bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of autophagy markers in clinical cases of sepsis
Authors: Madiraju Charitha , Mallarpu Chandra Shekar , Prasad Sudhir , Singarapu Maneendra , Brar Harvinder , Bratic Nemanja , Haririparsa Neda , Kim Jean H. , Ponnana Meenakshi , Chelluri Lakshmi Kiran 
Published: January 2023

Abstract
Apoptotic cell death plays a key role in sepsis-induced immunosuppression and organ dysfunction. Autophagy may serve as a compensatory protective mechanism in sepsis owing to its potential role in reversing cell death-induced immunosuppression. The goal of our study was to investigate for the presence of autophagy markers in septic patients. Our preliminary study design included patients diagnosed with, and treated for, sepsis in clinical settings (N =13). Healthy volunteers served as control subjects (N = 10). Markers of autophagy were assessed in serum, peripheral blood mononuclear cells (PBMCs) and PBMC lysates derived from patients and healthy controls. Samples were analyzed by ELISA and flow cytometry methods. Data and statistical analyses were performed using GraphPad Prism v7.0. Results from flow cytometry analysis showed significantly elevated levels of autophagy markers in PBMCs derived from septic patients compared to that observed in PBMCs from control subjects (p &lt; 0.01 from unpaired t-test analysis). Results from ELISA experiments showed significantly lower levels of the autophagy marker in patient serum samples when compared to that seen in control serum samples (p &lt; 0.01 from unpaired t-test analysis). ELISA analysis showed a concomitant increase in the same autophagy marker in PBMC lysates obtained from patients with sepsis compared to that observed in PBMC lysates from control subjects. Preliminary results serve as a basis for us to investigate the role of autophagy in the prediction of clinical outcomes in sepsis.
URT bacterial microbiota interacted with H1N1 infection by IL-1 pathway in C57BL/6
Authors: li heng , Wu Qiongwen , Guo Lei , Li Nan , Zheng Huiwen , Li Hongzhe , Yang Zening , Huang Xing , Yang Jinxi , Chu Manman , Liu Longding 
Published: January 2023

Abstract
The bacterial microbiota correlated with the inflammatory response, and inflammations are developed with high frequency when infections happened in the upper respiratory tract (URT). However, it has rarely been studied that the mechanisms in the interaction between the bacterial microbiota and the infections appeared in URT. In our subjects, we researched the interaction between H1N1 infection and URT bacterial microbiota by IL-1 pathway in C57BL/6. We extracted the DNA in URT and performed 16S rRNA amplicon sequencing. When IL1 gene was knocked out, Streptococcus, Bergeyella and Enterococcus increased as major parts in the bacterial microbiota, and Staphylococcus, Rothia and Atopostipes decreased noticely. And then, the wild type mice and IL1−/− mice were infected by H1N1 in 1500TCID50, and the samples on Day1, Day3 and Day7 were collected to detect the URT bacterial microbiota. We found that these bacterias correlated with IL1 maybe play important roles in H1N1 infection. We validated the increase of streptococcus pneumoniae, Bergeyella zoohelcum and Enterococcus faecalis, and the decrease of Staphylococcus lentus and staphylococcus aureusby real time PCR. The RDA analysis and regression analysis showed that the virus load of H1N1 in URT correlated with the bacterial microbiota composition noticeably. The detection of the IgG, IgA and memory B cells showed that there were simmilar trends in wild type mice and IL1−/− mice, and the level of memory B cells in wild type mice were more. We analysized comprehensively the results above, and indicated that the clear correlation between the bacterias in URT and the H1N1 infection, maybe the URT bacterial microbiota could play roles in the immune system to response to the H1N1 infection.
Resistin immunomodulation in healthy and septic patients
Authors: Li Jiang , Bonenfant Jeffrey , Nasouf Luqman , Miller Joseph , Mittal Aarti , Klein Walter , Nair Meera G 
Published: January 2023

Abstract
Sepsis is a major healthcare challenge worldwide with no effective therapies. Sepsis pathogenesis involves immune dysregulation, however, the underlying mechanisms of inflammation that are protective or pathogenic in sepsis remain unclear. Human resistin is an immune cell-derived protein that is elevated in sepsis. Employing human resistin-expressing transgenic mouse we identified a protective role for resistin in preventing fatal LPS endotoxic shock. Resistin binds to the LPS receptor, Toll-like receptor 4, through its N-terminal helix and triggers a switch from pro-inflammatory to anti-inflammatory responses. We hypothesize that resistin is a novel therapeutic for sepsis. We generated recombinant resistin and resistin N-terminal helices and tested their anti-inflammatory function in peripheral blood mononuclear cells (PBMC). Resistin, or its N-terminal helix alone, inhibited LPS-induced TNFa secretion by PBMC from healthy donors, but this inhibitory activity was abrogated without the helical structure. Next, we recruited 46 septic patients; 52% infection with LPS-rich gram-negative bacteria, and 30% mortality. Preliminary analysis revealed that circulating resistin was significantly higher in all septic patients compared to healthy donors, but that there were three distinct groups in the septic samples: high, medium and low resistin expression. Flow cytometry analysis revealed striking changes in immune cell subsets including monocytes, neutrophils, T cells and natural killer cells. Ongoing studies are investigating the immunomodulatory potential of resistin and its N-terminal helix in septic samples and associations with the infectious pathogen, circulating cytokines and immune cell subsets.
HIV infection drives immune activation of angiogenic T cells
Authors: Tong Li , Schmidt Marcel , Zhu Ziang , Chen Jinya , Wellstein Anton , Kumar Jai , Kumar Princy , Catalfamo Marta 
Published: January 2023

Abstract
In patients with HIV infection, chronic immune activation, systemic inflammation and endothelial dysfunction have been identified as the main drivers of cardiovascular risk/disease. In addition, recent reports have shown that, T cells with angiogenic properties (Tang) contribute to vascular repair by promoting new vessels formation in vivo and in vitro. In the present study, we hypothesized that HIV drives immune activation of Tang cells. We measured the frequency and phenotype of circulating Tang cells defined as CXCR4+CD31+. Patients with HIV infection and well controlled viral replication by cART (n= 25) showed a decreased proportion of both CD4 and CD8 Tangs cells when compared to healthy controls (n= 12), although this difference was more striking in the CD8 Tang subset. CD8 Tang but not CD4 Tang cells were significantly decreased in HIV negative patients whom are undergoing PrEP (Pre-Exposure Prophylaxis) therapy, (n=5). In addition, we found that: angiogenic T cells as defined by the surface markers CXCR4 and CD31 are a heterogenous population including naïve, memory and terminal effector memory phenotypes. Tang cells of HIV infected patients showed an activated phenotype with increased expression of granzymes A (GZA) and B (GZB) when compared to healthy controls. Lastly, CD4 and CD8 Tang cells show increased expression of CD49f (integrin a-6). The frequency of Tang GZA+GZB+ in patients with HIV infection was positively associated with 10yr cardiovascular risk score (ASCVD), CD4 Tang (R= 0.51, p= 0.02) and CD8 Tang (R= 0.6, p&lt; 0.01). These results suggest that in the context of HIV infection, angiogenic T cells possess an immune activated phenotype with a proinflammatory potential that may alter their ability of vascular repair
Endoplasmic reticulum stress regulates immunosuppressive function of myeloid derived suppressor cells in leprosy
Authors: Kelly-Scumpia Kindra , Shirazi Roksana , Modlin Robert 
Published: January 2023

Abstract
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells defined by their phenotype along with the ability to suppress adaptive T cell responses. Although MDSC are expanded in response to microbial infection, the factors that regulate the suppressive function of MDSC in this context are not known. Here, we studied MDSC in patients with leprosy, a chronic infectious disease caused by Mycobacterium leprae, in which the clinical manifestations including bacterial load present on a spectrum that correlates with the type of immune response. We found cells with a granulocytic MDSC phenotype are increased in patients across the spectrum of leprosy. However, only MDSC from leprosy patients with disseminated multibacillary infection, not patients with localized paucibacillary disease or healthy controls, suppress M. leprae- specific T cell proliferation and IFN-γ production. An increase in an ER stress gene signature was seen in MDSC from multibacillary patients vs paucibacillary patients. Additionally, the immunosuppressive function of MDSC from multibacillary patients was reversed by either treatment with a free radical scavenger or blockade of interleukin (IL)-10. Conversely, induction of ER stress in MDSC-like cells from paucibacillary patients was sufficient to induce suppressor activity. These studies of human leprosy link multibacillary infection, ER stress and MDSC suppressive function.
Commensal microbiota as possible pathobiont in autoinflammatory disease
Authors: Siak Jay , St. Leger Anthony , Raychaudhuri Kumarkrishna , Mattapallil Mary , Fuss Ivan J , Goldbach-Mansky Raphaela , Strober Warren , Caspi Rachel R 
Published: January 2023

Abstract
The ocular surface has an associated microbiome that contributes to maintenance of local immune homeostasis and protects the ocular surface from fungal and bacterial infections. However, in individuals with a dysregulated immune response, commensal flora could cause pathology. In this study, we seek to understand how an ocular commensal colonizing humans and mice, C. mastitidis (C. mast), stimulates immunity in the immunologically perturbed host. Cryopyrin Associated Periodic Syndrome (CAPS) patients suffer from systemic and ocular autoinflammatory disease caused by a hyperactive NLRP3 inflammasome. Knock-in mice bearing a mutated NLRP3 gene cloned from a CAPS patient responded to ocular colonization with C. mast by increased conjunctival neutrophilia, which progressed to overt ocular surface disease. Compared to wild type (WT) controls, their BM dendritic cells produced elevated IL-1 in response to C. mast. Additionally, gd T cells, which were primarily the Vg4 subset, isolated from eye-draining lymph nodes of C. mast-associated mutant mice were more activated and produced more IL-17, suggesting a qualitatively analogous but quantitatively amplified response compared to WT. Importantly, the same commensal elicited strongly elevated IL-17 production from leukocytes of inflammasome disease patients when compared with healthy controls. Our results suggest that C. mast induces an abnormal immune response in the NLRP3 mutant and acts as a pathobiont, in contrast to its behavior in the immunologically normal host. Based on these data, we hypothesize that the recurrent non-infectious conjunctivitis observed in CAPS patients may be driven by a hyperactive immune response to their own ocular surface bacteria.
Modulation of respiratory syncytial virus-induced epithelial proinflammatory mediator HMGB1 via activation of histone deacetylase
Authors: Kempaiah Kempaiah Rayavara , Kurosky Alexander , Hosakote Yashoda Madaiah 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of serious respiratory illness in children and a major cause of severe respiratory morbidity and mortality in the elderly, for which no effective treatment or vaccine is currently available. High Mobility Group Box-1 (HMGB1) is a redox-sensitive multifunctional nuclear protein that translocates to the cytoplasm and subsequently released to the extracellular space during infection and injury, and regulates immune and inflammatory responses as a damage-associated molecular pattern. Our studies show that RSV-induced oxidative stress hyperacetylates, phosphorylates and oxidizes HMGB1 to promote its extracellular release and that secreted HMGB1 triggers inflammatory responses by activating innate immune cells to promote inflammation. The goal of this study was to investigate the effect of histone deacetylases HDAC1 and sirtuin 1 (SIRT1) activation on RSV-induced epithelial HMGB1 extracellular release and its proinflammatory function. Studies were conducted in airway epithelial cells, a human lung carcinoma cell line and normal small alveolar epithelial cells. Cells were transfected with HDAC1 and SIRT1 siRNA followed by infection with RSV and determined HMGB1 levels by Western blot, ELISA and RT-PCR. Our studies demonstrated that inhibition of deacetylase activity enhanced RSV-induced HMGB1 secretion due to increased acetylation of HMGB1, which promotes inflammation. Activation of deacetylases using resveratrol significantly inhibited RSV-induced HMGB1 release. These studies will lead to the modulation of the RSV-induced epithelial HMGB1 proinflammatory function, which may pave the way for the development of novel therapeutic interventions for RSV infections.
Skin transcriptomics reveals novel insights into pathophysiological mechanisms in humanized mice models of Group A Streptococcal Necrotizing Soft Tissue Infections
Authors: Nookala Suba , mukundan Santhosh , Scheidegger Adam , Ambigapathy Ganesh , Combs Colin , Kotb Malak 
Published: January 2023

Abstract
Despite prompt surgical debridement, clindamycin treatment with adjunct intravenous immunoglobulin and hyperbaric oxygen therapies, Necrotizing Soft Tissue Infections (NSTI) caused by Group A Streptococcus (GAS) bacteria progress rapidly into deeper layers of tissues, fascia, or muscle, portending significant morbidity and mortality. Our previous findings strongly support a role for host genetic factors, specifically, polymorphisms in HLA-Class II alleles in driving differential disease severity and NSTI outcomes. To facilitate a better understanding of pathophysiological mechanisms underlying NSTI, this study used a combined network and pathway analysis of the transcriptome data of GAS infected skin lesions from transgenic mice expressing human HLA-II alleles associated with varying susceptibility to NSTI. Our data analysis not only reaffirmed known modulators of NSTI susceptibility but revealed novel transcription factors and signaling pathways unique to immune functions. From these data we predict potential mechanisms by which GAS adapts in previously unidentified host niches. Our findings also provide new insights into the consequences of these extreme adaptations of GAS in the host during NSTI.
Macrophage-associated lipin-1 enzymatic activity promotes inflammation in vitro and in vivo
Authors: Vozenilek Aimee E , Woolard Matthew D 
Published: January 2023

Abstract
During atherosclerotic progression, macrophage lipid handling dictates macrophage responses. As macrophages process modified low-density lipoproteins (modLDLs), glycerolipid synthesis is turned on to process lipids into storage sites for excess cholesterol. The key regulatory enzyme in this pathway is lipin-1, a phosphatidic acid phosphohydrolase. In vitro studies provide evidence that lipin-1 enzymatic activity initiates a PKCα/βII-ERK1/2-cJun signaling cascade that primes the macrophage to be hyper-responsive to subsequent pro-inflammatory stimulus. Our in vivo data demonstrated that mice lacking lipin-1 enzymatic activity in myeloid-derived cells (lipin-1mEnzyKO) had decreased atherosclerosis. However, it is currently unknown if the loss of lipin-1 and as a result the decreased inflammatory response is responsible for the decreased severity of atherosclerosis observed in our lipin-1mEnzyKO mouse model. We defined the transcriptome regulated by lipin-1 within modLDL/lipopolysaccharide stimulated wild-type and lipin-1mEnzyKO macrophages. The loss of lipin-1 led to a reduction of pro-inflammatory transcripts. To link the decrease in inflammation in the lipin-1mEnzyKO BMDMs with the decrease in atherosclerosis severity seen in vivo, we collected RNA from the aortic arch of lipin-1mEnzyKO and wild-type mice. Analysis of the RNA using an Atherosclerosis RT2 Profiler Array indicated that the lipin-1mEnzyKO mice showed increases in anti-apoptotic gene transcripts and decreases in transcripts related to extracellular matrix degradation suggesting lipin-1mEnzyKO mice may have more stable plaques.
Loss of testosterone impairs anti-tumor neutrophil function
Authors: Markman Janet , Wakita Daiko , Porritt Rebecca A. , Posadas Edwin , Crother Timothy R. , Arditi Moshe 
Published: January 2023

Abstract
In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown.

Methods
We used B16 and YUMM melanoma lung metastatic models. Neutrophil depletion, castration, testosterone (T) replacement, and bone marrow transplant (BMT) were performed. Neutrophils from prostate cancer patients were analyzed.

Data
In castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Remarkably, replacement of T effectively normalized the tumor burden in castrated male mice. Neutrophil depletion increased tumor burden only in males, suggesting a sex difference in neutrophils. Sex BMT experiments showed that the hormonal microenvironment is crucial, not the sex of the immune cell. Further, a BMT from ARTfm mice with a truncated androgen receptor increased tumor burden and impacted neutrophil function towards a pro-tumor phenotype. Finally, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype.

Conclusion
Our data indicate that innate immunity is important for the response against melanoma colonization and suggest a sex specific response of neutrophils with impaired function in the absence of T. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.
IL-15 Activates Liver Sinusoidal Mucosal-associated Invariant T Cells to Exert TCR/MR1-independent Innate-like Cytotoxicity
Authors: Rha Min-Seok , Han Ji Won , Kim Jong Hoon , Koh June-Young , Park Hye Jung , Kim Soon Il , Kim Myoung Soo , Lee Jae Geun , Park Jun Yong , Park Su-Hyung , Joo Dong Jin , Shin Eui-Cheol 
Published: January 2023

Abstract
Mucosal-associated invariant T (MAIT) cells are the most dominant population of innate-like T cells in the human liver and predominantly localized in liver sinusoids. MAIT cells can be activated by MR1-dependent TCR stimulation or cytokines such as IL-12 and IL-18. However, effects of IL-15 on MAIT cells have not been comprehensively studied, particularly in the aspect of their innate-like cytotoxic activity. In the present study, we examined effects of IL-15 on liver sinusoidal MAIT cells obtained from donor liver perfusates during liver transplantation. IL-15 activated MAIT cells to have a cytotoxic phenotype and induces cellular proliferation. Moreover, IL-15-activated liver sinusoidal MAIT cells exerted innate-like cytotoxicity that is independent of TCR and MR1. Increased target cell conjugation and NKG2D-dependent stimulation were responsible for innate-like cytotoxicity of IL-15-activated MAIT cells, and PI3K–mTOR pathway was critically required for IL-15-induced innate-like cytotoxicity. Furthermore, we observed an increased NKG2D expression in intrahepatic MAIT cells from patients with acute hepatitis A, in which liver injury is known to be mediated by IL-15-induced innate-like cytotoxicity of T cells (Immunity 2018, 48:161). In summary, our data demonstrate IL-15 activates liver sinusoidal MAIT cells to exert TCR/MR1-independent cytotoxicity, and suggest a potential role of liver sinusoidal MAIT cells in immune responses or immunopathogenesis in liver diseases.
Clonal selection of cross-reactive memory B cells dominates recall responses against heterologous flaviviruses without a requirement for secondary affinity maturation
Authors: Wong Rachel , Richner Justin , Zhao Haiyan , Shlomchik Mark J , Diamond Michael S , Bhattacharya Deepta 
Published: January 2023

Abstract
Members of the flaviviridae family include a number of globally relevant pathogens such as West Nile (WNV), Japanese Encephalitis (JEV), Dengue, and Zika viruses. Upon clearance of a primary flavivirus infection, both neutralizing and non-neutralizing antibody specificities are generated and maintained. These antibodies can play protective or pathogenic roles after subsequent infection with heterologous flaviviruses. To define the cells capable of responding to secondary heterologous infections, we utilized a WNV and subsequent JEV vaccination model. Using tetramer reagents directed at the potently neutralizing lateral ridge epitope on envelope protein domain III (DIII) of WNV. We found that memory B cells were more antigenically diverse and cross-reactive than were long-lived plasma cells. To determine how this memory B cell diversity is generated and subsequently utilized, we generated a mouse model in which deletion of activation induced cytidine deaminase (AID) is temporally driven by hCD20-CreERT2. Deleting AID during ongoing germinal center reactions against WNV did not affect the antigen specificity or quantity of memory B cells or bone marrow plasma cells. Deletion of AID during the memory phase following WNV vaccination did not alter the cellular response to JEV compared to wild type mice. Thus, cross-reactive B cells selectively enter the memory B cell compartment and are excluded from the long-lived plasma cell compartment through a B cell receptor affinity maturation-independent mechanism. Analysis of germline-reverted monoclonal antibodies derived from DIII-specific memory B cells and long-lived plasma cells suggests that the fate of a B cell is imprinted at the naive state.