bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel lentiviral vector-based approach to generate CAR T cells targeting Aspergillus fumigatus
Authors: Kumaresan Pappanaicken , Wurster Sebastian , da Silva Thiago , Bavasi Karishma , Albert Nathaniel , Hauser Paul , Neelapu Sattva , Kontoyiannis Dimitrios 
Published: November 2024

Abstract
Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the scFv domain of AF-269-5 mAb and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited potent release of cytotoxic effectors and type 1 T-cell cytokines. Furthermore, AF-CAR T cells generated from peripheral blood mononuclear cells of four healthy human donors and expanded with cytokine stimulation (IL-2, IL-7+IL-15) regimens significantly suppressed mycelial growth of AF-293 after 18 h of co-culture. Moreover, cyclophosphamide-immunosuppressed NSG mice with invasive pulmonary aspergillosis that received two doses of 5 million AF-CAR T cells on days 0 and 2 after AF infection showed significantly reduced morbidity on day 4 post-infection (p&lt;0.001) and significantly improved 7-day survival (p=0.049) compared to mice receiving non-targeting control T cells. In conclusion, we developed a novel lentiviral strategy to obtain AF-CAR T cells with high targeting efficacy, yielding significant anti-AF activity in vitro and short-term protection in vivo.
Novel highly immunogenic DNA vaccine regimen potently activates lymph nodes in macaques.
Authors: Felber Barbara , Moussa Maha , Karaliota Sevasti , Rosati Margherita , Devasundaram Santhi , Goldfarbmuren Katherine , Bear Jenifer , Burns Robert , Khandhar Amit , Reed Steven , Pavlakis George 
Published: November 2024

Abstract
Background
We evaluated a novel DNA vaccine delivery by LION™ nanoparticles for its ability to induce innate and adaptive immune responses in Rhesus macaques.
Methods
CoV-2 Spike or HIV Env DNA were formulated with a cationic nanocarrier (Lipid InOrganic Nanoparticle; LION™) administered via the IM route. Chemokine/cytokine and vaccine-specific responses were monitored in blood and lymph nodes (LN) by proteomics, flow, antibody assays.
Results
DNA/LION™ induced strong cellular and higher humoral responses than DNA/Electroporation and induced rapid (4-24hr) transient innate responses. Flow analysis showed activation of T, B, myeloid incl. dendritic cells in blood and their trafficking to LN with a strong increase of Tfh, Germinal Center Tfh CD4 and CD8 cells. Cell subsets were activated by cytokine networks incl. CXCL11, IL-7 and IL-15. GC-B cell activation directly correlated with increase of FLT3L and CXCL12 and importantly with antibody levels.
Conclusion
DNA/LION™ led to robust induction of cellular and humoral responses against different immunogens, serving as promising platform of effective nucleic acid vaccine delivery. Transient cytokine responses, incl. IL-15, resulted in strong activation of draining lymph nodes, and contributed to shaping adaptive (cellular and humoral) immunity. Our data showed rapid and coordinated cytokine responses to the vaccine and highlight the important role of innate responses to vaccination in modulating adaptive immunity.
Early life exposure to Candida albicans disrupts regulatory T cells
Authors: Crozier Shaunessey , Greenfield Kara , Avni Joshi , Knoop Kathryn 
Published: November 2024

Abstract
Fungal species are immunogenic members of the commensal microbiota, on the skin and the intestine. Opportunistic Candida albicans is associated with numerous allergic disorders, like atopic dermatitis, with ~90% of cases diagnosed by age 6. With an increased lifetime risk to other allergic disorders, C. albicans exposure in early life may contribute to the development of allergic-type responses. Premature infant stool sequencing found frequent C. albicans colonization suggesting colonization in the human GI tract. Previous observations found mice exposed to C. albicans prior to, but not post, weaning maintain colonization into adulthood. Neonatal colonization of C. albicans in the intestine, resulted in long term colonization and presented significantly decreased FoxP3+ T regulatory cells (Tregs) post-weaning in the mesenteric lymph nodes, small intestine, and colon lamina propria (LP). Additionally, RORγt+ and C-MAF+ Th17-cells were increased in the LP. By comparison, adult exposure to C. albicans through the skin or intestine, showed no disruption of FoxP3+ Tregs, suggesting neonatal exposure to C. albicans may be more disruptive to developing Tregs. Future research will focus on the impact of C. albicans presence to early microbiota complexity and diversity development. Treg establishment in early life is vital for tolerance and maintenance of commensal organisms, thus Treg disruption potentially links C. albicans colonization towards the development of allergic responses.
Mechanisms of TFR cell-mediated regulation of microbiota-reactive IgA responses
Authors: Abdi Abdullahi , Dent Alexander 
Published: November 2024

Abstract
The rising prevalence of food allergies impacting over 10% of the U.S. population requires innovative diagnostic approaches and therapeutic interventions. Gut microbiota alterations play a crucial role in food allergy development, with immunoglobulin IgA (IgA) actively regulating gut microbiome composition. While T follicular helper (TFH) cells aid in high-affinity antigen-specific IgA production, T follicular regulatory (TFR) cells' role in generating microbiota-specific IgA remains unclear. Using a unique TFR cell-deficient mouse model (Bcl6FC) and flow cytometry staining, we found increased fecal IgA-coated bacteria over time in Bcl6FC compared to WT mice after sensitization. IgA-seq revealed differential baseline microbiota IgA-coating in naïve Bcl6FC, displaying increased alpha diversity and more taxa with higher relative abundance than WT mice. Calculating the IgA-index demonstrated elevated IgA binding in Bcl6FC mice to specific taxa, primarily Firmicute members, indicating TFR cells' suppression of taxon-specific IgA in the peanut allergy model. Ongoing experiments, including the adoptive transfer of WT TFR cells into Bcl6FC mice and the assessment of IgA-coated biome function via Fecal Microbiota Transplantation (FMT) into germ-free mice in a peanut allergy model, aim to validate TFR cells' role in generating microbiota-specific IgA responses. This contributes essential insights for potential therapeutic antibodies targeting specific commensals.
The inhibitory effects of Hispidulin on mast cell-mediated allergic airway inflammation
Authors: Lee Soyoung , Jeong Seungwon , Park Chul-Kyu , Kim Sang-Hyun 
Published: November 2024

Abstract
Allergic asthma is a type 2 immune-response-mediated chronic respiratory disease. Recent studies have shown that mast cell activation influences the development and aggravation of allergic asthma. Therefore, the development of mast cell-targeting pharmacotherapy is important for regulating allergic airway inflammation. We investigated the efficacy of hispidulin (HPD) – natural flavone – in a mast cell-mediated ovalbumin (OVA)-induced allergic airway inflammation model. HPD alleviated symptoms of allergic asthma, mast cell infiltration, and reduced the levels of eosinophil peroxidase, β-hexosaminidase, and type 2 cytokines (IL-4, IL-5 and IL-13) in the bronchoalveolar fluid (BALF) and the level of immunoglobulins in serum. Furthermore, we confirmed the efficacy of HPD through the evaluation of IgE-mediated allergic responses in a mast cell line. HPD treatment inhibited mast cell degranulation through inhibition of the FcεRⅠ signaling pathway, and suppressed the expression of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-13) through suppression of the NF-κB signaling pathway. In addition, the antioxidant effects of HPD in activated mast cells were identified through modulation of antioxidant enzymes (SOD, Catalase) and the Nrf2/HO signaling pathway. In conclusions, HPD is a potential therapeutic candidate for allergic airway inflammation of asthma and acts by suppressing mast cell activation and oxidative stress.
SREBP signaling is important for pathogenic B cell responses in allergy.
Authors: Maldeney Alexander , Jiang Wenxia , Luo Wei 
Published: November 2024

Abstract
Severe IgE antibody-mediated allergic conditions impacts millions worldwide, significantly influencing both the survival and quality of life of those affected. Our previous research indicated the critical role of sterol regulatory element-binding protein (SREBP) signaling in mediating lipid homeostasis during B cell activation and the formation of germinal centers following immunization and viral infection. However, it remained unclear whether this pathway is also involved in the pathogenic B cell responses triggered by chronic allergen sensitization. Our latest findings show that ablation of SREBP signaling in B cells doesn't affect overall IgE levels in the serum. However, during chronic sensitization to house dust mites (HDM), SREBP signaling was essential for allergen-triggered germinal center responses and pathogenic antibody production. These results suggest the potential of targeting the B cell SREBP pathway as a treatment approach for allergies.
Peptide DMS-DA6 have immunomodulatory effects in a mouse model of actinomicetoma by N. brasiliensis
Authors: Duarte Diana , Rosenstein Yvonne , Vazquez-Marmolejo Anna , Mejia-Torres Manuel , Auvynet Constance , Salinas-Carmona Mario 
Published: November 2024

Abstract
Actinomycetoma is an infectious disease recognized by the World Health Organization as a neglected tropical disease. In the Americas, the most common etiologic agent is the Gram-positive bacteria, Nocardia brasiliensis. Current treatment is prolonged, toxic and resistant strains have emerged. A promising solution is the use of host defense peptides, which are recognized for their bactericidal activity and ability to control infection by modulating the host immune system. Recently, the peptide DMS-DA6, a dermaseptin from the skin of the frog Pachymedusa dacnicolor, was reported to be bactericidal against Gram-positive bacteria. However, the function of the DMS-DA6 in host defense against infection remains unknown. In this study, we investigated the in vivo properties and effects of DMS-DA6 in a mouse model of actinomicetoma by N. brasiliensis. After peptide administration, a significant reduction in the volume of the affected limb was observed; furthermore, flow citometry showed that DMS-DA6 modified systemic leukocyte populations, such as monocytes/macrophages, neutrophils and CD8+ T lymphocytes were significantly reduced in spleen and peripheral blood. Interestingly, the combination of DMS-DA6 with the antibiotic linezolid had the opposite effect, significantly inducing CD4+ and CD8+ T lymphocyte influx into the spleen. These results suggest that the peptide DMS-DA6 is a promising alternative approach and a valuable addition to the current anti-infective strategy.
A Role for NOD2 in Intestinal Memory T cell Formation and Function
Authors: Tsankov Boyan , Carr Charles , Nathan Nayanan , Bayer Giuliano , Philpott Dana 
Published: November 2024

Abstract
Aberrant resident memory T cell (TRM) responses have been associated with increased intestinal inflammation and Crohn’s disease (CD) pathology in humans. Genetic mutations in NOD2 are associated with the highest risk of CD development. NOD2 has been shown to be critical for initiating adaptive immune responses at systemic sites. However, the role of NOD2 in establishing memory T cell responses in the intestine remains unclear. Using an acute model of LCMV infection, we interrogated the role of NOD2 in intestinal memory T cell generation and function. Littermate wildtype or NOD2-deficient mice were infected intraperitoneally with LCMV-Armstrong, and the intestinal T cell priming, effector, and memory T cell responses were profiled in the mesenteric lymph nodes (mLN) and small intestinal lamina propria (SILP). Augmented NOD2 signalling at homeostasis and during infection increased endogenous and LCMV-specific CD4+ T cell numbers in the mLN, but not in the spleen. This effect was due to a NOD2-dependent increase in T cell homing to the mLN. Furthermore, NOD2-deficiency resulted in decreased effector and memory T cell numbers in the SILP. This effect was associated with decreased memory T cell functions in NOD2-deficient mice during ex vivo and in vivo recall experiments. Taken together, our experiments suggest a role for NOD2 in mediating optimal T cell priming in the mesenteric lymph nodes, which later affects effector and memory T cell functions in the intestine.
Host-pathogen interactions in Leptospirosis
Authors: Gupta Suman , Matsunaga James , Haake David , Sutterwala Fayyaz , Cassel Suzanne 
Published: November 2024

Abstract
Leptospirosis is an emerging zoonotic disease, predominant in tropical and sub-tropical climates, with increasing sporadic outbreaks worldwide causing around 60,000 deaths per year. The spirochetal bacteria Leptospira interrogans is the major causative agent of leptospirosis. Canines and livestock animals are particularly susceptible to Leptospira and develop acute symptoms. Rodents, on the other hand, serve as reservoir hosts in which the bacteria chronically colonize the kidneys and get excreted in the urine. Humans are incidental hosts but can develop fulminant disease which can prove fatal. The host immune response to Leptospira spp. remains poorly defined. Leptospiral lipopolysaccharide and lipoproteins can activate TLR4 and TLR2. In addition, leptospires have been shown to activate the NLRP3 inflammasome. However, we observed that L. interrogans induced a poor inflammasome response particularly in mouse macrophages when compared to other bacteria known to activate NLRP3 inflammasome. In contrast, L. interrogans induced robust type I IFN responses in both mouse macrophages and human monocytes. In vivo studies suggest a potential role of type I IFN response in controlling bacteria loads in mouse models. Interestingly, we found the type I IFN response to be dependent on both cGAS-STING and TLR4-TRIF pathways. Further, differences in disease susceptibility in mouse and humans, when infected with Leptospira, may be explained by differences in host-specific immune responses.
Cold-stored platelets do not potentiate detrimental monocyte and neutrophil proinflammatory responses in vitro
Authors: Chitrakar Alisha , Thomas Kimberly 
Published: November 2024

Abstract
Cold-stored platelets (CSP) have increased hemostatic function compared to room temperature-stored platelets (RTP), leading to recent FDA conditional approval for CSP transfusion in bleeding patients. However, the immune consequences of CSP transfusion are not well defined. CD62P and CD40L expression is increased in CSP, potentially enhancing interaction with neutrophils (PMN, CD62P:PSGL-1) and monocytes (Mo, CD40L:CD40). We hypothesized CSP would form aggregates with leukocytes more readily than RTP, thereby increasing tissue factor/CD142 expression, inflammasome assembly, and neutrophil extracellular trap (NET) formation – functions potentiated by native platelets. We stored apheresis platelets in plasma (PLT) for 7 days at 22oC (RT) or 4oC (CS), and incubated PLT with freshly isolated PBMC or PMN at a 1:14 ratio. We measured CD142 and Apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) expression by flow cytometry in Mo, and ASC specks and NET formation in PMN using fluorescent microscopy. We found no difference in CD142 or ASC GMFI expression in monocytes incubated with RT or CS PLT, and no difference in ASC specks or NET formation between neutrophils incubated with RT and CS PLT. Therefore, our in vitro study shows CSP do not potentiate detrimental acute proinflammatory responses by monocytes or neutrophils, further supporting CSP use in actively bleeding patients and paving the way for precision transfusion medicine.
NK-like CD8+ T cells in CMV-seronegative and -seropositive individuals
Authors: Kim Dong-Uk , Moon Bae-Hyeon , Koh June-Young , Shin Eui-Cheol 
Published: November 2024

Abstract
Human cytomegalovirus (CMV) infection is widespread, with a seroprevalence exceeding 50% globally. Although typically asymptomatic in healthy individuals, CMV establishes latent infection, which significantly impacts the immune system, particularly influencing T and NK cell compartments. Notably, the frequency of CD8+ T cells expressing natural killer (NK) receptors, such as NKG2C and KIR, is increased in CMV-seropositive individuals compared to CMV-seronegative individuals. In the current study, we aimed to examine the characteristics of the NK-like CD8+ T cell population in the context of CMV infection. Single-cell RNA sequencing analysis identified common transcription factor IKZF2 (Helios) expression in NK-like CD8+ T cells. Among 7 IKZF2 clusters, 2 IKZF2 clusters (CD56 IKZF2 and CD161 IKZF2 clusters) were found to be increased in CMV-seropositive individuals. The CD56 IKZF2 cluster exhibited a unique TCR repertoire and characteristics similar to stem-like IKZF2 clusters, which are similar to the thymus CD8αα T-cell population. In contrast, the CD161 IKZF2 cluster exhibited a TCR repertoire similar to IKZF2 TEMRA clusters, which in turn are akin to that of IKZF2(-) TEMRA clusters. Taken together, our study has identified characteristics of the NK-like CD8+ T cell population in the context of CMV infection.
∆9-THC attenuates neurodegeneration seen in HIV-gp120 transgenic mice through downregulation of microglial cell activation, astrocytosis and by reversing gut dysbiosis
Authors: Halder Urmi , Kakkar Khadija , Wilson Kiesha , Carter Tayler , Weyer Chloe , Mohammed Amira , Kaul Marcus , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: November 2024

Abstract
The GFAP-gp120Tg mice express soluble HIV-envelope protein gp120 in astrocytes and share many neuropathological features observed in the CNS of AIDS patients. Here, we investigated the effect of a cannabinoid, ∆9-THC, on gp120-mediated neuroinflammation and progression of neurodegeneration. We treated groups of GFAP-gp120Tg and C57/BL6 WT mice with ∆9-THC or the vehicle. Immunofluorescence imaging, flow cytometry, snRNA-sequencing, and shotgun sequencing were performed to understand the cellular and molecular level incidents. ∆9-THC reduced the neuroinflammation driven by gp120 by down-regulating the inflammatory chemokine receptors such as CCR5, CXCR4 on immune cells that directly access the CNS. Pronounced astrocytosis and microglial activation seen in Tg mice was significantly reduced following treatment with ∆9-THC. Neuroglial gene expression was also reversed after ∆9-THC treatment. Tg mice exhibited significant gut microbiota dysbiosis which was reversed by ∆9-THC. Members of the genera Alistipes, Prevotella, Plasmodium, Helicobacter, Desulfovibrio had higher relative abundance in Tg mice but reduced after ∆9-THC treatment. Taken together, this study demonstrates that ∆9-THC treatment significantly improves HIV-gp120-mediated pathogenesis of neurodegeneration, neuroinflammation, and helps to reshape gut microbiota (This work was supported in part by NIH grants R01ES030144, P01AT003961, P20GM103641, and R01AI123947, R01AI160896).
Variation in HIV-1 Tat activity is a key determinant in the establishment of active versus latent infection
Authors: Gomez-Rivera Francisco , Terry Valeri , Collins Kathleen 
Published: November 2024

Abstract
Despite effective treatment, Human Immunodeficiency Virus (HIV) remains latent as a transcriptionally silent provirus. Latent cells can evade the immune system and the harmful effects of the virus, thereby creating a long-lasting reservoir of HIV. To gain a deeper insight into the molecular mechanisms of HIV latency establishment, it is crucial to create tools that can detect and isolate cells that are infected with the virus but remain latent. We established a series of HIV-1 reporter constructs to better understand the factors that lead to latency. All the reporters identified the latent cell subset by flow cytometric detection of fluorescent probe expressed from the constitutive promoter without expression of a second fluorescent probe from the HIV LTR. The reporters can distinguish active and latently infected T cell lines and primary cells, including CD4+ T cells, and hematopoietic stem and progenitor cells. We observed that the proportion of active-to-latent infection increased with increasing virus inoculum, shifting the balance towards active infection regardless of the total infection rate. This suggested the hypothesis that at low viral inoculum, the availability of a viral factor needed for active infection was limiting. We demonstrated a reduced effect of inoculum size when tat was overexpressed regardless of whether exogenous Tat was introduced before or after integration. These results provide new insight into the mechanisms that govern latency establishment.
Targeting microglia with mannose-coated nanoparticles to improve pathology and behavior in a mouse model of Alzheimer’s disease.
Authors: badr Asmaa , Daily Kylene , Amer Amal 
Published: November 2024

Abstract
Neuroinflammation is a hallmark of Alzheimer’s disease (AD) pathobiology. Microglia in AD brains show elevated levels of microRNA-17 (miR-17), which maintains a balance between pro- and anti-inflammatory cytokine production. Microglia play an essential role in the production of cytokines; however, the role of microglial miR-17 in controlling neuroinflammation is not clear. We hypothesized that targeting miR-17 in microglia in vivo will decrease neuroinflammation and dampen immune cell activation, reducing amyloid beta (Aβ) deposition and preventing behavioral changes in AD mice. We generated mannose-coated lipid nanoparticles (MLNPs) enclosing an inhibitor to miR-17 (Anti-17 MLNPs) as mannose binds receptors on microglia. We used a 5XFAD mouse model that recapitulates AD-related phenotypes observed in humans. Anti-17 MLNPs were delivered to 5XFAD mouse brains by intra-cisterna magna injection. Our results show that MLNPs specifically deliver Anti-17 to microglia in vivo and in vitro. Anti-17 MLNPs attenuated the microglial inflammatory response to Aβ. Also, the Aβ burden in the brains of Anti-17 MLNPs mice was significantly lowered. A significant decrease in immune cell activation and cytokine production pathways was also identified in the brains of Anti-17 MLNPs-injected mice. This reduced spatial memory deterioration and decreased anxiety-like behavior in 5XFAD mice. We concluded that specific targeting of microglia with miR-17 antagomir improves pathology in AD.