bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sepsis-induced immune dysregulation and dysbiosis impairs cognitive abilities
Authors: Giridharan Vijayasree Vayalanellore , Generoso Jaqueline S , Lee Juneyoung , Petronilho Fabricia , Dal-Pizzol Felipe , Morales Rodrigo , Barichello Tatiana 
Published: February 2023

Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to microbial infection. More than 50% of sepsis survivors suffer from long-term cognitive deficits. Recently the disruption of gut microbiota at both compositional and functional levels was reported in sepsis patients. In this context, we aimed to explore if experimental sepsis-induced immune dysregulation and dysbiosis accelerates Alzheimer’s disease (AD) pathology. Male, 50-day-old APP/PS1 mice were subjected to cecal ligation and perforation (CLP) surgery for sepsis induction. Longitudinally, at 3, 30, and 120 days after sepsis or sham surgery, feces were collected for 16S rRNA sequencing and short-chain fatty acid (SCFA) evaluation. The brain was removed to measure Aβ expression and inflammatory cytokines levels. Cognition was tested using novel object recognition (NOR) task at 30 and 120 days after sepsis. Alpha and beta diversity analyses revealed higher disruption of intestinal communities at 30 and 120 days after sepsis. The levels of SCFA, such as acetic acid, butyric acid, isovaleric acid, and isobutyric acid, decreased in sepsis mice. At 30 days, IFN-γ, IL1-α, IL-12 (p40), eotaxin, and TNF-α were increased; at 120 days, anti-inflammatory cytokines IL-6, IL-10, and IL-13 were decreased in the hippocampus of sepsis mice as compared to control. At 120 days after sepsis, the AD pathological marker, Aβ expression, was elevated in the sepsis group. Further, at 30 and 120 days, the sepsis group demonstrated a significant cognitive decline. Sepsis-induced dysbiosis precedes overt cognitive impairment in APP/PS1 mice. Therefore gut microbiota can be targeted to impact outcomes from sepsis-related long-term cognitive decline positively.
Elucidating the mechanism of Interferon Beta (IFNβ) mediated neuroprotection in HIV associated neurocognitive disorder (HAND)
Authors: Koury Jeffrey , Singh Hina , Kaul Marcus 
Published: February 2023

Abstract
37 million people worldwide are diagnosed with Human Immunodeficiency Virus (HIV). An estimated 15–55% of these individuals develop HIV-associated neurocognitive disorder (HAND). Previous studies, including work in our lab identifies a transient increase of interferon beta (IFNβ), an anti-inflammatory and anti-viral type 1 interferon, preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and Simian Immunodeficiency Virus (SIV) models, suggesting a neuroprotective role for IFNβ in early HIV infection. We have previously shown that exogenous intranasal IFNβ treatment is sufficient to confer neuronal protection in HIVgp120 transgenic mice. However, the mechanism by which IFNβ mediates neuroprotection remains unclear. Here we focus primarily on the microglial contribution to IFNβ mediated neuroprotection, as HIV productively infects macrophage/microglia in the CNS.
In this study, we show that abrogating IFNβ down regulates expression of viral sensor, RIG-I, as well as interferon regulatory factors, IRF9, and most robustly IRF7 in the cortex of IFNβ KO HIVgp120tg mice. In addition, using the HMC3 human microglial cell line we show a robust dose dependent increase in innate immune anti-viral genes including IRF7, IFIT1, GBP1 and GBP4. Beyond its anti-viral effects, IFNβ treated microglia are potent inducers of the neuroprotective beta chemokines MIP-1a (CCL3), MIP-1b (CCL4) and RANTES (CCL5). Taken together, this data suggests that IFNβ may be conferring neuroprotection through microglial specific induction of anti-viral genes and neuroprotective beta chemokines CCL3, -4 and -5.
The Parkinson’s disease-associated variant Lrrk2 G2019S confers hyper-susceptibility to inflammasome-mediated cell death and Mycobacterium tuberculosis pathogenesis
Authors: Weindel Chi Gidley , Vail Krystal , Bell Samantha , Martinez Eduardo , Patrick Kristin , Watson Robert Owen 
Published: February 2023

Abstract
Leucine-rich repeat kinase 2 (LRRK2), a multifunctional kinase linked to Parkinson’s disease (PD), has been repeatedly implicated in mycobacterial infection, although it’s function outside the nervous system is poorly understood. To create a replicative niche within the harsh environment of a macrophage, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), needs to manipulate two major innate immune pathways, the type I IFN response and regulated cell death (RCD). Previously, we found that loss of LRRK2 (Lrrk2−/−) in macrophages results in type I IFN defects during Mtb infection in vitro and in vivo. We mechanistically linked this type I IFN reprogramming to LRRK2-dependent mitochondrial dysfunction and leakage of mtDNA into the macrophage cytosol. To further investigate the role of LRRK2 in Mtb pathogenesis, we shifted focus to the G2019S variant of LRRK2, which is the greatest genetic risk factor for PD. While the type I IFN response is normal in Lrrk2G2019S macrophages, their mitochondrial network is fragmented and depolarized. These macrophages also are more prone to a pyroptotic form of regulated cell death (RCD) that is dependent on mtDNA. Importantly, during Mtb infection in vivo, Lrrk2G2019S mice experience hyperinflammation and elevated signatures of pyroptotic cell death. Collectively, these data suggest that Lrrk2G2019S impairs mitochondrial health and enhances inflammatory cell death (pyroptosis) with severe in vivo consequences during Mtb infection. The potent enhanced inflammatory response present in the periphery of G2019S mice in vivo might begin to suggest a model where increased inflammation in the periphery could trigger or exacerbate neurodegeneration in carriers of this allele.
Clostridia metabolites promote intestinal barrier integrity to protect from food allergy.
Authors: Kemter Andrea Maria , Patry Robert T. , Hesser Lauren A. , Arnold Jack , Littmann Eric , Campbell Evelyn , Nagler Cathryn 
Published: February 2023

Abstract
We previously reported that a consortium of bacteria from the Clostridia class modulates intestinal barrier function through induction of IL-22 and prevents allergic sensitization to food in mice. We further investigated the properties of these bacteria and the mechanisms that underly their protective impact. Shotgun metagenomic sequencing of the anaerobically cultured Clostridia consortium identified genes which suggest the presence of flagellated bacteria. Motility was then confirmed using agar-based assays. Lysates generated from the consortium stimulated ileal tissue to produce IL-23 and IL-22 in vitro in a MyD88 and TLR5-dependent manner, specifically MyD88 signaling in CD11c+ cells. Together, these experiments support the presence of flagellin in our consortium. Flagellin is a TLR5 ligand that induces IL-23 production by CD11c+ dendritic cells, which stimulates IL-22 production in RORγt+ innate lymphoid cells (ILC3). In addition, we found that the Clostridia consortium produced indoles, known ligands for the aryl hydrocarbon receptor (AhR). In vitro stimulation of ileal tissue with indoles induced IL-22 production, and oral administration to antibiotic treated mice improved intestinal barrier function. Lastly, we observed impaired intestinal IL-22 production and barrier function, and exacerbated food allergy in mice that lack AhR signaling in RORγt+ cells such as ILC3, confirming the relevance of AhR signaling in our food allergy model. Production of flagellin and indoles are two potentially beneficial aspects of allergy-protective commensal bacteria and our knowledge of these pathways and metabolites will allow us to develop targeted therapeutics for the prevention or treatment of food allergy.
Gastrointestinal dysbiosis caused by a lack of Paneth cells promotes diet-induced obesity and trafficking of inflammatory immune cells into adipose tissues.
Authors: Joldrichsen Marisa R , Kim Eunsoo , Cormet-Boyaka Estelle , Boyaka Prosper N 
Published: February 2023

Abstract
Paneth cells regulate many aspects of gastrointestinal health through the antimicrobial products and cytokines they produce. Loss or defective Paneth cell function leads to dysbiosis and is one of the causes of Inflammatory Bowel Disease (IBD). The prevalence of obesity is growing in the general population and among recently diagnosed IBD patients, leading to the speculation that obesity increases IBD incidence, but the underlying mechanisms remain to be elucidated. We address whether gastrointestinal dysbiosis caused by a lack of Paneth cells influences obesity. Analysis of their fecal bacterial composition showed that Sox9ΔIEC mice, which lack Paneth cells due to a Sox9 gene deletion within the intestinal epithelium, have more Firmicutes bacteria (p&lt;0.001) in their feces. These mice were then fed a high fat diet for 13 weeks. When Sox9ΔIEC mice were fed a high-fat diet, they exhibited increased bacterial dysbiosis. Furthermore, intestinal permeability measured by FITC-dextran absorption in vivo was increased (p&lt;0.05) in Sox9ΔIEC mice. Finally, Sox9ΔIEC mice gained weight faster and ultimately became more obese than the wild-type mice and displayed impaired glucose tolerance (p&lt;0.0001) indicating the presence of a metabolic disorder. The Sox9ΔIEC mice developed larger abdominal fats, which included increased numbers of inflammatory immune cells such as macrophages (p&lt;0.05), neutrophils (p&lt;0.05), and T cells (p&lt;0.05). Interestingly, B cells were the most increased (p&lt;0.0001) immune cell population in abdominal fat tissues. These results suggest a new role for Paneth cells as regulators of diet-induced obesity via their effect on gastrointestinal dysbiosis and immune cell infiltration of omental fat tissues.
High-sugar diet predisposes colitis via promoting mucus degrading bacteria in the gut
Authors: Zaki Hasan , Khan Shahanshah 
Published: February 2023

Abstract
The Western diet characterized by high fat and high sugar is considered a risk factor for many inflammatory disorders including colitis. However, the impact of dietary sugars, such as glucose, fructose, and sucrose, on colitis remains poorly understood. We, therefore, investigated the role of dietary simple sugars in colitis using dextran sulfate sodium (DSS) and Il10−/− mice models. We fed WT mice with high sugar in drinking water or diet, followed by administration of 2.5% DSS plus high-sugar diet. Sugar-fed wild-type mice showed extreme sensitivity to DSS-induced colitis. Consistently, Il10−/− mice spontaneously developed severe colitis with the consumption of high sugar. To understand the underlying mechanism of detrimental effect of dietary sugar on colitis, we measured pathophysiological changes in the healthy gut. Interestingly, while there was no induction of cell death, inflammatory mediators, and activation of inflammatory pathways, gut microbiota composition was significantly altered in sugar-fed healthy mice. Notably, the abundance of mucus degrading bacteria Akkermansia muciniphila and Bacteroides fragilis was increased. Consistently, bacteria-derived mucolytic enzymes were enriched and the colonic mucus layers were eroded in sugar-fed mice. Furthermore, germ-free mice colonized with microbiota from sugar-treated mice showed higher abundance of mucus degrading bacteria and increased colitis susceptibility. By demonstrating the complex interplay between high-sugar diet, gut microbiota composition, and intestinal mucus barrier, this study, therefore, elucidates a novel mechanism of colitis pathogenesis.
The role of B cell-derived acetylcholine in the regulation of antiviral immunity
Authors: Prieto Antonio Cembellin , Murray Kaitlin , Reardon Colin , Baumgarth Nicole 
Published: February 2023

Abstract
Acetylcholine (ACh) is a neurotransmitter of signals from pre to post-synaptic neurons and from neural to muscle and gland cells, requiring the enzyme choline acetyltransferase (ChAT) for production. ChAT-GFP reporter mice recently showed that ACh is produced also by B and T cells. The physiological role of B cell-derived ACh remains largely unknown. Using ChAT-GFP mice, we show that naïve, conventional (B-2) as well as B-1 cells are major contributors to ChAT expression in spleen, lymph nodes, lung and pleural cavities, with B-1 cells expressing ChAT at the highest frequencies. In contrast, naive CD4 and CD8 T cells are ChATneg. To study the function of B cell-derived ACh we first infected ChAT reporter mice with influenza A/Puerto Rico/8/34. Infection led to increased ChAT+ B-1, but not B-2 cell numbers in the lungs at 3 days post-infection and of ChAT+ CD4 T cells at day 7. ChAT+ CD4 T cells were CD44hi, while the resting CD44lo naïve CD4 and CD8 T cells remained ChATneg. Mice with a B cell-specific deletion in Chat showed changes in lung cell composition, had decreased weight loss, and significant increases in influenza-specific serum IgG1 at day 14 but not later, compared to their wild-type controls. The data suggest that B cell-derived ACh significantly affects lung inflammation during influenza A infection and regulates the size of early extrafollicular B cell responses.
Diverse Functional Autoantibodies that Underlie Immune Perturbations in COVID-19
Authors: Mao Tianyang , Wang Eric Y. , Klein Jon , Dai Yile , Huck John D. , Liu Feimei , Zheng Neil S. , Zhou Ting , Goldman-Israelow Benjamin , Wong Patrick , Lucas Carolina , Silva Julio , Oh Ji Eun , Song Eric , Perotti Emily S. , Fischer Suzanne , Campbell Melissa , Fournier John B. , Wyllie Anne L. , Vogels Chantal B. F. , Ott Isabel M. , Kalinich Chaney C. , Petrone Mary E. , Watkins Anne E. , Cruz Charles Dela , Farhadian Shelli F. , Schulz Wade L. , Grubaugh Nathan D. , Ko Albert I. , Iwasaki Akiko , Ring Aaron M. 
Published: February 2023

Abstract
Infection with SARS-CoV-2 results in a broad spectrum of immunological and clinical outcomes for patients with COVID-19. While dysregulated innate immunity has been extensively explored in severe disease, autoantibody responses and their impact on disease trajectories remain uncharted. Here, we enrolled a cohort of 194 SARS-CoV-2 infected patients and uninfected individuals, and employed a high-throughput autoantibody discovery platform, Rapid Extracellular Antigen Profiling (REAP), to assess the prevalence of autoantibodies against 2,770 extracellular and secreted proteins in COVID-19 disease. We found that COVID-19 patients harbor dramatically expanded autoantibody repertoires compared to uninfected controls. We further established that immunomodulatory proteins including cytokines, chemokines, complements, and cell surface receptors, are frequent targets of autoantibodies. Longitudinal analysis revealed the existence of both pre-existing autoantibodies, as well as a broad subset of autoantibodies induced upon SARS-CoV-2 infection. We uncovered distinct mechanisms by which immune-targeting autoantibodies perturb immunological functions, including interference of immunoreceptor signaling, depletion of circulating leukocytes, and modulation of antiviral antibody responses. Concordantly, murine surrogates of these autoantibodies hinder immune activation and exacerbate disease severity in a mouse model of SARS-CoV-2 infection. In summary, through the lens of an unbiased proteome-scale survey for autoantibody targets, these findings implicate humoral immunopathology as an integral aspect of COVID-19 pathogenesis with diverse impacts on immune functionality and clinical outcomes.
Adoptive B cell therapy improves viral control during a chronic viral infection.
Authors: Chung Young Rock , Dangi Tanushree , Sanchez Sarah , Palacio Nicole M , Penaloza-MacMaster Pablo 
Published: February 2023

Abstract
T cell-based therapies have been explored for the treatment of cancer and chronic infection. However, B cell-based therapies have remained largely understudied. To evaluate the antiviral effect of adoptive B cell therapy, we adoptively transferred virus-specific B cells into mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). This resulted in a significant increase in antibody titers and reduction of viral loads. Interestingly, blockade of the IFN-I pathway using IFNAR1 blocking antibodies abrogated the antiviral effect of adoptive B cell therapy, suggesting that IFN-I signaling is necessary to control infection after adoptive B cell therapy. These findings provide a proof-of-concept that adoptive B cell therapy can be effective for the treatment of chronic infections.
Intrinsic antibody mediated enhancement of ZIKV infection in placental macrophages
Authors: Moore Kathryn , Zimmerman Matthew G , Kauffman Robert C , Wrammert Jens , Suthar Mehul S 
Published: February 2023

Abstract
Zika virus (ZIKV) vertical transmission from mother to child in utero is associated with a number of neonatal abnormalities, including congenital microcephaly. Yet, the mechanism by which ZIKV infects the placenta and subsequently the fetus remains poorly understood. ZIKV and Dengue virus (DENV) endemic regions are commonly overlapping, and DENV specific antibodies can cross-react with ZIKV. We and others have previously demonstrated that cross-reactive DENV IgG can mediate ZIKV infection of placental cells though increased viral entry via Fc receptors. Specifically, we found that infection with ZIKV immune complexes (ZIKV-IC) generated from cross-reactive anti-DENV monoclonal IgG was enhanced in human placental macrophages called Hofbauer cells, which are found within the chorionic villus stroma near the fetal vasculature. In this study, we aimed to characterize the intrinsic cellular changes that occur in Hofbauer cells as a result of ZIKV-IC infection. We performed RNA sequencing on Hofbauer cells infected with ZIKV complexed with different concentrations of anti-DENV monoclonal IgG. Principal component analysis revealed that while ZIKV incubated with anti-influenza IgG had a similar gene expression profile to ZIKV alone, ZIKV-IC infection with increasing anti-DENV IgG skewed gene expression towards a unique phenotype. We identified a number of transcriptional profiles related to anti-DENV IgG dose. Notably, we observed a pattern of decreased interferon stimulated genes with increasing anti-DENV IgG dose. Yet, increasing anti-DENV IgG also increased ZIKV viral RNA. These results may indicate that ZIKV-IC infection makes Hofbauer cells more permissive to ZIKV replication by modulating the innate antiviral response.
Differential use of complementarity-determining regions by synthetic nanobodies identifies multiple epitopes on receptor binding domain of SARS-CoV2
Authors: Dhobi Javeed Ahmad , Jiang Jiansheng , Boyd Lisa F , Natarajan Kannan , Margulies David H 
Published: February 2023

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, enters host cells through the receptor angiotensin-converting enzyme 2 (ACE2). Identification of numerous variant strains of SARS-CoV-2 have demanded unprecedented attention in developing rapid diagnostics, effective therapies, and safe vaccines to bring the current pandemic under control. Rapid progress is underway in the characterization of fundamental aspects of the structure and mechanisms of viral adsorption to cells, entry, and replication as well as in studies of the immune response to the virus. Here we report binding studies and crystal structures of the spike protein receptor binding domain (RBD) in complex with two individual synthetic nanobodies (sybodies) (Sb16 and Sb45). These bind the RBD at the previously identified ACE2 interface, positioning their complementarity determining region (CDR)2 and CDR3 in diametrically opposite orientations with large buried surface area. We also solved a structure of the RBD simultaneously bound by two sybodies, Sb45 and Sb68. In this structure, Sb45 binds at the ACE2 interface and Sb68 interacts at a second site. Comparison of structures of Sb16 both free and bound to RBD reveals a large movement of its CDR2 loop. Structural insights gained from these synthetic nanobody complexes will be helpful in designing new vaccines and expand the possibilities of using high affinity antibodies or linked bifunctional antibodies for therapy.
T-bet expression marks a transcriptionally and functionally distinct population of memory B cells
Authors: Risley Christopher A , Scharer Christopher D. , Boss Jeremy M. , Lund Frances E 
Published: February 2023

Abstract
Memory B cells (Bmem) rapidly differentiate and mount antibody (Ab) responses to previously encountered antigen (Ag). Mouse Bmem can be subdivided using BCR isotype or expression of CD73, CD80, and PD-L2. Many of these Bmem populations were discovered following vaccination with alum-adjuvanted Ag, which drives a distinct immune response from those generated after infection with IFN-inducing viruses. We previously demonstrated that the IFNγ-inducible transcription factor T-bet is required for Bmem recall responses to influenza but not nematode infections, suggesting that T-bet might regulate anti-viral Bmem. Therefore, we hypothesized that the anti-viral Bmem compartment likely contained cells that were distinct from the established subpopulations. Here, we show that T-bet expression within the flu-specific Bmem is heterogeneous and not restricted to any of the previously described Bmem subsets. Furthermore, B cell-intrinsic T-bet ablation caused the loss of one of these Bmem subpopulations, and inducible deletion of T-bet in Bmem caused the loss of the same subpopulation. To determine how T-bet regulates the Bmem compartment, we performed single-cell RNAseq and CITEseq on flu infection-induced Bmem. We identified numerous transcriptionally distinct clusters of Bmem, several of which express T-bet as well as genes associated with plasma cell function. Consistent with this, in vitro assays show that T-bet+ Bmem differentiate more robustly than T-betneg Bmem. These data show that the anti-viral Bmem compartment is heterogeneous and includes a T-bet expressing subpopulation that appears poised for rapid Ab responses. Thus, T-bet appears to be important for the maintenance and function of some, but not all, Bmem.