bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of host innate immune receptors by influenza (158.23)
Authors: Vigerust David , Shepherd Virginia 
Published: January 2023

Abstract
Influenza virus A (IVA) is a significant cause of morbidity and mortality each year and is one of the most important infectious diseases in the United States Very little is known about the interaction between influenza and the macrophage. Interactions between influenza and macrophages may affect acute symptomology, inmmune evasion and disease outcome by preventing the proper function of the macrophage in the clearance of harmful pathogens. Our hypothesis is that host innate defense molecules are utilized as a receptor of entry and target of down-regulation by influenza A viruses leading to dysregulation of macrophage function. The HIV-1 Nef protein was shown to interact with MR tail to down-regulate the expression of the MR on macrophages. Sequence comparison of the interacting domains of the HIV-1 Nef molecule and the sequence of influenza A NS1 and PB1 reveals similarity in several motifs that indicate a potential for MR regulation by influenza. Our initial data demonstrates that infection of MR expressing cells results in a significant decrease in surface expression of MR by 48 hours post-infection. Further, in vitro transient transfection of influenza proteins leads to removal of MR from the surface at levels approaching 30% for NS1 and PB1. Removal of MHC-I from the cell surface was also seen as early as 5 hours post-transfection. Our data suggests that influenza regulates critical host innate defense molecules in a fashion that is similar to that seen with HIV-1 Nef.
Ligation of CD4 on human blood monocytes triggers macrophage differentiation (158.8)
Authors: Kitchen Scott , Krutzik Stephan , Levin Bernard , Rezek Valerie , Kitchen Christina , Zack Jerome 
Published: January 2023

Abstract
Human monocytes/macrophages (M/M) have an important role in innate immune responses and in controlling adaptive immune responses. One unique aspect of human M/M is that they express the CD4 molecule. The role of the CD4 molecule in human monocyte/macrophage function and development is not known. To investigate the role of CD4 expressed on human M/M, human blood monocytes were treated with soluble HLA Class II (sHLA II), a natural CD4 ligand. We determined that sHLA II:CD4 ligation triggered the differentiation of human monocytes into functional mature macrophages. These newly developed macrophages had an increased ability to induce T cell activation, suggesting enhanced immune function following CD4 ligation of these cells. We observed a calcium flux and the modulation of gene and cytokine protein expression following CD4 ligation on peripheral monocytes. This indicates that ligation of CD4 transmits a functional signal in this cell type. We found that intracellular signaling of CD4 in primary monocytes occurs through src family kinases as well as via the MAPK pathway to trigger macrophage differentiation. We show that HLA II on IFN-γ-induced HUVECs can ligate CD4 on monocytes and trigger differentiation of these cells into functional macrophages. In all, our results have identified a new function for the CD4 molecule on human peripheral monocytes in triggering the differentiation of these cells into functional macrophages following their interaction with HLA II.
Increased caspase activity primes human lyme arthritis synovial γδ T cells for proliferation and death (160.11)
Authors: Thai Phan , Collins Cheryl , Fortner Karen , Koenig Andreas , Hayes Sandra , Budd Ralph 
Published: January 2023

Abstract
γδ T cells function between the innate and adaptive immune responses, promoting antigen-presenting cell function, presenting antigen, and manifesting cytolytic activity. Their numbers increase in infections, such as HIV, and at sites of chronic inflammation. However, the turnover dynamics of human γδ T cells are poorly understood. Here we find that despite more rapid proliferation, human Lyme arthritis synovial γδ T cells of the Vδ1 subset have reduced cell number expansion in vitro compared to αβ T cells due to increased cell death by the γδ T cells. Because caspases are involved in cell proliferation and death, and signaling is more efficient through the γδ-TCR than the αβ-TCR, we examined active caspases during cell cycling and following TCR restimulation. We observed higher overall caspase activity in Borrelia-reactive γδ T cells than comparable αβ T cells. This was paralleled by greater spontaneous and TCR restimulation-induced cell death of the γδ T cells. Furthermore, the transition from cell growth to death was associated with a transition of active caspases from the cell membrane to the cytoplasm. Our current findings thus are consistent with a model where human γδ T cells evolved to function quickly and transiently, in an innate fashion.
Atypical T cell receptor usage defines a population of Natural Killer T cells with distinct glycolipid antigen recognition properties (160.13)
Authors: Godfrey Dale , Uldrich Adam , Patel Onisha , Cameron Garth , Pellicci Daniel , Day E. , Sullivan Lucy , Kyparissoudis Konstantinos , Kjer-Nielsen Lars , Vivian Julian , Brooks Andrew , Besra Gurdyal , Turner Stephen , Porcelli Steven , McCluskey James , Smyth Mark , Rossjohn Jamie 
Published: January 2023

Abstract
Lipid Ag reactive T cells represent an important component of the T cell repertoire. The most well studied example is the classical (or Type-1) NKT cells that respond to the glycolipid Ag α-galactosylceramide (α-GalCer) presented by CD1d. While often referred to as 'invariant' due to the expression of an invariant TCR-α chain (Vα14-Jα18), in fact, Type-1 NKT cells carry a diverse TCR-β repertoire that influences Ag recognition. Furthermore, we have identified a completely novel population of NKT cells (Type-1A cells), that expresses a previously unidentified, canonical, Vα10-Jα50 TCR α-chain. These cells exhibit a different pattern of glycolipid Ag reactivity, including a preference for α-glucosylceramide (α-GlcCer) over α-GalCer and a bias towards Th2 cytokine production. Two populations of Type-1A NKT cells (TCRhi and TCRlo) are present in the thymus and they also have diverse TCR-β chains. We also provide the first structural analysis of a non-classical NKT TCR-CD1d-glycolipid complex, showing that the Type-1A TCR-CD1d-α-GlcCer complex displayed a similar docking mode to that of Type-1 NKT TCRs, although differences at the Ag-binding interfaces accounted for the altered specificity. The discovery of a second invariant TCR α-chain expressed by CD1d-restricted NKT cells provides new insights into the repertoire diversity and its influence on glycolipid recognition by NKT cells, and has significant implications for the immunologic role of glycolipid-specific T cell responses.
Regulation of memory CD4 T cell repertoire diversity upon peptide and protein vaccination (160.18)
Authors: Baumgartner Christina , Malherbe Laurent 
Published: January 2023

Abstract
Diverse antigen-specific memory TCR repertoires are essential for protection against pathogens. Subunit vaccines that combine peptide or protein antigen with TLR agonists are very potent in inducing T cell immune responses but their capacity to elicit stable and diverse memory CD4 T cell repertoire has not been evaluated. Here, we tracked the development of antigen-specific memory CD4 T cells after peptide or protein vaccination. Both vaccination regimens induced equally diverse effector CD4 TCR repertoires but a skewing toward high affinity clonotypes was observed in the memory TCR repertoire elicited by peptide vaccines. This skewing did not occur after protein vaccination leaving the antigen-specific TCR repertoire essentially intact in the transition from effector to memory. Clear understanding of the factors regulating the TCR repertoire diversity after peptide and protein vaccination contributes to our knowledge of T-cell mediated immune responses and has practical relevance to the design of vaccines against infections requiring robust T cell immunity.
Cross-reactivity and repertoire connectivity of CD8+ T cells in adults (160.19)
Authors: Petrova Galina , Naumova Elena , Gorski Jack 
Published: January 2023

Abstract
Measuring the extent to which a T cell repertoire raised against one epitope can recognize slightly different epitopes is important for questions of response to escape variants or novel pathogens. Analyzing the MHC-peptide structures that can be recognized can provide insight into the nature of the cross-reactive TCR in the initial repertoire. We measured the cross-reactivity of the highly polyclonal BV19 T cell repertoire that responds to influenza M158-66 in HLA-A2 individuals by using an incremental epitope modulation approach. In three HLA-A2 adult subjects we identified the BV19 clonotypes in the recall response to the influenza epitope M158-66 and then in the response to twelve M1 peptides substituted at TCR contact positions 63 or 65. Six of the twelve peptides were recognized by some fraction of the M158-66 repertoire. The fraction of cross-reactive clonotype as defined by recognizing at least one additional peptide varies from 45 to 58%. The maximal extent of cross-reactivity defined as an additional number of peptides recognized is six. The BV19 cross-reactive clonotypes form a completely connected network identifying a well defined set of related MHC-peptide structures that can be recognized if they should be part of a novel pathogen or escape variant.
Antibiotic treatment reduces intestinal non-defensin protein and facilitates Klebsiella pneumoniae translocation (161.11)
Authors: Chen Lee-Wei , Wu Ying-Ying , Hsu Ching-Mei 
Published: January 2023

Abstract
Effects of microbiota disruption on intestinal permeability and immunity were examined in C57BL/6 mice receiving combined antibiotic treatment. Antibiotic decreased the total number of bacteria including specific aerobic group Enterobacteriaceae and Enterococcus, and specific anaerobic group Lactococcus/Bifidobacterium and Bacteroides in intestinal mucosa and lumen. Although only a slight increase in the intestinal permeability, the bacterial translocation (BT) to mesenteric lymph nodes (MLN) increased significantly. Antibiotic treatment decreased the mucosal killing activity and increased the translocation of pathogen K. pneumonia, suggesting that the increase of BT to MLN after antibiotic treatment is likely due to a reduction in gut immunity. This is further supported by that antibiotic treatment decreased the expression of non-defensin family including RegIIIβ, RegIIIγ, CRP-ductin and RELMβ but not the defensin family. Both Myd88-/- mice and germ-free mice demonstrated decreased non-defensin protein expression and increased K. pneumonia translocation. Furthermore, killed E.coli supplementation reversed antibiotic effect on intestinal immunity and K. pneumonia translocation. Collectively, antibiotic treatment facilitates K. pneumonia translocation through the reduction of intestinal non-defensin protein. Oral dead E.coli supplementation restores antibiotic-induced innate immune deficit and decreases K. pneumonia invasion by increasing intestinal non-defensin protein.
Dynamics and functionality of CD8 T cell immunity within the female reproductive tract (161.4)
Authors: Schenkel Jason , Casey Kerry , Fraser Kathryn , Vezys Vaiva , Masopust David 
Published: January 2023

Abstract
The female reproductive tract (FRT) is a heterogenous mucosal tissue that is exposed to commensal flora, undergoes periodic remodeling, and supports fertilization, yet serves as a major site of microbial infection. Due to its unique physiology and vulnerability to microbes, it is important to have a better understanding of the dynamics of the adaptive immune response within the FRT. We paired flow cytometric analyses with immunofluorescence microscopy in order to characterize the kinetics, localization, phenotype and function of antigen specific CD8 T cells present in the FRT during a systemic infection. Effector CD8 T cells migrated into the vagina, cervix, uterine horns and ovaries, where they localized within the lamina propria, epithelium, or unexpectedly, in large lymphoid aggregates where they were associated with CD11c/MHCII+ cells. After pathogen clearance, maintenance of memory CD8 T cells varied greatly based on location within the FRT. Memory CD8 T cell phenotype was also heterogenous; only a subset retained high levels of granzyme B after pathogen clearance. The cellularity of the lymphoid aggregates changed dramatically throughout the response. We are now exploiting local challenge models to visualize the role of these structures in CD8 T cell migration, antigen trafficking and presentation, and supporting in situ recall responses. These studies should be highly relevant for understanding protective cell-mediated immunity within the female genital mucosa.
NSG-hu mice generate antigen specific human immune responses after gp96 vaccination (161.9)
Authors: Gonzalez Louis , Strbo Natasa , Podack Eckhard 
Published: January 2023

Abstract
NOD.SCID il-2r γc-/- (NSG) KO mice have no functional adaptive immune system and readily accept human xenografts. We have generated NSG mice with human adaptive immunity (NSG-hu) by transplanting CD34+ hematopoietic stem cells isolated from fetal hepatic tissue. These early progenitors give rise to all members of the human adaptive and innate lineages and can be found localized to immunologically relevant compartments (spleen, thymus, mLN, IEL and LPL). Human engraftment appears stable over time and reaches a high proportion of human CD45+ cells when compared to murine CD45+ cells in peripheral blood (54%±24%). Higher proportions of human CD45+ cells were detected in specific tissues (spleen, PEC, IEL and mLN) (82%±29%). We have also found that by using ACK2, an antagonistic anti-mouse stem cell antibody, to further ablate murine hematopoietic stem cells, human engraftment can be boosted (81%±6%). Previously, our lab has developed a cell secreted heat shock protein gp96 based vaccine expressing HIV gag (293gp96HIVgag). NSG-hu vaccinated with 293gp96HIVgag i.p. generates HIV gag-pentamer positive CD8 T cells in the gut. In addition, an interferon gamma ELIPOST response is also observed in the mucosa when stimulated with relevant peptide but not in spleen. We conclude that NSG-hu mice are able to establish and maintain stable hematopoiesis from CD34+ precursor cells. Furthermore, NSG-hu mice are capable of mounting a human HIV-specific immune response after gp96 vaccination.
Glycyrrhizin (GL) improves the resistance of humanized NSG chimeras intradermally infected with Pseudomonas aeruginosa (162.12)
Authors: Chin Jihyang , Lee Jong , Cruz Sharon , Yoshida Shohei , Kobayashi Makiko , Herndon David , Suzuki Fujio 
Published: January 2023

Abstract
In murine studies, GL is shown to be inhibitory on P. aeruginosa burn wound infection. Impaired β-defensin production in tissues surrounding the burn area is restored in mice treated with GL. As a translational study, the effect of GL on HBD-1 production in humanized chimeras was examined. The chimeras were X-irradiated NSG mice grafted with the unburned patient skin (10 x 10 mm: skin-chimeras) and inoculated i.d. with 1~10 x 105 cells/mouse of IMC isolated from patients syngeneic or allogeneic to skin donors (skin/IMC-chimeras). These chimeras were treated i.p. with GL (Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan) and anti-mouse skin-AMP rabbit IgG. Two days after grafting, tissues excised from grafted sites were homogenized and the amounts of HBD-1 in the homogenates were measured. In the results, 19 to 86 ng/ml of HBD-1 were detected in the grafted site tissues of skin-chimeras. The peptide production was inhibited by 77~84% in skin/IMC-chimeras. However, HBD-1 (17~90 ng/ml) was detected in the grafted site skin homogenates of skin/IMC-chimeras treated with 10 mg/kg of GL. P. aeruginosa grew in kidneys of skin/IMC-chimeras infected with 100 CFU/mouse of P. aeruginosa, but the pathogen was not detected in kidneys of the same chimeras treated with GL. These results indicate that HBD-1 is produced at grafted site tissues of skin/IMC-chimeras treated with GL, and sepsis stemming from P. aeruginosa grafted site-infection does not develop in these chimeras.
Glycyrrhizin restores impaired antimicrobial peptide production by human skin tissues cultured with immature myeloid suppressor cells (162.13)
Authors: Yoshida Shohei , Chin Jihyang , Lee Jong , Kobayashi Makiko , Herndon David , Suzuki Fujio 
Published: January 2023

Abstract
We have previously demonstrated that CD34+ CD31+ immature myeloid cells (IMC) appearing in burn patients suppress antimicrobial peptide production by cultured human skin keratinocytes. In the present study, the effect of glycyrrhizin (GL) on the peptide production by unburned patient skin (skin removed for the auto-grafting surgery) transwell-cultured with CD34+ CD31+ IMC was examined. Using a lineage cell depletion kit and flow cytometry, CD34+ CD31+ IMC were isolated from peripheral blood of burn patients. Unburned patient skin tissues (4 x 4 mm) were transwell-cultured with various numbers of IMC for 1 to 7 days in the presence or absence of GL (Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan). Culture fluids obtained were assayed for human β-defensin-1 (HBD-1) by ELISA. In the results, 1-5 ng/ml of HBD-1 were produced by unburned patient skin tissues 2 to 7 days after cultivation. When skin tissues were transwell-cultured with 1 x 104 cells/ml of IMC syngeneic to the skin donors, 86% of HBD-1 production was suppressed. However, HBD-1 was produced by unburned patient skin tissues transwell-cultured with syngeneic IMC and GL. Similarly, HBD-1 was produced by unburned skin tissues transwell-cultured with allogeneic IMC and GL. These results indicate that GL is inhibitory on the IMC suppressor cell activity in HBD-1 production by unburned patient skin tissues.
Dynamics of an innate myeloid cell response to acute CNS viral infection (162.16)
Authors: Nayak Debasis , Zinselmeyer Bernd , McGavern Dorian 
Published: January 2023

Abstract
Viral infections of central nervous system (CNS) often trigger an inflammatory response that gives rise to a wide range of pathological outcomes. The CNS is equipped with an elaborate network of innate immune sentinels that routinely serve as first responders to these infections. The meninges and perivascular spaces are inhabited by specialized macrophages, and the brain parenchyma contains microglia - the most abundant CNS myeloid cell. To gain novel insights into how myeloid cells respond to an acute CNS viral infection, we utilized genomics and two-photon imaging approaches to study a pure innate response to LCMV infection. This was accomplished by monitoring temporal gene expression patterns and myeloid cell dynamics in the brains of CX3CR1-GFP mice lacking LCMV-specific T cells. Two-photon imaging studies revealed that CNS myeloid sentinels responded significantly to acute infection by sequestering DsRed-labeled virus. Microglia but not peripheral myeloid cells proliferated following acute infection and responded directly to viral antigen by reducing process complexity, suggesting a localized response to the presence of virus. However, at the genomic level, acute infection triggered massive changes in CNS gene expression with the majority of genes being linked to innate viral control and the type I interferon system. These data suggest that localized detection of virus by CNS myeloid sentinels can translate into engagement of an extensive anti-viral program.
Chronic morphine administration induces tolerance to suppressive morphine effects in two canonical LPS-induced innate immunity responses in mice. (162.20)
Authors: Molina Martínez L. , Cruz S. , González Espinosa C. 
Published: January 2023

Abstract
The immunosuppressive effects of acute morphine administration are well described. However, little is known about chronic morphine treatment actions using different administration schedules. The aim of this work was to study the effects of various morphine administration schemes on peritoneal Tumor Necrosis Factor-α (TNF-α) release and serum corticosterone levels after i.p. injection of bacterial lipopolysaccharide (LPS) in mice. Our results show that morphine per se (0.1-10 mg/kg) had no effects on TNF-α levels. Morphine inhibited LPS-induced TNF-α release but this effect occurred only at high doses (3.1 y 10 mg/kg) and was not dose dependent. Serum corticosterone levels increased after a single LPS challenge and morphine dose-dependently prevented this effect. After repeated administration, tolerance developed to the inhibitory effects of morphine on peritoneal TNF-α release and serum corticosterone levels in response to LPS. These data suggest that morphine inhibitory effects on innate immunity depend on the opioid administration schedule and duration treatment.
Toll-like receptor 2 activation induces lung endothelial permeability and coagulopathy (162.6)
Authors: Xu Fengyun , Hellman Judith 
Published: January 2023

Abstract
Toll-like receptors (TLRs) recognize components of microbes and initiate host responses in sepsis. TLR2, the receptor for microbial lipoproteins, is important in the inflammatory effects of bacteria and fungi. Endothelial cell (EC) activation, coagulopathy, and vascular leak contribute to sepsis-induced lung injury. We previously found that bacteria shed TLR2 agonists into the blood in sepsis models, that TLR2 activation increases EC expression of inflammatory markers and EC PMN trafficking, modulates EC expression of coagulation factors, increases EC monolayer permeability, and causes lung inflammation and decreased arterial blood oxygenation in mice. We hypothesized that TLR2 activation by the lipopeptide, Pam3Cys, causes lung vascular leak and coagulopathy. Treatment of human lung microvascular EC with Pam3Cys led to increased plasminogen activator inhibitor 1 levels in culture supernatants, and increased monolayer permeability to albumin (p&lt;0.05). Intratracheally administered Pam3Cys also significantly (p&lt;0.05) increased albumin levels in lung homogenates and bronchoalveolar lavage fluid, and increased lung fibrin deposition. The alterations that we observed in lung microvascular EC function closely resemble those that occur in patients with sepsis. Our studies here suggest that TLR2 activation contributes to sepsis-induced EC dysfunction, coagulopathy, and respiratory failure, and suggest that EC TLR2 pathways could potentially be targeted for sepsis interventions.
Resistance to Yersinia pestis infection decreases rapidly and substantially with age in B10.T(6R) mice (162.9)
Authors: Lambert Nathaniel , Nilles Matthew , Bradley David 
Published: January 2023

Abstract
We have previously demonstrated that 2-3 month old, female B10.T(6R) mice are highly resistant to a delta pgm strain of Yersinia pestis and by 5 months of age these mice are highly susceptible to Y. pestis infection. In the current study we further characterize this observation in female B10.T(6R) mice. The LD50 of Y. pestis was ~14000 CFU/ml in young (2-3 month) mice while only ~60 CFU/ml in middle aged (&gt;5 month) mice. Significantly elevated bacterial burden was found in both the spleen and liver of middle aged mice while a significant infiltration of immune cells was observed in resistant young mice. The cellular infiltrate in susceptible middle aged was comparable to susceptible young C57BL6/J mice. Sera and spleens from Y. pestis-infected middle aged B10.T(6R) contained elevated levels of KC, MCP-1 (CCL2), MIP-1a (CCL3), G-CSF, IL-6 and Eotaxin. In many cases, cytokine/chemokine levels in middle aged mice increased in an infectious dose-dependent manner and were comparable to Y. pestis infection in C57BL6/J mice with both experimental groups being significantly increased when compared to infected young B10.T(6R) mice with the exception of IL1b that was only increased in both serum and spleen samples from young mice. These findings suggest that IL1b may be critical to prevent Y. pestis infection and may provide insight into defense mechanism(s) necessary to develop resistance to the plague.