bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do immune genes influence which pigs will have persistent Porcine Reproductive and Respiratory Syndrome virus (PRRSV) infections? (45.5)
Authors: Lunney Joan K. , Rowland Raymond , Nelson Eric , Molina Ramon , Hermann Joseph , Kuhar Daniel , Christopher-Hennings Jane , Leathers Valerie , Zimmerman Jeff 
Published: January 2023

Abstract
This study, a part of the “Big Pig” project, was aimed at highlighting differences in immune responses between control pigs and pigs with PRRSV infections, from early times post inoculation (pi), 14 dpi, to long term persistent infections (as evidenced by viral RNA in tissues). Our goal is to identify immunological or virological correlates of persistent infection. Two-week old pigs (n=109) were inoculated with PRRSV ATCC VR-2332 and 56 age-matched animals served as uninoculated controls. Sets of PRRSV infected and control pigs were euthanized at 2 week intervals through 203 dpi; blood and tissues were collected. RNA and cDNA was prepared from respiratory and regional mucosal tissues [lung, tracheobronchial lymph nodes (TBLN), tonsil] and assayed for expression of a panel of 23 immune markers, representing innate, T helper and regulatory genes. As expected, only low levels of interferon-gamma and certain innate immune genes were expressed by infected pigs early after inoculation. Our studies are aimed at determining whether there is a pattern of cytokine expression that might help predict which pigs will clear virus, and distinguish them from those that remain persistently infected. To date no pattern has been found with lung or TBLN; tests are continuing with tonsils and sera cytokine levels. We hope to identify regulatory pathways that would stimulate PRRSV immunity.
Supported by USDA ARS and NRI PRRS CAP1 funds.
Regulation of immune response by HSV-1 via inhibitory PILR (45.6)
Authors: Arase Hisashi , Kawaguchi Yasushi , Lanier Lewis L. , Satoh Takeshi 
Published: January 2023

Abstract
Herpes simplex virus type 1 (HSV-1) is a neurotropic human pathogen capable of infection and spread in a variety of cells. Cells infected with HSV-1 escape immune recognition by down-regulating cell surface expression of MHC class I molecules and/or by other unsolved mechanisms. In this study, we found that HSV-1-infected cells express a ligand for inhibitory paired immunoglobulin-like type 2 receptor (PILR), which is mainly expressed on macrophages, granulocytes, dendritic cells, and NK cells. When PILR ligand expressed on HSV-1-infected cells was analyzed by using mass spectrometry, the PILR ligand was revealed to be a viral product of HSV-1. Indeed, when the cDNA for the PILR ligand of HSV-1 was transfected into 293T cells, the transfectants were recognized by PILR-Ig. Furthermore, target cells transfected with PILR ligand of HSV-1 showed resistance to the cytotoxicity by NKL cells expressing inhibitory PILR. Our results suggest that HSV-1 encodes a ligand for PILR and downregulate the activation of immune cells expressing inhibitory PILR. Our findings provide a novel mechanism of immune evasion by HSV-1.
HCV does not interfere with ability of hepatocytes to express class I MHC or B7-H1 at the cell surface (45.7)
Authors: Kassel Rachel , Taylor Nicholas Alexander , Hahn Young Shin 
Published: January 2023

Abstract
T cell responses play a pivotal role in resolution of hepatitis C virus (HCV) infection. The high rate of HCV persistent infection (&gt; 70% of HCV patients) is likely due to impaired T cell responses. To examine whether the impaired T cell responses result in part from ineffective antigen presenting functions of HCV-infected hepatocytes, we determined the expression of class I MHC and co-stimulatory molecules in HCV-infected hepatocytes. Modified HCV cell culture system (Huh 7.5 containing the full-length HCV genome or the non-structural region only) was used in our studies as well as parental Huh 7.5 cells. Huh 7.5 are a hepatocellular carcinoma cell line, permissive for HCV replication, which express low levels of class I MHC and the inhibitory ligand B7-H1 and lack co-stimulatory ligands CD40, CD80, or CD86. Elevated concentrations of IFN-γ characterize inflamed livers, and parental Huh 7.5 cells significantly up-regulate surface expression of class I MHC and B7-H1 following IFN-γ stimulation. Huh 7.5 cells stably transfected with HCV mRNAs encoding the complete genome are also able to up-regulate class I MHC and B7-H1 following stimulation with recombinant IFN-γ. This suggests that HCV may not interfere with the antigen processing/presentation capability.
FoxP3 Enhances HIV-1 Gene Expression by Modulating the LTR Occupancy of NFkappaB in Human T Cells (45.8)
Authors: Holmes Derek , Knudsen Geoffrey , Mackey-Cushman Stephanie , Su Lishan 
Published: January 2023

Abstract
FoxP3 determines the development of CD4+CD25+ regulatory T (Treg) cells and represses IL-2 expression in Treg cells. However, FoxP3+ Treg cells support higher levels of HIV-1 replication than FoxP3-CD4+ T cells. We report that FoxP3 enhances HIV-1 LTR but inhibits IL-2 promoter activity. This FoxP3 activity is mapped at the C-terminal forkhead domain and inactivated by human IPEX mutations. FoxP3 enhances HIV-1 LTR via specific NFkappaB binding sequences in an NFkappaB-dependant fashion. FoxP3 also enhances a minimal promoter containing the NFkappaB sequences derived from LTR but not from the MHC promoter in T cells, but represses both the HIV-1 LTR and MHC promoter in 293T cells. Interestingly, FoxP3 does not alter NFkappaB nuclear translocation but enhances its binding to the HIV-1 promoter in T cells. Therefore, FoxP3 distinctively modulates T cell activation and HIV-1 replication in human T cells by modulating NFAT and NFkappaB activity, respectively.
Adaptive immune cells temper initial innate responses¿ (46.1)
Authors: Fu Yang-xin , Kim kwang dong , Zhao Jie , Tang Hong 
Published: January 2023

Abstract
Immunocompromised hosts often die of acute infection, presumably, due to lack of an adaptive immune response to clear pathogens. However, we have now demonstrated that an unleashed innate immune response can also be a direct cause of death. After viral infection, nude mice produced higher levels of proinflammatory cytokines but died even though titers of virus remained comparable to wild type mice. Administration of poly I:C, a ligand for toll-like receptor 3, also led to cytokine storm in immunocompromised mice in an NK cell and TNF dependent fashion. Remarkably, addition of T cells suppressed the cytokine surge by innate cells in an antigen-independent fashion. Splenocytes of neonate also produces much higher level of cytokines in response to TLR stimulation. New pathway is required for such suppression. The concept of an unleashed innate response in the absence of adaptive modulation may lead to new diagnosis and treatment for neonate or individuals with adaptive immunodeficiencies.
IL-10 regulates movement of intestinally-derived CD4+ T cells to the liver (46.12)
Authors: Bliss Susan K. , Bliss Stuart P. , Beiting Daniel , Alcaraz Ana , Appleton Judith 
Published: January 2023

Abstract
Diseases that affect the intestine may have hepatic manifestations, but the mechanisms involved in establishing hepatic disease secondarily remain poorly understood. We previously reported that IL-10 knockout (KO) mice developed severe necrotizing hepatitis following oral infection with Trichinella spiralis. Here, we used this model of intestinal inflammation to further examine the role of IL-10 in regulating hepatic injury. Hepatic damage was induced by migrating newborn larvae (NBL). By delivering the parasite directly into the portal vein, we demonstrated that an ongoing intestinal immune response was necessary for the development of hepatitis. Intestinally-derived CD4+ cells accumulated in the livers of IL-10 KO mice, and depletion of CD4+ cells in wildtype (WT) mice led to a decrease in IL-10 production by hepatic leukocytes. Moreover, adoptive transfer of intestinally primed CD4+ T cells from IL-10 KO mice caused hepatitis in infected immunodeficient animals. Conversely, transfer of WT donor cells reduced the severity of hepatic inflammation in IL-10 KO recipients, demonstrating regulatory activity. Our results revealed that IL-10 prevented migration of intestinal T cells to the liver and inhibited the development of hepatitis.
This work was supported by National Institutes of Health Grants AI 14490 (J.A.A.) and DK 67290 (S.K.B.).
REGULATORY CYTOKINE ENVIRONMENT AS A PATHOGENIC MECHANISM FOR HBV PERSISTANCE (46.13)
Authors: Berrueta Lisbeth , Barboza Luisa , Salmen Siham , Goncalves Loredana , Colmenares Melisa , Peterson Darrell , Montes Henry , Cartagirone Raimondo , Gutierrez Maria del Carmen 
Published: January 2023

Abstract
The T cell response to HBV has been shown to be vigorous in patients with acute hepatitis who clear the virus, whereas it is weak and narrowly focused in patients with chronic disease. We hypothesized that inappropriate early activation events of T cells could contribute to viral persistence during chronic infection. Therefore, we investigated the induction of activation receptors and cytokine production in lymphocytes stimulated with HBcAg, in a group of chronically infected patients and naturally immune subjects. Chronic patients did not increase CD40L or CD69 following stimulation, compared to subjects that resolved the infection. The presence of a CD4+CD25+ cell population was observed which produced elevated levels of IL-10 and TGF-β following specific stimulation with HBcAg, cytokines that are known to be suppressors of the immune response. These results suggest that a predominant inhibitory environment may be responsible for altered T cell costimulation, representing a mechanism for viral persistence.
Is there a role for Tregs in SIV infected non-human primates? (46.15)
Authors: Pereira Lara Elizabeth , Villinger F. , Onlamoon N. , Bryan P. , Cardona A. , Pattanapanysat K. , Mori K. , Hagen S. , Picker L. , Ansari A. A. 
Published: January 2023

Abstract
A study was performed to identify, characterize and compare the level and function of peripheral Tregs in uninfected and SIV-infected rhesus macaques (RM) and sooty mangabeys (SM) to determine if Tregs contribute to the muted immune response that is evident in SIV-infected disease-resistant SM but readily detectable in SIV-infected disease-susceptible RM. Results show that SIV-infected SM maintain the level and function of Tregs but a substantial decline was noted in RM. A strong correlation between plasma VL and the level of Tregs was observed in SIV-infected RM but not SM. RM VL controllers exhibited lower levels of immune activation and recovered pre-infection levels of Tregs that were fully functional when tested for suppressive activity in vitro. ICC assays showed that Treg-depleted PBMC fractions from RM but not SM exhibit increased CD4+ and CD8+ T-cell responses to select SIV peptide pools suggesting that Tregs play a role in the SIV-specific immune response at least in RM. The decline in Tregs in SIV-infected RM as a general consequence of viral pathogenesis may further contribute to the increased immune activation and viral replication exhibited by disease progressors. Although the role of Tregs in SM remains unclear, the data imply that therapeutic manipulationof the frequency and function of Treg-cell in RM and perhaps HIV-infected hosts could improve immune controlof viral infection.
NIH RO1 27057, AIDS & Health Sciences Research Grants, Ministry of Health Labor & Welfare in Japan.
Rapid alteration of blood brain barrier (BBB) tight junction proteins by antigen specific CD8 T cells (46.16)
Authors: Johnson Aaron , Suidan Georgette , Chen Yi , McDole Jeremiah , Pirko Istvan 
Published: January 2023

Abstract
CNS vascular permeability is a feature of numerous neurological diseases as diverse as shock, multiple sclerosis, Alzheimer’s disease and viral hemorrhagic fevers. The role of inflammatory immune cells in promoting opening of the blood brain barrier (BBB) in neurological disease remains poorly understood. Our laboratory has created a novel in vivo system to study BBB disruption using the Theilers murine encephalomyelitus virus (TMEV) model of multiple sclerosis. During acute TMEV infection, 70% of CNS infiltrating CD8 T cells are specific for a TMEV peptide, VP2 121–130, presented in the context of the Db Class I molecule. Intravenous injection of the VP2 121–130 peptide during the peak of CD8 T cell expansion in the CNS results in fatal vascular permeability characterized by: 1.) Astrocyte activation as detected by GFAP upregulation, 2.) Alteration of BBB tight junction proteins Z0-2, Occludin and Claudin 5, 3.) Vascular permeability as measured by quantifiable T1 weighted MRI, and 4.) Severe motor deficit. Astrocyte activation and BBB tight junction protein alteration by CD8 T cell is rapid, occurring within four hours of peptide administration. We have also determined that perforin is critical for vascular permeability to occur. To our knowledge, this is the first demonstration of an antigen specific T cell response altering tight junction proteins of the BBB.
Novel role of NK cells in the development of adaptive immunity against mycoplasma respiratory disease (46.23)
Authors: Bodhankar Sheetal , Woolard Matthew D , Simecka Jerry W 
Published: January 2023

Abstract
A complex balance between the detrimental and beneficial effects of immunity determines the course of mycoplasma respiratory infection. NK cells were shown to dampen innate immunity in the lungs. The purpose of this study was to determine if NK cells similarly impacted the development of adaptive immunity against mycoplasma disease. Anti-asialoGM1 Ab was used to transiently deplete NK cells prior to nasal-pulmonary immunization with mycoplasma membrane Ag. Unimmunized and mice receiving only anti-asialoGM1 Ab served as controls. The treatment was repeated 7d later and the mice were challenged on day 14 with M. pulmonis. DX5+ NK cell numbers returned to normal by day 14. Colony forming units (CFUs) in lungs and nasal passages were determined 3, 7 and 14d later.
There was a significant decrease (&gt;1 log) in CFUs in the NK cell depleted, immunized mice as compared to immunized or control mice. No such effect was seen in SCID mice, indicating adaptive immunity was affected. Further support that the protection rendered due to depletion of NK cells prior to immunization, was lymphocyte-mediated, was demonstrated when protection was shown to be adoptively transferred to naïve mice using total lung lymphocytes, purified T and/or Non T cells.
In conclusion, NK cells dampen the generation of protective adaptive immunity associated with nasal-pulmonary immunization, and this effect is on the generation of lymphoid cell mediated response. These results should provide insights into approaches to generate optimal protective immunity against mycoplasma respiratory diseases.
HIV gp120 alone may mediate lymphopenia and lymphadnopathy in HIV infected individuals (46.4)
Authors: Green Daniel Saul , Morgan Ross , Curcio-Bonner Chrystal , David Center M , Cruikshank William W 
Published: January 2023

Abstract
Lymphopenia is the hallmark of HIV infection and is thought to be mediated by virus infection and subsequent killing of CD4+ T cells. However, recent data suggests that decrease in peripheral CD4+ T cells may initially involve sequestration of these cells in secondary lymphoid tissues (SLT). T cell homing to SLT is facilitated by SLT-specific chemokines, CCL19 and CCL21 while egress from SLT requires expression of functional sphingosine-1-phosphate (S1P) receptors. As lymphadnopathy is observed in most HIV-1 infected individuals, we investigated the potential of HIV-1 envelope glycoprotein, gp120, to affect parameters of T cell homing to SLT. Normal human T cells were exposed to gp120 for 1 to 24h prior to migration induced by CCL19 or CCL21. We also investigated the effects of gp120 on responsiveness to S1P induced migration. We found that exposure to gp120 for 1h augmented, by 2-fold, chemoattraction induced by CCL19 and CCL21, but did not effect migration induced by the SLT independent chemokine CCL11. Conversely, these cells became completely unresponsive to S1P induced migration (2–3 fold migration blocked to 0). The gp120 mediated inhibition of migration was completely reversed by the p56lck inhibitor herbimycin A, indicating a requirement of CD4 signaling. Taken together our data indicates that gp120 alone could facilitate CD4+ T cell homing and sequestration in the SLT of HIV infected indiivduals.
In vitro and in vivo induction of B7-H1 and B7-DC expression by human rhinovirus infection of airway epithelial cells (46.5)
Authors: Kim Jean , Heinecke Lowella F , Proud David , Schleimer Robert P 
Published: January 2023

Abstract
We have found that human airway epithelial cells express costimulatory molecules B7-H1, B7-H2, B7-H3 and B7-DC mRNA and cell-surface protein. IFN? and TNF? selectively induce B7-H1 and B7-DC and glucocorticoid fluticasone (FP) inhibits this induction. We now report that human rhinovirus infection (HRV-16), a key trigger of exacerbations of chronic rhinosinusitis and asthma, results in selective induction of B7-H1 and B7-DC expression in airway epithelial cells both in vitro and in vivo. In vitro exposure of human primary bronchial epithelial cells (PBEC) to HRV-16 (TCID50 5 X 103.1) resulted in induction of cell surface expression of B7-H1 as measured by flow cytometry (from 42±9 to 56±8 MFI, p&lt;0.05) and B7-DC (from 5±1 to 9±2 MFI, p&lt;0.01) (n=6). Pretreatment with FP (10-7 M) inhibited the induction of B7-H1 by 64% (p&lt;0.05) and B7-DC by 95% (p&lt;0.01). Additionally, in vitro exposure of PBEC to TLR3 agonist dsRNA (25 ug/ml), a surrogate for HRV16 infection, mirrored the effect of HRV-16 infection. Nasal scrapings taken at the time of peak symptom scores 4 days after infection of 6 human subjects with HRV-16 showed selective increases in levels of mRNA for B7-H1 (8.5±2.5 fold, p&lt;0.03) and B7-DC (3.2±1.1 fold, p&lt;0.07). These data show that exposure to TLR3 agonist dsRNA or HRV-16 infection induces B7-H1 and B7-DC on epithelial cells and this may influence the development of adaptive immune responses in the airways.
Differential Susceptibility in a Murine Model of Melioidosis (46.7)
Authors: Tan Gladys Gek Yen , Liu Yichun , Ooi Eng Eong 
Published: January 2023

Abstract
Melioidosis, an emerging infectious disease with protean clinical manifestations and caused by Burkholderia pseudomallei, is endemic to SE Asia and Northern Australia. A murine model was set up to study host-pathogen interactions associated with different acquisition modes. Aerosol, intranasal, intraperitoneal, subcutaneous routes of infection were performed on BALB/C and C57Bl/6 mice, with virulent Bp strain KHW. Based on LD50 values and disease progression, the lethality, in decreasing order, was aerosol&gt; intranasal&gt; intraperitoneal&gt; subcutaneous. Regardless of the portal of entry, LD50 values of C57Bl/6 mice were at least 100-fold higher than those of Balb/c mice, suggesting C57Bl/6 mice were more resistant and Balb/c mice more susceptible to Bp infection. Comparing the pathogenesis of Bp infection with 20 CFU bacteria via inhalational routes, overwhelming bacterial burdens were found in the lungs, nasal cavity, spleen, liver and blood of Balb/c mice, against low to undetectable bacterial loads in C57Bl/6 mice post infection. High levels of proinflammatory cytokines were detected in Balb/c mice, while a transient and moderate cytokine level was observed in C57Bl/6 mice. Despite the presence of inflammation in Balb/c mice, the innate immune response was unable to control infection, leading to severe immune-mediated pathology and death.
This study was funded by D30 grant from DSTA, Singapore.
Modulation of malaria-induced immunopathology by concurrent nematode infection (46.8)
Authors: Segura Mariela , Matte Christine , Thawani Neeta , Su Zhong , Stevenson Mary M. 
Published: January 2023

Abstract
Gastrointestinal nematode infections, highly prevalent in malaria endemic areas, are known to modulate host immune responses to unrelated pathogens. However, the complex relationship between worms and malaria and the impact on malarial incidence vs. severity are unclear. Previously, we observed that C57BL/6 (B6) mice infected with the gastrointestinal nematode Heligosomoides polygyrus (Hp) for 2 wks before blood-stage Plasmodium chabaudi AS (Pc) infection developed significantly higher parasitemia compared to mice infected with Pc alone. Despite this, malaria-induced body weight loss, anemia and hepatosplenic damage were not exacerbated in co-infected mice. Indeed, there was less severe hypothermia and hypoglycemia and more robust reticulocytosis in co-infected mice. Co-infection with Hp suppressed type 1 immune responses induced by P. chabaudi infection with significantly reduced plasma levels of IFN-γ, TNF-α and nitric oxide, but increased IL-6 and IL-10 levels. Co-infected STAT-6−/− mice, which have disrupted Th2 responses, experienced only slightly more severe hypothermia, hypoglycemia, and anemia than co-infected WT B6 mice while in vivo administration of anti-IL-10R (1B1.2) mAb resulted in higher mortality in co-infected WT mice. Although concurrent nematode infection resulted in increased parasitemia due to impaired anti-malarial type 1 immunity, our data suggest that malaria-associated pathology is alleviated by a complex immunoregulatory network, possibly involving IL-10, and, to a lesser extent, Th2 cytokines.
Cytokine and phenotypic profiles of specific T cells induced by newborn BCG vaccination (47.1)
Authors: Hanekom Willem , Soares Andreia , Scriba Tom , Hussey Greg , Kaplan Gilla 
Published: January 2023

Abstract
Bacillus Calmette-Guerin (BCG), the only currently available TB vaccine, is the most widely administered vaccine in the world. However, the immune response to BCG has not been fully characterized. This knowledge is critical for studies of protective immunity induced by vaccination and for developing novel, improved TB vaccines.
We aimed to describe phenotypic and cytokine profiles of specific T cell subsets in blood of 10-week old infants following their routine vaccination with BCG at birth.
Whole blood of 30 infants was incubated with BCG for 12 hrs; Brefeldin A was added for the last 5 hrs. Red cells were lysed and white cells fixed and cryopreserved. Thawed cells were permeabilized, stained and analysed by multiparameter flow cytometry.
We observed predominant expression of presumably protective Type 1 cytokines: distinct Type 1 CD4+ and CD8+ T-cell subsets were identified, based on IL-2, TNF and IFN-gamma expression. TNF expression was virtually absent from CD8+ T cells. IL-4 could not be detected; IL-10 expression was low, but only in cells that did not express Type 1 cytokines. The distinct phenotypes of IL-2, TNF and IFN-gamma expressing cells will be described: the most common phenotypes were CD45RA-CCR7+/−CD27+.
We conclude that newborn BCG vaccination induces predominantly Type 1 cytokine responses in CD4+ and CD8+ T cells. Significant numbers of specific T-cells did not produce IFN-gamma, suggesting that assays relying on detection of this cytokine alone do not measure the entire mycobacteria-induced response. Type 1 cytokine expressing CD4+ and CD8+ T cells have predominantly effector and central memory phenotypes. We will now apply this knowledge to a large ongoing study of BCG-induced immune correlates of protection against TB in children.