bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-HIV, anti-inflammatory and safety profile of the PDB microbicide candidate (HUM8P.342)
Authors: Mueller Yvonne , Fraietta Joseph , Ratner Deena , Boesteanu Alina , Gupta Phalguni , Katsikis Peter 
Published: January 2023

Abstract
Topical microbicides (vaginal gels) are one mechanism to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1). We show here that a new class of microbicides, abasic phosphorothioate 2’ deoxyribose backbone (PDB) oligomers, has significant anti-HIV-1 activities in human PBMC cell cultures when either the virus or cells are pre-incubated with the compound. HIV infection is also inhibited in an explant model of human cervical tissue. A second function of PDB other than its anti-HIV activity is its capacity to inhibit HIV-triggered TLR7/9 activation. PDB suppresses the release of HIV-induced pro-inflammatory cytokines/chemokines in cultures of human PBMC and ectocervical tissues. We also demonstrated that PDB is safe and non-toxic in in vitro cell cultures and in an in vivo murine vaginal toxicity model. The effect of PDB is stable as this compound retains activity at pH 4.4 and after transition to a neutral pH, following incubation with biological fluids (seminal plasma, vaginal fluids) and a normal vaginal flora Lactobacillus strain. PDB does not affect the growth of Lactobacillus strains. Phosphorothioate 2’ deoxyribose oligomers are novel microbicide candidates with dual-acting anti-HIV and anti-inflammatory activities and an excellent safety and stability profile.
Long term impairment of CD4 T cell responses after sepsis (HUM8P.327)
Authors: Cabrera-Perez Javier , Condotta Stephanie , James Britnie , Rai Deepa , Kucaba Tamara , Badovinac Vladimir , Griffith Thomas 
Published: January 2023

Abstract
Patients that survive the acute stages of sepsis tend to have severely compromised T cell immunity and increased susceptibility to infection. Interestingly, little is known about the mechanism(s) behind decreased CD4 T cell function after sepsis. Using a cecal-ligation and puncture (CLP) model of sepsis, we utilized p:MHCII tetramers to track the recovery of Ag-specific CD4 T cell populations after septic injury, and to probe responses to infection during or after recovery. In agreement with previously published data, we observed a systemic loss of CD4 T cells early on (48h after CLP), but there was no discernible numerical difference in the CD4 T cell compartment of sham- and CLP-treated animals after 30d. Despite this seemingly complete recovery, we detected changes in the distribution of Ag-specific CD4 T cell precursor pools, with quantitative reductions in some populations persisting up to 30d after surgery. Importantly, incomplete recovery of Ag-specific precursor numbers correlated with impaired primary expansion and decreased Ag sensitivity after infection. Moreover, Vβ clonotype composition analysis demonstrated changes intrinsic to an Ag-specific population’s heterogeneity. Our results reiterate the stochastic nature of CD4 lymphopenia during sepsis, and suggest that recovery is accompanied by deleterious alterations to the Ag-specific CD4 T cell repertoire. These findings may explain why patients are disparately predisposed to opportunistic infections after sepsis.
Investigating immunological pathways and diseases with a comprehensive compendium of human data (HUM8P.347)
Authors: Zaslavsky Elena , Gorenshteyn Dmitriy , Fribourg Miguel , Park Christopher , Kleinstein Steven , Sealfon Stuart , Troyanskaya Olga 
Published: January 2023

Abstract
The exponential growth of high throughput immunological data motivates the need to leverage this global effort to guide new investigation and to contextualize domain-specific results. Improved specificity and accuracy over currently utilized approaches such as ontological analysis would be advantageous. To develop such a resource (ImmuNet), we used immunological pathway-guided Bayesian integration of a comprehensive, heterogeneous compendium of human data to assemble functional relationship networks. The utility of ImmuNet was evaluated in various applications. We studied the cellular gene response signature to virus infection, using ImmuNet to guide confirmatory experiments into functionally relevant responses to different viruses. We also demonstrated that ImmuNet can accurately predict disease associated genes in the vicinity of GWAS loci and to explore processes and pathways underlying immune-mediated diseases. By unlocking immunological information captured within the global biomedical research effort, ImmuNet should be widely beneficial to future studies investigating the mechanisms of the human immune system and immunological disease. An interactive user-friendly web interface for investigators is publicly available at immunet.princeton.edu.
Age-associated inflammation enhances macrophage-pathogen interactions in vitro. (INC7P.400)
Authors: Turner Joanne 
Published: January 2023

Abstract
Increasing age is associated with elevated levels of circulating pro-inflammatory cytokines, termed inflammaging. This inflammatory state can modulate a variety of immune functions and contribute to the increased susceptibility of the elderly to numerous infection diseases. Using Mycobacterium tuberculosis (M.tb) as a model pathogen we evaluated the influence of inflammation on macrophage function in vitro using the aged mouse model. We detected elevated basal levels of inflammatory cytokines in the lungs of naïve old mice, and pulmonary macrophages were shown to be in a pre-activated state(elevated mRNA for IRF-1, IRGM1 and CIITA). Furthermore, lung macrophages from old mice had altered trafficking marked by enhanced phago-lysosome (P-L) fusion upon infection with M.tb in vitro, which was refractory to enhancement by IFN-gamma activation. When old mice were placed on a diet of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen for 2 weeks prior to isolation of lung macrophages, this pre-activated phenotype was reversed in old mice. These data demonstrate that the hyper-inflammatory state of the lung in old mice can influence the early interactions of immune cells with M.tb and that this phenotype can be reversed by NSAIDs. These data suggest that inflammaging in the lung could have a beneficial impact on innate immune function during infection, but the long term consequences of this phenotype in the context of M.tb infection are currently unknown.
The role of microbial pattern recognition mechanisms in bacterial-induced autophagy in the social amoeba Dictyostelium discoideum (INC7P.416)
Authors: Snyder Michelle , Fink Marc , Weichseldorfer Matthew , Stephens Kierra , Zapf Ava , Pflaum Katherine 
Published: January 2023

Abstract
Signaling downstream of innate immune pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), results in activation of various responses, including the induction of autophagy. Recent evidence suggests that autophagy plays a protective role against invading intracellular microbes. We have found that upon incubation with bacteria or with the microbial pattern LPS, autophagosomal maturation is stimulated in the model organism Dictyostelium discoideum, which uses bacteria for nutritional purposes. In addition, the rate of bacterial clearance by D. discoideum cells is increased upon exposure of cells to the autophagy-inducing drug rapamycin. Conversely, lysosomal transport of bacteria is decreased in D. discoideum lacking the autophagy protein, Atg1. Although the D. discoideum genome does not encode for TLRs, it does encode for a number of TIR (toll/interleukin-1 receptor) domain-containing proteins, including TirA. Cells lacking TirA are deficient in responses to Gram-negative bacteria. We have found here that TirA plays a role in bacterial-induced generation of reactive oxygen species, a potential stimulant of autophagy. We are investigating the role of TirA as well as the role of reactive oxygen species in pathogen-induced autophagy. These studies are aimed at linking microbial pattern recognition and the induction of autophagy in this model organism to provide insight into conserved mechanisms underlying bacterial detection.
Genetics of differential susceptibility to pneumonic Burkholderia pseudomallei infection (INC7P.424)
Authors: Emery Felicia , Parvathareddy Jyothi , Pandey Ashutosh , Cui Yan , Williams Robert , Miller Mark 
Published: January 2023

Abstract
Burkholderia pseudomallei (Bp) is a pathogenic gram-negative bacterium that causes the severe human disease melioidosis. Bp is listed as a CDC Tier 1 select agent and is considered a potential bioterrorism agent that poses a threat to national security if intentionally released into the human population. Our goal is to use a murine model of Bp infection to gain a better understanding of the interactions between this bacterium and its hosts. We have utilized fully genotyped recombinant inbred BXD mice and a powerful array of complementary computer-based modeling algorithms and databases collectively known as the GeneNetwork. Preliminary studies revealed that Bp infection elicits phenotypically distinct innate immune responses in terms of immune cell recruitment to the lungs, survival and weight loss following pneumonic infection in parental and BXD mice. Preliminary interval mapping of our survival and weight loss phenotypic data using GeneNetwork revealed that survival is a complex trait involving loci on chromosomes 5, 7, and 9 and weight retention involves loci on chromosome 12. Furthermore, we have identified several potential candidate genes within the significant and/or suggestive interval on these chromosomes that appear to correlate with differential susceptibility to Bp infection. These results form the foundation for future work that will significantly increase our understanding of the interactions between Bp and its genetically diverse hosts.
Towards delineating the role of dendritic cells and macrophages in SIV disease control and progression (INC9P.447)
Authors: Swan Zachary , Smith Amanda , Bouwer Anthea , Barratt-Boyes Simon 
Published: January 2023

Abstract
In HIV infection, sustained inflammation and immune activation are signature pathologies of individuals that progress to AIDS. Dendritic cells (DC) and macrophages mediate host inflammatory and antiviral responses and some evidence suggests these cells could be involved in influencing HIV disease outcome, but to what extent is unclear. Here, we longitudinally followed the kinetics of DC and macrophages in peripheral and mucosal tissues from Mamu-B*008+ rhesus macaques intrarectally infected with pathogenic SIVmac251. Mamu-B*008 is a rhesus macaque MHC class I allele highly correlated with control of SIV replication, as greater than 50% of SIV-infected Mamu-B*008+ macaques control chronic phase viral load and do not advance to disease; hence this serves as a model for controlled and progressive HIV disease in humans. We used flow cytometry to access the impact of SIV infection on DC and macrophage proportions, proliferation, and homing to lymph nodes and mucosa. Our preliminary findings reveal a divergent effect of SIV infection on each of the aforementioned DC and macrophage parameters as a function of viral load and tissue compartment. Ongoing experiments will examine the impact of SIV infection on the antigen-presenting cell properties and inflammatory nature of DC and macrophages in the context of SIV disease-progressing and -controlling hosts. These studies should provide clarity on whether DC and macrophages serve a beneficial or detrimental capacity in SIV pathogenesis.
HSV-2 increases TLR4-dependent phosphorylated IRFs and IFN-beta induction in cervical epithelial cells (INM9P.460)
Authors: Li Hui , Liu Hongya , Chen Kai , Feng Wenqiang , Guo Juanjuan 
Published: January 2023

Abstract
The innate immune pathway in response to HSV-2 in its natural host cells remains unclear. Our study has established an in vitro HSV-2 acute infection model with Human Cervical Epithelial (HCE) cells to investigate the role of TLRs-mediated innate immune response to HSV-2. Our previous studies demonstrated that HSV-2 infection up-regulates TLR4 expression and induces NF-kB activity, thereby facilitating innate immune response in human cervical epithelial cells. This process requires involvement of TLR4 adaptors, Mal and MyD88. In the current study, we found that HSV-2 infection increases levels of phosphoryalted IRF3 and IRF7, then regulating expression of type I IFN. As expected, these changes induced by HSV-2 infection depended upon TLR4. To study involvement of the downstream adaptors, we found that overexpression of TRIF and /or TRAM further increased induction of NF-kB activity, while siRNA experiments demonstrated that adaptor molecules TRIF and TRAM were also required for the TLR4-mediated both NF-kB activity and expression of IFN-beta. Our results demonstrate for the first time that IRF3 and IRF7 are both involved in inducing TLR4-dependent IFN- beta expression in response to HSV-2 in its primary infected genital epithelial cells. Thus, TLR4-Mal/MyD88 and TLR4-TRIF/TRAM signaling may synergize and /or cooperate in innate immune response of cervical epithelial cells to HSV-2 infection. (This work was supported by National Natural Science Foundation of China 81072419)
Impaired TLR8 expression toTLR7/8 agonists in patients with chronic hepatitis C virus infection (INM9P.461)
Authors: Lin Tsun-Mei , Lin Chih-Wen , Wang Chiou-Huey , Eng Hock-Liew 
Published: January 2023

Abstract
Toll-like receptors (TLRs) play pivotal roles in the innate immune system and control inflammatory responses and adaptive immunity. TLR7 and TLR8, located in X chromosome, recognize single-stranded RNA and play a significant role in anti-HCV immune response. We consecutively enrolled 50 chronic hepatitis C patients and 50 anti-HCV-negative healthy individuals as controls. The expressions of TLR7, TLR8 and cytokines in peripheral blood before and after TLR7/8 agonist stimulation were measured by RT-PCR and ELISA. Over expression of TLR7 and TLR8 was detected in chronic hepatitis C patients as compared to controls (p &lt; 0.01). Serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were also increased in patients (p&lt;0.05). On stimulating the whole blood with R837 (20 μM) and CL075 (20 μM) for 24 hrs, TLR7 and TLR8 expressions were enhanced in healthy controls, but with lower response of TLR8 induction in chronic hepatitis C patients (p&lt;0.01). Increased cytokines production was observed after challenge with TLR7/8 agnonists but no significant difference between the two groups. In conclusion, up-regulation expression of TLR7 and TLR8 and increased proinflammatory cytokines occur in patients with chronic HCV infection, whereas upon agonist stimulation, the patients were demonstrated to modulate immune responses by impairment TLR8 synthesis. The molecular mechanisms of HCV infection and TLR8 hyporesponsiveness need further investigation.
Morphine exacerbates experimental sepsis by modulating IL17/IL22 response (IRC8P.488)
Authors: Meng Jingjing , Li Dan , Roy Sabita , Wang Fuyuan 
Published: January 2023

Abstract
Sepsis ranks as the top 10 cause of mortality in the intensive care units (ICU) in USA and the standard management of pain in these patients are opioids. However, very few studies have investigated the influence of opioids on development and progression of sepsis. In the present study, we determined the effects of morphine on sepsis progression using the murine cecal ligation and puncture model, which resembles many aspects of the human pathology. Our studies demonstrate that morphine treatment increases bacterial dissemination at the early stage of sepsis (24 hours) and significantly attenuates pathogen clearance at late stage of sepsis (72 hours). In addition, IL17a and IL22 responses to pathogen stimulation are impaired following morphine treatment, resulting in delayed neutrophil recruitment to peritoneal cavity, thereby compromising pathogen clearance. This is the first study to demonstrate that IL17a and IL22 responses play important roles in host defense against polymicrobial sepsis, and that this crucial response is impaired following opioid treatment. These studies imply that IL17a and IL22 may be potential therapeutic targets to treat or prevent sepsis, especially in opioid use and abuse population.
IL-33 promotes IFN-γ production by group 1 innate lymphoid cells in viral hepatitis (IRC8P.490)
Authors: Liang Yuejin , Jie Zuliang , Sun Jiaren 
Published: January 2023

Abstract
Innate immune response is the first line of the defense against the viral pathogens. The damage associated molecular patterns (DAMP) molecule IL-33 has been proved to be critical for T cell response in viral persistent infection. However, its role in modulating the innate immune response in viral infection is not clear. Herein, we injected the mice with lymphocytic choriomeningitis virus (LCMV) Clone 13 and found that the hepatic gene expression of IL-33 was upregulated at 1 day post-infection (dpi) and reached the peak at 6 dpi. Deficiency of IL-33 not only led to impaired anti-viral T cell responses (low IFN-γ and TNF-α), but also resulted in less numbers of IFN-γ+ innate immune cells, such as NK and γδT cells at 16h postinfection. Treatment of recombinant IL-33 (rIL-33) significantly increased the percentages of IFN-γ +γδT cells. In vitro, rIL-33 inhibited proliferation of IL-17+γδ T cells, but increased IFN-γ+γδ T cells in a dose-dependent manner. rIL-33 treatment also upregulated IFN-γ and granzyme B expression in NK cells in vitro culture. More importantly, hepatic dendritic cells (DC) in IL-33 knockout mice expressed lower level of IL-12 compared with control mice, indicating that deficiency of IL-33 may impair the DC priming. Our data reveal the key role of IL-33 in promoting IFN-γ production by group 1 innate lymphoid cells and subsequently regulate the anti-viral T cell response in viral hepatitis.
Natural killer (NK) cells but not NK T cells attenuate renal fibrosis after acute kidney injury (AKI). (IRC8P.480)
Authors: Vincent Isaah , Moscalu Stefan , Chhoun Christopher , Ye Hong , Huang Liping , Sung Sun-Sang , Okusa Mark 
Published: January 2023

Abstract
Renal fibrosis is the common pathway of various kidney diseases that lead to progressive renal failure and end stage renal disease. NK and NK T cells have been linked to regulating fibrosis in several different organ systems. However, there is debate as to whether they are pro-fibrotic or anti-fibrotic. To determine their role in renal fibrosis, mice were administered PK136 mAb (200μg i.p), which depletes both NK and NKT cells, twice weekly for 14 days starting 5 days after 26 minutes of unilateral kidney ischemia-reperfusion (uIRI) or folic acid (250 mg/kg, i.p.). In both models, compared to IgG-treated mice, kidneys of mice treated with PK136 had increased fibrosis as assessed by Masson’s Trichrome and mRNA expression of collagen 1 and α-SMA. This suggests that NK/NKT depletion increases extracellular matrix deposition and myofibroblast number. This may be due to changes in the kidney microenvironment as kidneys of PK136-depleted mice had decreased expression of IFN-γ and increased expression of IL-10 and TGF-β compared to IgG-treated mice. We next subjected Jα18-/- and CD1d-/- mice to unilateral IRI to determine the specific role of NKT cells in renal fibrosis. Compared to wild-type mice, Jα18-/- and CD1d-/- mice subjected to uIRI demonstrated no increase in fibrosis, thus we conclude that the that NK but not NKT cells attenuate renal fibrosis after AKI. Further investigation will focus on determining the mechanism by which NK cells regulate fibrosis within the kidney.
The pro-atherosclerotic milieu promotes the conversion of murine T regulatory cells to a spectrum of Foxp3+IFNγ+ T cell phenotypes. (IRC8P.481)
Authors: Butcher Matthew , McGary Christopher , Galkina Elena 
Published: January 2023

Abstract
T cell subsets play diverse roles in inflammation but may also display limited plasticity. The existence of a population of Foxp3+ T regulatory (Treg) cells that co-express Interferon-γ (IFNγ), has been demonstrated in several models of inflammation. In atherosclerosis, circulating Treg content inversely corresponds with atherogenesis, suggesting that inflammation affects peripheral Treg (pTregs) maintenance. Thus, we sought to examine the fate of pTregs within atherosclerotic Apolipoprotein E-deficient (Apoe-/-) mice. Foxp3+IFNγ+ T cells were elevated within the aorta, spleen, and peripheral lymph nodes (PLNs) of atherosclerotic Apoe-/- mice in comparison to C57BL/6 mice. Further phenotyping of Foxp3+IFNγ+ T cells revealed variable expression of both Treg and Th1 markers, including PD1, GITR, CD25, CD73, Tbet, CXCR3, and CCR5. To determine whether Foxp3+IFNγ+ T cells arise from de novo differentiation or peripheral conversion, we performed fate tracking experiments with co-adoptively transferred naïve T cells and pTregs within Apoe-/- mice. In this system, naïve T cells failed to generate Foxp3+IFNγ+ T cells. In contrast, adoptively transferred Tregs lost Foxp3 expression (50%), maintained Foxp3 expression (40-45%), or adopted a Foxp3+IFNγ+ phenotype (5-10%) within all of the tissues examined. Together, these results demonstrate that inflammation during atherogenesis affects the maintenance of pTregs, resulting in the generation of phenotypically diverse Foxp3+IFNγ+ T cells.
The co-stimulatory molecule GITR intrinsically enhances type 1 and follicular helper CD4 T cell responses to establish early control of a persistent viral infection and potentiate the late humoral response (IRC9P.700)
Authors: Clouthier Derek , Wortzman Michael , Zhou Angela , Luft Olga , Levy Gary , Watts Tania 
Published: January 2023

Abstract
During persistent infection, the immune system must be tightly regulated to balance immune control against pathology. The glucocorticoid-induced TNFR (GITR) is an important co-stimulatory molecule that plays a critical CD4 T cell-intrinsic role in the control of a mouse model of chronic viral infection, LCMV clone 13. 8 days post-infection (dpi) of wild-type (WT) and GITR-/- mice revealed that GITR-/- mice have 2-fold fewer LCMV-specific CD8 T cells, with higher PD-1 and Tim-3 levels. These defects became more striking at 45 dpi, when GITR-/- mice have a ~9-fold deficit in IFNγ+CD107+TNF+ CD8 T cells. GITR-/- mice had impaired viral control, with 35- and 10- fold higher viral load in the kidney at 8 and 45 dpi, respectively. Depletion of CD4 cells largely abrogated the differences between WT and GITR-/- mice at 8 dpi, suggesting that CD4 T cells underscore the impaired T cell responses of GITR-/- mice. GITR-/- mice have 3-4-fold fewer IFNγ+ and IL-2+ Th1 cells at 8 dpi. Using DEREG mice, we found that the compromised immunity and viral control in GITR-/- mice are independent of Foxp3+ Tregs. GITR-/- mice also had 2-fold fewer follicular helper (Tfh) cells at 21-45 dpi, with concomitant impairment in LCMV-specific IgG titres. Mixed bone marrow chimeras revealed a CD4 T cell-intrinsic role for GITR in potentiating Th1 and Tfh responses. Our findings reveal a critical role for GITR in co-stimulation of CD4 helper T cell subsets for optimal cell-mediated and humoral immunity.