed on myeloid cells. We previously demonstrated a host-protective role for MGL in Mtb infection, with MGL-1 deficient (MGLKO) mice exhibiting increased bacterial burden and production of pro-inflammatory cytokines. Additionally, more lipid-laden cells were observed in the vicinity of granulomatous TB lesions in MGLKO mice, as compared to WT littermates. Extracellular flux analysis further revealed baseline differences in Mφ metabolism, with MGLKO BMDM exhibiting a glycolytic bias, consistent with the pro-inflammatory bias in vivo. LC-MS/MS lipidomic analysis of Mtb-infected whole-lung homogenate and BMDM revealed significant differences in lipid species between MGLKO and WT, with greater accumulation of DHA and other LCPUFA species observed in MGLKO samples. Importantly, these lipids were also observed to be concentrated within TB lesions of MGLKO and WT mice via mass spectrometry imaging (MSI), highlighting the relevance of these findings to disease outcomes. Taken together, we identify a novel role for MGL as a determinant of host immunometabolic response to Mtb infection.
Two immunodominant antigens from Madurella mycetomatis were identified by IgG antibodies in infected mice
Authors: Espinoza Martínez Pablo , Salinas Carmona Mario , Vázquez Marmolejo Anna , Vera Cabrera Lucio , Solís Marfil Pedro 
Published: November 2024

Abstract
Madurella mycetomatis is the most frequent etiological agent of eumycetoma, a chronic infectious disease that is acquired by traumatic inoculation of the microbe, mainly in the lower limbs. It usually affects young people between the ages of 15 and 30 and its treatment is complicated, involving surgical approach and chronic use of antifungals. To date there is lack of accessible immunological test for the diagnosis of this disease. In this work we obtained protein antigens from the cellular extract of M. mycetomatis, which can be used in the design of an immunodiagnostic test. 8-12 week old female BALB/C mice were infected with a suspension of M. mycetomatis using 3 different inoculation routes: intraperitoneal, dorsal subcutaneous and foot pad. Crude cellular extract of M. mycetomatis, protein antigens were analyzed on an SDS-PAGE gel, which were recognized by serum of mice infected with M. mycetomatis using the Western blot technique. The IgG anti-M. mycetomatis identified 2 immunodominant antigens were recognized by antibodies in all infected mice with M. mycetomatis. The identification of these antigens in sera from patients with eumycetoma has diagnostic potential.
Ifit2 interacts with murine-β-coronavirus RSA59 nucleocapsid protein to restrict its replication and spread
Authors: Sharma Madhav , Sarma Jayasri 
Published: November 2024

Abstract
The antiviral efficacy of Ifit2, an interferon-induced protein with tetratricopeptide repeats 2, is known for its ability to restrict the neurotropic murine-β-coronavirus, RSA59 infection. Intracranial injection of RSA59 in Ifit2 deficient (-/-) compared to wild-type (WT) mice results in impaired microglial activation and peripheral lymphocyte infiltration into the brain with severe morbidity and mortality in the acute phase of the disease. RSA59-infected Ifit2-/- mice also showed extensive viral replication, spreading throughout the spinal cord with impaired microglial activation and T-cell infiltration. Cervical-lymph-nodes of RSA59-infected Ifit2-/- mice exhibited reduced activation of CD4+ T cells and impaired IFNγ expression while preserving the blood-brain barrier integrity. To understand Ifit2's impact on the chronic demyelination phase, Ifit2-/- and Ifit2+/+ (WT) mice were observed for neuropathological outcomes upon RSA59 infection. The chronic disease phase in RSA59-infected Ifit2-/- mice demonstrated severe demyelination and persistent viral load. Furthermore, understanding molecular interactions in a reductionist approach using co-immunoprecipitation showed that upregulated Ifit2 in RSA59-infected primary astrocytes can interact with viral nucleocapsid protein. Thus, this study highlights that Ifit2's direct interaction with viral nucleocapsid protein can restrict RSA59 spread throughout the CNS in the acute phase, thus limiting severe chronic demyelination.
THE ROLE OF THE VIRAL PROTEIN VPR IN THE EPIGENETIC REGULATION OF HIV-1 LATENCY
Authors: Lewis Catherine , Browne Edward 
Published: November 2024

Abstract
The primary obstacle to HIV-1 cure is the persistence of a long-lived latent reservoir, best characterized in memory CD4+ T cells. New research supports latency prevention as a therapeutic strategy. However, such an approach will require a better understanding of how HIV-1 establishes latency. We recently showed that histone deacetylases (HDACs) are critical for entry into latency. Whether HDACs interact with specific viral factors, particularly the HIV-1 accessory protein and coactivator Vpr, to regulate latency establishment is unknown. We therefore sought to determine how Vpr, both alone and in combination with the HDAC inhibitor vorinostat (VOR), regulates HIV-1 latency establishment. In a primary CD4+ T-cell model, we observed a p300-dependent synergy between Vpr and VOR in maintaining viral gene expression. We next assessed whether Vpr delivery during latent infection, a stage when viral proteins are not normally expressed, could enhance the ability of VOR alone to induce viral gene expression. We found that Vpr delivery reactivated latently infected CD4+ T cells to a greater extent than VOR treatment alone and that the combination of Vpr delivery and VOR treatment led to the highest level of reactivation. An improved understanding of how host and viral factors interact during HIV-1 latency establishment in CD4+ T cells will aid in the development of new therapies that prevent HIV-1 entry into the latent reservoir or that reverse latency in latently infected cells.
ZBP1 regulates cytokine production and cell death in lung fibroblasts following influenza virus infection
Authors: Jordan Summer , Boyd David , Gautam Avishekh , Balachandran Siddharth 
Published: November 2024

Abstract
Regulated cell death following influenza viral infection is an important determinant of disease severity and is required for effective viral clearance. However, extensive cell death can lead to severe tissue damage and compromised lung function. Z-DNA binding protein-1 (ZBP1) is a critical sensor of influenza A virus (IAV) that can activate both apoptotic (non-inflammatory) or necrotic (inflammatory) cell death pathways. The cell type-specific effects of ZBP1 activation during influenza virus infection have not been clearly defined. Here, our single-cell gene expression studies identified lung fibroblasts as a cell type expressing high levels of Zbp1 following IAV infection in vivo. Following infection in vitro, we observed that ~20% of primary lung fibroblasts were readily infected by IAV but did not support high levels of spreading infection. Lung fibroblasts from wildtype mice underwent cell death with ~50% reduction in cell survival at 24 hours while lung fibroblasts from Zbp1 knockout mice were almost completely resistant to cell death. Analysis of cytokine production prior to cell death demonstrated that IAV infection in lung fibroblasts triggered an early ZBP1-dependent production of inflammatory proteins. Knockout of ZBP1 reduced inflammatory cytokine/chemokine production, but left interferon pathways intact. These studies identify lung fibroblasts as a key cell type activating Zbp1-mediated cytokine production and cell death during influenza virus infection.
Distinct roles for interferon-α and interferon-β in recovery from Sindbis virus encephalomyelitis
Authors: Nguyen Benjamin , Stanley Elise , Chen Emily , Griffin Diane 
Published: November 2024

Abstract
Alphaviruses are viruses that can cause encephalomyelitis, which is inflammation of the brain and spinal cord due to the immune response to viral infection. Neurons are the primary target cells of Sindbis virus (SINV), the prototypic alphavirus. Interferon (IFN) regulatory factor (IRF) 7 is a transcription factor important for amplification of type I IFN and is required for survival from SINV infection. Irf7-/- mice do not produce IFNα and rapidly succumb to infection – despite local production of IFNβ – while wild type (WT) mice recover. Treatment of Irf7-/- mice with IFNα increases survival and promotes viral clearance, suggesting that IFNα is required for recovery, and further, myeloid-specific expression of IRF7 is necessary for survival. Additionally, Ifnb-/- mice do not phenocopy Irf7-/- mice, further suggesting that IFNα is critical for survival while IFNβ is dispensable despite usage of the same receptor. Interestingly, Ifnb-/- mice have similar peak viral titers to Irf7-/- mice but clear virus with kinetics similar to WT mice, implying that the protective effects of IFNα go beyond restriction of viral replication. Irf7-/-Ifnb-/- double knock-out mice have disease similar to Irf7-/- mice but with earlier onset, suggesting an immunomodulatory role for IFNβ in delaying clinical disease. These findings show subtype-specific differences in protection by type I IFN and can inform treatment options for more severe forms of alphavirus-induced encephalomyelitis.
Co-evolution of antibody responses against human immunodeficiency virus (HIV-1) envelope
Authors: Arora Juhi , Birungi Kevina , Schramm Chaim , Johnston Timothy , Henry Amy , Nortelus Sarah , Jacob Sari , Zemil Michelle , Kavusak Erin , Rao Mekhala , Smith Gabriel , Lewitus Eric , Bose Meera , Sanders-Buell Eric , Rolland Morgane , Polonis Victoria , Douek Daniel 
Published: November 2024

Abstract
Broadly neutralizing antibodies (bNAbs) target epitopes on the Envelope (Env) glycoprotein of HIV-1 and neutralize diverse strains with high breadth and potency. Studying the ontogeny of bNAb development will help identify better immunogens for vaccine design. RV217 is an acute infection cohort with samples collected prior to seroconversion and continued 2+ years following detection of viral RNA (RNA+). From participant 40512, living with CRF01_AE infection, we isolated several bNAbs at day 646 post-RNA+ that targeted the membrane proximal external region (MPER) on the HIV Env. These included the VRC42 lineage, with neutralization breadth of 97% on multi-subtype pseudovirus panels. Sequence analysis revealed sequential mutations in the HIV-1 Env, indicating virus evolution. The participant acquired another CRF01_AE HIV-1 infection (i.e., superinfection) between days 330-401 post-RNA+, increasing antigenic diversity, and continued to develop breadth to 98% at day 1142 post-RNA+. Using rapid amplification, transfection, and production of immunoglobulins (RATP-Ig), we sorted MPER+ B cells and isolated an additional 22 VRC42 lineage mAbs at day 1142 post-RNA+. Interestingly, origins of the 4 sublineages were traced back to day 154 post-RNA+. These mAbs continued to evolve out to day 1142 and showed greater activity against late autologous viruses, suggesting that co-evolving HIV-1 Env and antibodies led to development of neutralization breadth.
First lung infection permanently enlarges LN and enhances new T cell responses
Authors: Stolley Michael , Masopust David 
Published: November 2024

Abstract
Humans experience about four respiratory infections per year. Immunology and vaccinology studies in mice are typically performed in naïve specific pathogen free (SPF) animals responding to their very first respiratory challenge. We found that the first respiratory infection induces lifelong enlargement of lung-draining mediastinal LNs. Furthermore, infection-experienced medLNs supported better naïve T cell surveillance and effector responses to new unrelated infections and engendered more biased accumulation and memory establishment within the lung. Moreover, we observed that weight loss induced by influenza infection was substantially reduced in mice that had recovered from a previous unrelated respiratory viral challenge. These data show that the lack of infectious history in SPF mice alters their immune response to lung infections. Preclinical vaccination and immunology studies should consider the previous infectious experience of the model organism.
Glycolysis and HIF-1α signaling are important for granulocytic myeloid-derived suppressor cell activity during Staphylococcus aureus biofilm infection
Authors: Arumugam Prabhakar , Horn Christopher , Roy Zachary , Heim Cortney , Fallet Rachel , Bertrand Blake , Shinde Dhananjay , Thomas Vinai , Romanova Svetlana , Bronich Tatiana , Hartman Curtis , Garvin Kevin , Kielian Tammy 
Published: November 2024

Abstract
Prosthetic joint infection (PJI) is a severe complication following hip and knee arthroplasty and is reported to affect 1-2% of total arthroplasties. Staphylococcus aureus (S. aureus) contributes to most PJIs, with a higher treatment failure rate partly due to biofilm formation. Granulocytic myeloid-derived suppressor cell (G-MDSC) expansion and IL-10 secretion are critical for inducing an immunosuppressive environment that supports S. aureus persistence during PJI. Recently, S. aureus-derived lactate was shown to promote IL-10 production by G-MDSCs. However, the importance of G-MDSC metabolism in programming their anti-inflammatory activity is unknown. Single-cell RNA sequencing (scRNA-seq) of infected tissues from a mouse model of S. aureus PJI revealed enrichment of glycolysis and hypoxia pathway genes in G-MDSCs. Increased glycolytic activity in G-MDSCs was confirmed following S. aureus biofilm co-culture and attenuating glycolysis with either 2-deoxyglucose or granulocyte-specific HIF-1a deletion reduced bacterial growth during S. aureus PJI. These changes coincided with less G-MDSC suppressive activity and a transformation towards a proinflammatory phenotype. scRNA-seq of samples from PJI patients revealed heightened glycolysis and hypoxia signatures, supporting findings with the mouse PJI model. Together, these results suggest that glycolysis and HIF-1a pathways are critical for the anti-inflammatory activity of G-MDSCs during S. aureus biofilm infection.
Natural IgM Maintains Ocular Homeostasis into Old Age
Authors: Webster Sarah , Les Sydney , Heck Daken , Tsuji Naomi , Clemente Michael , Jones Prentiss , Holodick Nichol 
Published: November 2024

Abstract
The eye is designed to properly focus light through optically clear structures, the cornea and lens, at the anterior onto photosensitive nervous tissue, retina, at the posterior for vision. Maintaining these tissues is critical, but the integrity of eye tissues is often lost with age, leading to disease. Although the eye is immune privileged, lymphocytes may enter retinal tissue under certain circumstances, usually in disease. Natural antibodies, such as natural IgM, are produced by B cells without infection or immunization and maintain tissue homeostasis. We found that vitreous humor contains IgM and IgG. We examined mice deficient in secreted IgM (ms-/-) and found young mice developed cataracts and mild retinal degeneration, which was enhanced with age. Examination of aged ms-/- mice revealed significant reactive gliosis by the resident Müller glia and increased microglia infiltration into retinal layers. The retina of aged ms-/- mice displayed an increased pro-inflammatory cytokine profile and increased retinal death resulting from apoptosis. We found B cells localized to the retinal pigment epithelium responsive to LPS stimulation and display a diverse repertoire influenced by age and lack of IgM. These data demonstrate a critical role for natural IgM in maintaining ocular homeostasis, which preserves anterior clarity and posterior retinal health. A better understanding of intraocular maintenance will enable the development of therapeutics to support vision into old age.
Characterizing the mechanism of catecholamines transport in the Mesenteric lymph Node (MLN) using Fast Scan Cyclic Voltammetry (FSCV).
Authors: Ojha Sarbeshwar 
Published: November 2024

Abstract
Neuroimmune communication is one of the key components in regulating the body’s response to physiological challenges and maintaining homeostasis while facilitating immune stress response. Within the gastrointestinal tract, the mesenteric lymph nodes play a key role in governing the immune response, and this regulation involves communication between immune cells and neural components.Sympathetic neurons are thought to co-release norepinephrine and dopamine to modulate cytokine signaling during inflammation and therefore measurements of these neurochemicals in the lymph node are critical for understanding immunity. Here, we have expanded our electrochemical waveform and way of performing the experiment in ex vivo lymph node slices to study how these neurochemicals communicate in the lymph node during different conditions. We have also tried blocking the different neurotransmitter transporter with different antagonist drugs for different catecholamines to see the differential change and came to know that these transport blockers have significant effect on holding the neurochemical in the extracellular space when we block their transporter.
This work presents the first-time detection on role of different transport blocker and their impact in the mechanism of catecholamine release in the MLN on a millisecond timescale, which will provide significant insight into the mechanisms of neuron-immune communication and different drug related studies.​
A20 is a negative regulator of both NF-κB and JNK signaling following T cell receptor stimulation in humans
Authors: Dabbah-Krancher Gina , Ruchinskas Allison , Snow Andrew 
Published: November 2024

Abstract
A20 is a ubiquitously expressed, inducible ubiquitin-editing enzyme that restrains NF-kB-dependent inflammatory signaling throughout the body. In T cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-kB and c-Jun partner AP-1. Utilizing WT and A20KO Jurkat T cells, we demonstrate A20 is required to negatively regulate both NF-kB and JNK/AP-1 signaling. By employing a novel set of A20 mutant constructs with NF-kB and AP-1 driven reporter systems in Jurkat transfectants, we discovered the ZnF7 domain is essential for CBM localization and signal modulation. We confirmed these findings in CRISPR-mediated A20 knockout human primary effector T cells, demonstrating sustained TCR-induced NF-kB and JNK signaling, enhanced upregulation of activation markers, and increased cytokine secretion associated with a skewed Th9/Th17 phenotype. Moreover, loss of A20 altered apoptosis sensitivity in primary human T cells, resulting in decreased restimulation induced cell death (RICD) and increased cytokine withdrawal induced death (CWID). These findings further elucidate the mechanism of A20-dependent regulation of both NF-kB and c-Jun in T cells, and highlight the functional importance of A20 in maintaining adaptive immune homeostasis.
Sequential regulation of Lck K63-ubiquitination and autophosphorylation by the E3 ligase UBR2 and the phosphatase DUSP22 in TCR signaling
Authors: Tan Tse-Hua , Chuang Huai-Chia 
Published: November 2024

Abstract
Dual-specificity phosphatase 22 (DUSP22, also named JKAP) downregulation in peripheral blood T cells is correlated with human SLE nephritis and T-cell leukemia. DUSP22 also dephosphorylates and inactivates Lck in the turn-off stage of TCR signaling, leading to suppression of autoimmune disease.
We found that DUSP22 dephosphorylated the E3 ligase UBR2, leading to SCF E3 ubiquitin complex-mediated UBR2 ubiquitination and degradation. Remarkably, UBR2 induced Lck K63-linked ubiquitination, leading to subsequent Lck Tyr394 autophosphorylation and activation upon TCR signaling. Thus, DUSP22 also can inactivate Lck indirectly by inducing UBR2 degradation. Moreover, the proinflammatory cytokine induction and inflammatory responses in DUSP22 KO mice was blocked by knocking out UBR2 in DUSP22/UBR2 double KO mice. The UBR2-Lck interaction and Lck Lys63-linked ubiquitination were indeed induced in T cells of human SLE patients. Taken together, DUSP22 dephosphorylates UBR2 and induces its degradation, leading to inactivation of Lck and suppression of inflammation. Overall, our results reveal a novel activation mechanism of Lck by K63-linked ubiquitination in TCR signaling.
Mechanism of Treg conversion to exTreg in atherosclerosis
Authors: Lyu Qingkang 
Published: November 2024

Abstract
Foxp3+ regulatory T cells arise from precursors in the thymus and can be induced from naïve CD4 T cells. They are indispensable for maintaining self-tolerance and limiting collateral damage during an immune response. Under inflammatory conditions, Treg cells acquire plasticity and instability, ultimately leading to a loss of CD25 and FoxP3. These exTregs lose suppressive function. exTregs have been reported to express lineage-defining transcription factors of helper CD4 T cell like Th1, Th2, Th17 or Tfh cells. In mouse models of atherosclerosis, conversion of Tregs to exTregs is accelerated. The molecular mechanism of Tregs conversion to exTregs is unknown. Previous studies have shown that plasma IL-6 was increased in atherosclerosis. The IL6 receptor heterotrimer IL6R (CD126) and gp130 (CD130) is expressed in Treg cells. We hypothesized that IL-6 may play a role during the conversion of Treg to exTreg. Using Treg and exTreg cell lineage-tracker mice (FoxP3eGFP−Cre-ERT2 ROSA26CAG-fl-stop-fl-tdTomato) on the Apoe-/- background, we are able to distinguish Treg from exTreg that lost Foxp3 expression in mice model of atherosclerosis. We established an in vitro culture system for Treg cells based on bead-bound anti-CD3 and anti-CD28. Preliminary data showed that IL-6 dramatically increased the proportion of exTreg cells in vitro. These data suggest that IL-6 may promote Treg to exTreg conversion.