bluuebunny/crossref_metadata_2025_split huggingface dataset:
What UV is what you get: skin injury by ultraviolet (UV) light results in renal cell loss and damage in the presence of a CD177high neutrophil population
Authors: Cortez Angelique , Mendyka Lindsay , Kolling Fred , Skopelja-Gardner Sladjana 
Published: August 2023

Abstract
Immune-mediated communication between organs has been implicated in the pathogenesis of many inflammatory and autoimmune diseases. We previously showed that skin injury by UV light triggers neutrophil migration to the kidney, stimulating expression of renal injury genes. This skin-kidney axis is highly relevant to lupus patients, for whom skin exposure to UV sunlight rays can lead to kidney disease flares. Here, we applied 10X single-cell RNA-seq on saline-perfused digested kidneys and Ly6G-enriched neutrophils of B6 mice, prior to and 2 days after a single dose of UV, to define renal cell subsets damaged by skin exposure to UV and how neutrophils mediate the injury. Dimensional reduction analysis revealed 14 kidney cell types and showed that exposure to UV led to the loss of podocytes and distal tubular cells (DTCs) and an expansion in endothelial and stromal cells. Differential gene expression analysis showed that podocytes and DTCs in UV-exposed mice upregulated genes associated with renal injury, including type I interferon genes, and downregulated genes important for cellular integrity and function. Neutrophil scRNA-seq revealed a unique activated CD177high neutrophil population in the kidneys of UV exposed mice, defined as the endpoint of the psuedotime trajectory by diffusion mapping. Ligand-receptor pair analyses showed skin injury by UV altered neutrophil interactions with renal structural cells, with expanded binding to stromal cells. While the CD177high neutrophil cluster was dominant in the kidney, it was also found in the lung, but not in the skin and blood. These studies introduce a novel model by which CD177high neutrophils may mediate podocyte, DTC, and stromal kidney injury secondary to sterile skin inflammation.
Supported by grants from NIH (1R21AR079661 – 01, 5P20GM130454-02), The Department of Defense (W81XWH2110889), and Dartmouth Health Start Up Funds.
Effector response to necroptotic cell death: an ensemble of immune and stromal cells
Authors: Hughes Lindsey D , Altun Osman , Nevin James T , Wang Mamie , Kluger Yuval , Pelorosso Facundo , Leighton Jonathan A , Rothlin Carla V , Ghosh Sourav 
Published: August 2023

Abstract
Cell death manifests through a panoply of molecular pathways. We postulated that the tissue effector response to cellular corpses is similarly diverse. Apoptotic cell death in the lung, in the context of helminth infection and an IL-4-rich environment, is sensed by macrophages to direct resolution of inflammation and a tissue repair gene expression program. Apoptotic cell death, however, is commonplace in the gut and integral to homeostatic tissue renewal in this organ. Another specific molecularly-executed cell death modality – necroptosis – has been reported in the gut in settings of non-resolving inflammation and tissue damage, such as in inflammatory bowel disease. Here we report the discovery of an effector response to necroptotic corpses (NC). Using a chemo-genetic approach to specifically trigger necroptosis in the intestinal epithelium in vivo, we compiled an atlas of transcriptomic changes at a single-cell level and compared this to inflammatory and resolving injury models. Fibroblasts and macrophages, upon encounter with NC, displayed an excessive inflammatory response. Fibroblasts are the major stromal cells that play an essential role in tissue healing by undergoing fibroblast to myofibroblast transition under the influence of TGF-β. This step is a critical event in wound healing as the contractile forces generated by myofibroblasts bring the two apposed edges of the wounded tissue together for wound closure. Exposure to NC prevented this myofibroblast transition. Taken together, these findings point to an invariant code that informs effector tissue responses based on the type, context, and sensor of cell death.
Plasma Derived Extracellular Vesicles Modulate Monocyte IL-18, IFN-α and IL-10 responses in Adults with HIV-related Cognitive Impairment
Authors: Yeung Stephen T , Marques de Menezes Erika G , Friday Courtney , Liu Jocelyn S , Bowler Scott A , Abdel-Mohsen Mohamed , Shikuma Cecilia , Norris Philip J , Ndhlovu Lishomwa C 
Published: August 2023

Abstract

Background
HIV-associated neurocognitive dysfunction persists despite suppressive antiretroviral therapy (ART). Extracellular vesicles (EVs) are emerging modulators of immunological responses. We have previously shown that EVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment (CI). Whether these EV changes observed in people with HIV (PWH) influence innate cellular function among those with CI remains unclear.

Method
Purified EV samples from 58 HIV-infected individuals on ART with either cognitive impairment (CI, n=48) or normal cognition (NC, n=10) and 8 uninfected controls were isolated using differential centrifugation and co-cultured with PBMCs from a single uninfected donor for 18 hrs. Eight intracellular cytokines and 13 surface chemokines and myeloid differentiation markers were assessed by spectral flow cytometry. Non-parametric statistical T tests were used.

Result
Monocytes (mono) showed differential effects on multiple cytokine responses and cell surface receptors after exposure to EVs from HIV-infected individuals with or without CI. Levels of mono IL-18 were significantly lower after incubation with EVs derived from HIV-infected individuals compared to uninfected controls. Based on cognitive status, EVs from HIV-CI group significantly lower % of IL-18 mono responses and lower IFN-α and higher IL-10 responses on a per cell basis when compared to the NC group.

Conclusion
These results suggest EVs can modulate mono function irrespective of HIV status. PWH with CI exhibited altered EV driven mono cytokine responses. Our data support interventions that target EVs to reverse or restore mono perturbations and limit neuropathology in PWH on ART.

Supported by grants from NIH (R21NS106970 and R01NS117458)
Investigating a Role for Eosinophils in the Immune Response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Authors: Snow-Smith Maryonne , Baker Paul J , Bohrer Andrea C , Castro Ehydel , Torres-Juarez Flor , Anderson Charles F , Makiya Michelle M , Sereti Irini , Klion Amy D , Mayer-Barber Katrin D 
Published: August 2023

Abstract
Eosinophils rapidly decrease in the peripheral blood of patients during COVID-19, and eosinopenia has been correlated with disease severity. These clinical observations suggest that eosinophils may play a functional role in the response to SARS-CoV-2 infection. Murine studies have shown that eosinophils can be recruited to the lungs in response to infection with respiratory viruses, including RSV and influenza and parainfluenza viruses, yet the role of eosinophils in the lungs in response to SARS-CoV-2 infection is unknown. Here, we used a two-pronged approach employing mouse models of SARS-CoV-2 infection to study the role of eosinophils in the antiviral immune response and viral control and clinical samples to assess eosinophilia and eosinophil activation in patients during and after COVID-19. Our initial findings indicate that eosinophils are recruited to the lungs after SARS-CoV-2 infection in mice and that eosinophil-deficient mice may have increased lung viral titers early after infection. In keeping with this hypothesis, serum levels of eosinophil granule proteins (a marker of tissue eosinophilia) were increased during active SARS-CoV-2 infection in patients participating in a long-term follow-up study of COVID-19, at a time when eosinophil counts were depressed. These preliminary data suggest that eosinophils may have a protective role in early anti-viral host defense during SARS-CoV-2 infection in mice and that further studies are required to better understand the relative roles of eosinophils in protection and pathology to SARS-CoV-2 infection.
Funding for this study was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
IL-10 promotes tissue-resident memory T cells (TRM) in the respiratory tract during SARS-CoV-2 infection in rhesus macaques
Authors: Nelson Christine , Foreman Taylor , Namasivayam Sivaranjani , Kauffman Keith , Gomez Felipe , Sakai Shunsuke , Brooks Kelsie , Brenchley Jason , Via Laura , Barber Daniel L 
Published: August 2023

Abstract
T cells are thought to be important for control of SARS-CoV-2 infection, but little is known about the host factors that promote T cell responses in the respiratory tract. We used non-human primates to investigate the regulation of respiratory immunity during mild SARS-CoV-2 infection. We first examined the kinetics of viral replication, inflammation, and host immune responses. Foci of inflammation detected with 18FDG-PET/CT imaging peaked within 2–3 days of infection. Single cell RNA sequencing revealed an early influx of IFN-activated myeloid cells into the airways, which correlated with viral RNA loads. Antigen-specific T cell responses were first detected after inflammation and viral replication had resolved and were preferentially localized to the lower airways. We next examined the role of pro and anti-inflammatory cytokines, IFNγ and IL-10, on immunity to SARS-CoV-2 infection by blocking these cytokines with monoclonal antibodies early during infection. IFNγ blockade decreased lung inflammation but had no major impact on adaptive immune responses. In contrast, IL-10 blockade increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69+CD103+ tissue resident memory cells (TRM). While virus-specific T cells were undetectable in the nasal mucosa, IL-10 blockade similarly reduced the frequency of bystander TRM cells in the nasal mucosa. Thus, in the setting of mild SARS-CoV-2 infection IL-10 has a key role in suppressing local lung inflammation and the accumulation of SARS-CoV-2-specific T cells, while also promoting TRM at respiratory mucosal surfaces.
Division of Intramural Research at NIH
Interferon-lambda accelerates viral clearance and regulates CD8+ T cells immunity in a murine model of SARS-CoV-2 infection
Authors: Solstad Abigail , Kenney Adam D , Mahfooz Najmus Sahar , Zani Ashley , Kawahara Jeffrey , Robinson Richard T , Forero Adriana , Yount Jacob S , Hemann Emily A 
Published: August 2023

Abstract
SARS-CoV-2 remains a significant global health burden. A better understanding of the requirements for protective host immunity against SARS-CoV-2 will contribute to the development of novel therapeutic strategies to prevent disease. Type III interferon (IFN-lambda) limits SARS-CoV-2 infection in vitro and in murine models of infection. In clinical trials, IFN-lambda treatment accelerates viral clearance of SARS-CoV-2 and reduces risk of hospitalization. However, roles for IFN-lambda in regulating SARS-CoV-2 pathogenesis and protective immunity are not well understood. Infection of C57BL/6 (WT) and IFN-lambda receptor deficient mice (Ifnlr1−/−) with mouse-adapted SARS-CoV-2 lead to increased weight loss and viral load in Ifnlr1−/− compared to WT through day 5 post infection (pi). Global transcriptomics revealed differential regulation of proliferation and immune cell programming pathways in Ifnlr1−/− lungs compared to WT, suggesting IFN-lambda signaling regulates protective pathways outside of canonical interferon stimulated gene responses following SARS-CoV-2 infection. Histological and flow cytometric analysis confirmed an increase in proliferation in multiple cell subsets within lungs of Ifnlr1−/− lungs compared to WT following SARS-CoV-2 infection. Additionally, SARS-CoV-2 specific CD8+T cells in the lungs of Ifnlr1−/− mice are significantly reduced compared to WT on day 8 pi. Together, these studies suggest IFN-lambda signaling is required for regulation of proliferative repair pathways and CD8+T cell immunity against SARS-CoV-2. Overall, broadening the understanding of how IFN-lambda regulates SARS-CoV-2 infection, pathogenesis, and immunity may inform its therapeutic utilization.
SARS-CoV2 Decreases Human Beta-Defensin-1 and FoxI1 in the Oral Cavity Without Affecting CFTR
Authors: Ryan Lisa K , Barney Weston J , Tierney Paige K , Kim Jumin S , Robinson Tanya O , Dhaliwal Neha S , Wichman T Grant , Glover Sarah C 
Published: August 2023

Abstract
The ionocyte is a newly characterized cell, first identified in the airway, that is hypothesized to play a role in innate immunity. Single cell RNA seq analysis showed that ionocytes (FoxI1 and CFTR-expressing cells) are also found in the oral cavity, and highly express human beta-defensin-1 (hBD-1). We showed that hBD-1 expression is upregulated by influenza, Herpes simplex virus and Sendai virus infection of monocytes and plasmacytoid dendritic cells but is downregulated in epithelial cells. The role of hBD1 in oral ionocytes in relation to SARS-CoV-2 infection is unknown. We tested the hypothesis that SARS-CoV2 virus modulates the expression of hBD-1, and this is associated with CFTR and FoxI1 expression in ionocytes in the oral cavity. Buccal swabs from patients with Covid19 and without Covid19 (recovered from Covid19 and non-Covid19) were analyzed for gene expression via quantitative RT-PCR of hBD-1, FoxI1, and CFTR. HBD-1 and FoxI1 mRNA levels (relative to beta-actin) were significantly decreased, but CFTR mRNA remained unchanged in the Covid19 patient cohort compared with the non-Covid19 and recovered patients. This supported the in vitro observation that enveloped viruses decrease hBD-1 in epithelial cells that make up most of the buccal swab sample. Immunohistochemistry on normal minor salivary gland sections revealed that FoxI1, CFTR and hBD-1 are all associated in proximity in the duct of the minor salivary gland. However, crosslinking studies, followed by Western blot analysis, indicated that hBD-1 and CFTR were not interacting. In conclusion, SARS-CoV2 modulates innate immunity in the oral cavity, as indicated by the decrease in hBD-1, and affects ionocytes, possibly affecting pH and osmolality in salivary glands.
Research supported by a grant from NIH / NIDCR R01 DE031928 and the University of Louisville School of Dentistry Summer Research Scholar Program
STAT3 operates as a rheostat regulating sensitivity of NK cells to inflammatory cytokines
Authors: Grassmann Simon , Fan Sherry , Kim Ray , Beroshvili Giorgi , Sun Joseph Chai-Yuen 
Published: August 2023

Abstract
NK cells are innate lymphocytes that respond to a variety of cytokines during viral infection. Several homeostatic and inflammatory cytokines bind to receptors that signal via STAT3. STAT3 can form homodimers or heterodimers. To understand the role of STAT3 homodimers and heterodimers, we made use of knockout models in which NK cells lack STAT3 or specific cytokine receptors. We found that NK cells deficient in STAT3 expand less than wildtype NK cells during mouse cytomegalovirus (MCMV) infection. IL-21R and IL-10R are the only receptors expressed on NK cells that signal through STAT3 homodimers. However, IL-21R or IL-10R-deficient NK cells showed no or little expansion differences, suggesting additional cytokine receptors may be signaling through STAT3.
To evaluate whether STAT3 regulates the sensitivity of NK cells to cytokines that signal through heterodimerization partners STAT1 and STAT5, we performed cytokine titrations. We found that sensitivity towards IFN-a and IL-15 was reduced in STAT3-deficient NK cells. NK cells require inflammatory cytokines for antiviral expansion but proliferate poorly in hyper-inflammatory environments. Because STAT3 appears to regulate the sensitivity of NK cells to inflammatory cytokines, we hypothesized that STAT3-deficient NK cells would be shielded in settings of hyper-inflammation. Indeed, using high-dose MCMV infection, we observed that STAT3-deficient NK cells expanded better than WT NK cells. RNA-seq analysis further corroborated that in high-dose infection STAT3-deficient NK cells are nearly indistinguishable from WT NK cells during regular-dose infection. Thus, we believe STAT3 operates as a rheostat, modulating the sensitivity of NK cells to their inflammatory environment.
Supported by the Cancer Research Institute, Donald J. Gogel Postdoctoral Fellowship, CRI393
Interferon Regulatory Factor 7-mediated induction of interferon-α is required for survival from alphavirus encephalomyelitis
Authors: Nguyen Benjamin H , Troisi Elizabeth , Griffin Diane E 
Published: August 2023

Abstract
Alphaviruses are a group of arthropod-borne viruses that have the capacity to cause encephalomyelitis, which is inflammation of the brain and spinal cord due to the immune response to viral infection, and can result in fever, headache, and neurologic disease such as cognitive impairment, seizures, ataxia, and paralysis. Neurons are the primary target cells of Sindbis virus (SINV), the prototypic alphavirus; however, due to the indispensable nature of neurons, mechanisms of viral clearance from the central nervous system (CNS) during recovery cannot depend on immune-mediated killing of infected neurons and is therefore specialized. We have previously shown that interferon (IFN) regulatory factor (IRF) 7, a transcription factor important for amplification of type I IFN (mainly IFNα), is required for survival from infection with SINV. Mice deficient in IRF7 succumb to infection – despite local production of IFNβ – while wild type (WT) mice recover. Treatment of Irf7−/− mice with IFNα rescues the WT phenotype, suggesting that IRF7-mediated induction of IFNα and subsequent downstream signaling is required for survival from SINV infection. Additionally, Ifnb−/− mice do not phenocopy Irf7−/− mice, further suggesting that IFNα is required for survival while IFNβ is dispensable despite usage of the same receptor. Interestingly, Ifnb−/− mice have similar viral titers to Irf7−/− mice, implying that the protective effects of IFNα are independent from restriction of viral replication. These findings show subtype-specific differences in protection by type I IFN and can inform treatment options for alphavirus-induced encephalomyelitis.
These works have been funded by the U.S. National Institutes of Health (R01 NS087539 and T32 AI007417).
Transcriptomics approaches reveal neuronal antiviral immune mechanisms
Authors: Negatu Seble G , Vazquez Christine , Bannerman Carl , Saldana Xoshill , Jurado Kellie Ann 
Published: August 2023

Abstract
Arthropod-borne viruses exist worldwide and contribute to many neurological infections. Viral infections in the central nervous system (CNS) can lead to virus- and immune-mediated damage of the brain, which can cause severe physical and cognitive defects, or even death. While antiviral responses (such as Type I interferon) have been characterized in the periphery, it is not well understood how innate immune response are coordinated by the various cell types present in the brain. Certain neurotropic arboviruses, such as La Crosse Virus (LACV), predominantly infect neurons; however, it remains unclear how neurons mediate early innate immune responses in the CNS. Upon infection of primary murine cortical neurons and human IPSC-derived cerebral organoids with LACV, we observed widespread infection. Transcriptomics approaches revealed infection of neurons results in the upregulation of interferon-stimulated genes (ISGs) that are also detectable at the protein level. Notably, we found that bystander uninfected neurons have higher ISG expression than neighboring infected cells. Future directions aim to characterize how infected neurons communicate with uninfected bystander neurons during infection. To address this, I have optimized a ProbeSeq pipeline where I infect primary cortical neurons and further characterize infected and uninfected populations using fluorescence in situ hybridization and downstream RNA-sequencing.
Supported by the Penn Presidential PhD Fellowship.
Neuregulin-1 reduces vascular leak and airway epithelium permeability caused by respiratory viral infection
Authors: Hussain Syed-Rehan A , Santoro Jennifer , Rohlfing Michelle , Peeples Mark E , Grayson Mitchell H 
Published: August 2023

Abstract
Respiratory viruses, such as Respiratory Syncytial Virus (RSV), are associated with significant morbidity and mortality. Mice with pre-existing atopy are protected from mortality to Sendai virus (SeV), a rodent virus related to RSV. We found that lungs of atopic mice had increased levels of neuregulin-1(NRG1), and hypothesized that SeV induces death via lung vascular leak, and that NRG1 might inhibit vascular leakage. Non-atopic C57Bl/6 mice were treated with NRG1 (500ng/30 mcl, i.n) or PBS for five days before infection with SeV (2×105 pfu) or UV-inactivated SeV (UV-SeV) and 8 days post viral inoculation, Evan’s Blue Dye (EBD) was injected i.v with EBD concentration determined spectrophotometrically one hour later in homogenized lungs. Vascular leak in SeV-infected mice was 65.25% and 46.62% more than in UV-SeV-treated or SeV-infected mice pre-treated with NRG1, respectively. We also found that RSV infection of well-differentiated human bronchial epithelial cells (hBEC) grown at the air-liquid interface caused 70KDa FITC-Dextran leakage 8 days post-inoculation. NRG1 pretreatment for 5 days before RSV inoculation reduced epithelial leakage 8 days post-inoculation by 2.5 fold (p&lt;0.001). These results suggest NRG1 has the potential to improve epithelial barrier function in rodent and human systems and may explain the increased survival following a severe respiratory viral infection.
Abigail Wexner Research Institute at Nationwide Children’s Hospital, Start-up fund to MHG