bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early signaling events regulate Fas-induced apoptosis in CD4+ T cells (104.5)
Authors: Ramaswamy Madhu , Do Thao , Cora-Morges Adrian , Cruz Anthony , Siegel Richard 
Published: January 2023

Abstract
Autoreactive CD4+ T cells can be eliminated by the TNF superfamily member Fas through a process termed Restimulation Induced Cell Death (RICD). Previously, we have shown that effector memory CD4 T cells were the most Fas-induced apoptosis sensitive CD4 subset. This was due to efficient recruitment and activation of components of the death-inducing signaling complex (DISC) indicating a role for early signaling events in apoptosis regulation. To discover novel proteins recruited to the DISC, we used 2D-DIGE and Mass Spectrometry on Fas sensitive and resistant CTCL lines to identify differential binding partners in the Fas-DISC. We have identified a number of proteins including a SNARE family protein previously found to be involved in exocytosis. In transfection experiments, this protein interacted with Fas in a manner independent of the Fas death domain as shown by co-immunoprecipitation and Fluorescence Resonance Energy Transfer (FRET) between constructs fused to CFP and YFP. The endogenous protein preferentially interacted with Fas in cell lines and T cell subsets susceptible to Fas-induced cell death. These results suggest that that this protein is a novel component of the DISC and may regulate early events in Fas signaling, possibly through affecting receptor endocytosis or recycling to the plasma membrane. The mechanism by which this protein affects assembly and activation of the Fas DISC, and other proteins found in this proteomic screen are currently being investigated.
Defective CD8 T cell memory generated during latent gammaherpesvirus infection (105.11)
Authors: Freeman Michael , Burkum Claire , Jensen Meghan , Woodland David , Blackman Marcia 
Published: January 2023

Abstract
Antiviral CD8 T cells are essential for protection during murine gammaheresvirus-68 (γHV68) infection. We recently identified a large panel of epitope-specific CD8 T cell responses that were differentially regulated by antigen presentation during the establishment of viral latency, but how these T cell responses are maintained throughout latent infection is unclear. Here we show that recent thymic emigrants are primed during latency, accumulate over time, and can proliferate in response to experimentally-induced viral reactivation. We found that in contrast to ORF6487- and ORF61524-specific responses, CD8 T cells specific for the ORF75c940 epitope primed during latency were deficient in their ability to respond during reactivation. This defect was not a result of impaired generation of ORF75c940-specific cells during latency or a lack of antigen presentation during reactivation, but rather appears to be a consequence of reduced proliferation following stimulation. The finding of epitope-specific differences in proliferative capacity suggests that the functionality of latency-primed responses may be regulated by differential antigen presentation or viral gene expression during latency. These findings have important implications for the development of therapeutic vaccine strategies against latent gammaherpesvirus infections.
Unraveling how Rfv3/Apobec3 promotes the retrovirus-specific neutralizing antibody response (105.12)
Authors: Santiago Mario , Smith Diana , Barrett Bradley , Guo Kejun , Heilman Karl , Benitez Robert , Montano Mauricio , Pelanda Roberta , Hasenkrug Kim , Greene Warner 
Published: January 2023

Abstract
Recovery from Friend retrovirus gene 3 (Rfv3) is a classical autosomal dominant gene that facilitates recovery from viremia and disease by promoting a more potent neutralizing antibody (NAb) response. We previously reported that Rfv3 is encoded by Apobec3, a deoxycytidine deaminase that can restrict a broad range of retroviruses. However, the mechanism for how Apobec3 promotes NAb responses and the nature of protective NAbs remain unclear. Apobec3 is related to Activation Induced Deaminase, but hapten-specific antibody affinity maturation is unaffected in Apobec3 deficient mice. In contrast, Apobec3 restriction of acute FV infection in immune cells is associated with more vigorous induction of germinal center B cells, increased B cell maturation and decreased hypergammaglobulinemia. Surprisingly, while Apobec3 reduced acute plasma infectious virus titers, plasma viral RNA loads were maintained. These plasma virions encounter an early reverse transcription block with minimum G-to-A mutations. Thus, Apobec3 appears to promote NAb responses by (1) reducing virus-induced immune dysfunction, while (2) facilitating substantial release of noninfectious viral particles, presumably to prime the B cell response. Finally, enhanced NAb responses in Rfv3/Apobec3 resistant mice correlated with virus-specific IgG1 and IgG3 titers. These findings highlight a fascinating interplay between innate Apobec3 restriction and humoral immunity, with potential implications for HIV vaccine development.
Migration of cytotoxic lymphocytes in cell cycle permits local MHC-I dependent control of division at sites of viral infection (105.21)
Authors: Kang Silvia , Herz Jasmin , Kim Jiyun , Nayak Debasis , Stewart-Hutchinson Phillip , Dustin Michael , McGavern Dorian 
Published: January 2023

Abstract
Following virus infection, cytotoxic T lymphocytes (CTL) divide rapidly to eradicate the pathogen and prevent the establishment of persistence. The magnitude of an anti-viral CTL response is thought to be controlled by the initiation of a cell cycle program within lymphoid tissues. However, it is presently not known whether this division program proceeds during migration or is influenced locally at sites of viral infection. Here we demonstrate that anti-viral CTL remain in cell cycle while transiting to infected tissues. One third of virus-specific CTL within blood were found to be in cell cycle following infection with lymphocytic choriomeningitis virus (LCMV). Using two-photon microscopy, we revealed that effector CTL divided rapidly upon arrest in the virus-infected central nervous system (CNS) as well as meningeal blood vessels. We also observed that MHC I-dependent interactions (but not costimulation) influenced the division program by advancing effector CTL through stages of cell cycle. These results demonstrate that CTL are poised to divide in transit and that their numbers can be influenced locally at the site of infection through interactions with cells displaying cognate antigen.
Human herpes virus 8 infection induces a Th2 skewed cytokine and chemokine response in primary B lymphocytes in the absence of virus replication (105.30)
Authors: Knowlton Emilee , Rappocciolo Giovanna , Piazza Paolo , Jenkins Frank , Jais Mariel , Rinaldo Charles 
Published: January 2023

Abstract
Objectives: Cytokines-chemokines play an important role in Kaposi’s sarcoma (KS), including tumor-cell proliferation, angiogenesis and vascular permeability. As DC-SIGN expressing B cells are natural targets for HHV-8, we examined the production of soluble factors by HHV-8 infected B cells and their relationship to HHV-8 replication. Methods: B cells were loaded with purified HHV-8, UV-light inactivated HHV-8 (UV-HHV-8) or soluble HHV-8 glycoprotein B (gB). Intracellular staining and flow cytometry were used to determine cytokine-chemokine production by B cells. Supernatants were examined for protein secretion by Cytometric Bead Array. Results: Peak levels of TNF-α, IL-6, IL-8, MIP-1α and MIP-1β of 570 (TNF-α) to 2.5 x 104 (MIP-1β) pg/ml were detected in HHV-8 infected cultures by 24-48h, which were 16 to 100 fold higher than in uninfected B cell cultures. Treatment with gB or UV-HHV-8 induced a similar pattern of cytokine-chemokine production by B cells. Conclusions: Elevated levels of several inflammatory cytokines and MIP chemokines were detected in HHV-8 infected B cells. Similar production of these factors by HHV-8 gB and UV-HHV-8 implies that full cycle virus replication is not necessary to elicit a strong immune response to HHV-8 infection. Determining the cytokine-chemokine response to HHV-8 infection of B cells could be significant to our understanding of HHV-8 pathogenesis, and could provide novel targets for vaccine development.
IFNγ regulates CXCL12 expression and cell trafficking during WNV infection (105.39)
Authors: Durrant Douglas , Klein Robyn 
Published: January 2023

Abstract
West Nile Virus (WNV), a mosquito-transmitted neurotropic flavivirus, causes severe neuroinvasive disease in the elderly and immuno-compromised. For viral clearance and survival, it is essential that virus-specific T cells enter into the central nervous system (CNS) parenchyma in both human and murine subjects. The chemokine CXCL12 is a potent immune factor that dictates homing and motility of lymphocytes to specific microenvironments. In the context of WNV encephalitis, we have shown that CXCL12-mediated localization of lymphocytes to the perivascular space modulates their ability to efficiently control infection. This localization regulates the parenchymal entry of infiltrating leukocytes during neuroinflammatory diseases. However, the means by which CXCL12 is regulated and how this regulation influences cell trafficking during WNV remains unclear. We show that CXCL12 is up-regulated within the spleen and down-regulated in the CNS on day 8 post-WNV infection. However, in the absence of IFN-γ, there is an increase in CXCL12 expression in the CNS of WNV-infected mice. We propose that during WNV infection, IFN-γ regulates CXCL12 expression both in the periphery and in the CNS, which has an effect on the localization of leukocytes and therefore influences the function of these cells to efficiently control infection.
HIV and SIV mutational analysis reveals functional decoupling of HIV-1 Nef-mediated T-cell activation and chemotaxis (105.46)
Authors: Park In-Woo , He Johnny 
Published: January 2023

Abstract
HIV-1 Nef has been shown to induce activation of CD4+ T cells but inhibit their migration toward SDF-1α. However, it is unclear how this protein orchestrates these two distinct activities. We found that HIV-1 Nef activated T cells only in the presence of CD3/ CD28 stimulation, while SIVpbj1.9 Nef activated T cells with or without CD3/CD28, indicating differential activation patterns between these two Nefs. We also observed that HIV-1 Nef inhibited T cell chemotaxis toward SDF-1α, while SIVpbj1.9 Nef did not. Moreover, we determined that CD3 stimulation diminished surface expression of CXCR4 in CD4+ T cells, leading to reduced SDF-1α-oriented migration. To further investigate the activation/chemotaxis interplay, we replaced the N-terminal half of HIV-1 Nef with the corresponding half of SIVpbj1.9 and determined its effects on chemotaxis and T cell activation. The resulting construct, hybrid HSNef, completely abrogated the chemotaxis blockade by HIV-1 Nef, while failing to activate T cells unless they were CD3/CD28 co-stimulated. Further analysis demonstrated that mutations at the myristoylation and SH3 binding sites in the N-terminal half of Nef were unresponsive to CD3/CD28 stimulation, but reversed the migration inhibition. However, a mutant for the basic rich domain of Nef was deficient for both activation and migration. Taken together, our findings indicate that the signals for T cell activation by Nef do not necessarily parallel those for T cell migration.
Viral persistence drives CD4 T cell differentiation toward T follicular helper cells (105.7)
Authors: Fahey Laura , Wilson Elizabeth , Elsaesser Heidi , Brooks David 
Published: January 2023

Abstract
CD4 T cells are central mediators of the adaptive immune response and are crucial to prevent and control viral infection. Yet, virus-specific CD4 T cell activity is considered to be lost during many persistent viral infections because they do not produce the classic Th 1 cytokines. Considering CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. Recently, IL-21 was identified as a critical component of CD4 T cell help during viral persistence, suggesting that virus-specific CD4 T cells do not lose functionality but rather differentiate into a subset other than Th1. Thus, we sought to define how viral persistence impacts CD4 T cell differentiation such that it is capable of maintaining antiviral immunity during prolonged viral replication. We demonstrate that CD4 T cell function is not lost during viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively drives CD4 T cell development toward T follicular helper cells. The developmental program of CD4 T cells instituted during viral persistence is both molecularly and functionally distinct from that observed during an acute infection. Importantly, the progressive CD4 T cell differentiation and function is necessary to maintain B cell immunity and ultimately control persistent viral replication.
Treatment with Anti-CD137 (41BB) mAb enhances peptide vaccination against respiratory syncytial virus in aged mice (106.2)
Authors: Lee Sujin , Mittler Robert , Moore Martin 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the most important pathogen for lower respiratory tract illness (LRI) in infants and also a major cause of morbidity and mortality in the elderly. Using an aged mouse model of RSV pathogenesis, we found that aged mice had impaired antigen-specific CD8 T cell responses and delayed RSV clearance compared to young mice. We generated a peptide vaccine approach, TriVax, which is a co-mixture of a peptide representing an immunodominant RSV CD8 T cell epitope, a Toll-like receptor agonist, and a costimulatory anti-CD40 antibody. TriVax vaccination generated robust CD8 T cell responses and had a protective effect against RSV challenge in young BALB/c mice but not in aged BALB/c mice. We hypothesized that treatment of aged mice with agonistic CD137 (41BB) monoclonal antibody would stimulate T cells and enhance TriVax efficacy to RSV challenge in aged mice. We immunized 18-month old BALB/c mice twice with TriVax + anti-CD137 mAb. We found that co-administration of anti-CD137 mAb with TriVax enhanced antigen-specific CD8 T cell responses as well as showed a protective effect after RSV challenge. Thus, anti-CD137 mAb treatment rescued the deficient response to RSV TriVax vaccination in aged mice. The 41BB co-stimulatory pathway may be a target for enhancing T cell responses in the elderly.
The OmpA vaccine protects mice against lethal, extreme drug resistant-Acinetobacter baumannii infection (106.20)
Authors: Luo Guanpingsheng , Lin Lin , Ibrahim Ashraf , Spellberg Brad 
Published: January 2023

Abstract
Extreme drug resistant (XDR) Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. Prevention of such infections is a critical unmet medical need. Because diabetes is a clinical risk factor for A. baumannii infections, a diabetes ketoacidosis (DKA) mouse model of such infections was established to support a rational vaccine discovery program. Specific humoral immune responses to A. baumannii cell membrane proteins occurred during tail-vein infection with multiple clinical isolates in DKA mice. Western blots with paired pre-immune and immune sera identified outer membrane protein A (OmpA) as the immunodominant antigen. Vaccination of DKA mice with recombinant OmpA (rOmpA) with aluminum hydroxide adjuvant markedly improved survival, reduced tissue bacterial burden, and promoted inflammatory cytokine production in infected tissues. rOmpA is a promising vaccine candidate to prevent A. baumannii infections.
Schistosoma mansoni antigens induce IL-10 production and down-modulate the proinflammatory response in cutaneous leishmaniasis (106.21)
Authors: Araujo Maria Ilma , Bafica Aline , Varella Giuseppe , Oliveira Ricardo , Cardoso Luciana , Góes Alfredo , Loukas Alex , Carvalho Edgar , Oliveira Sérgio 
Published: January 2023

Abstract
S. mansoni infection or parasite products by induce regulatory cells and cytokines are able to down-modulate the Th1 inflammatory response involved in some autoimmune diseases. The objective of this study was to evaluate whether S. mansoni antigens are able to down-regulate the inflammatory immune response induced in vitro by the soluble Leishmania antigen (SLA) in cells of cutaneous leishmaniasis (CL) patients. Cytokines were measured in the supernatants of peripheral blood mononuclear cell (PBMC) culture stimulated with SLA in the presence and absence of S. mansoni recombinant antigens Sm29 and TSP2 and PIII, using a sandwich ELISA technique. Additionally, PBMC were evaluated for the expression of surface molecules CD14 and CD16, and also for intracellular cytokines (IL-12, TNF-alpha and IL-10). The addition of rSm29 and PIII to the cell cultures reduced the levels of IFN-γ in 54 and 58% of patients, respectively (mean reduction 49 and 56%). The three antigens used in the study were able to down modulate the production of TNF-alpha in 30% of CL patients and increased IL-10 production in 70 to 100% of them. The use of S. mansoni antigens also resulted in a lower frequency of classical and proinflammatory monocytes expressing IL-12 and TNF-alpha, while increased the frequency of monocytes expressing IL-10. The S. mansoni antigens used in this study down-modulated the inflammatory response in vitro induced by SLA in cells of CL patients.
Lactoferrin enhances BCG efficacy to protect against tuberculosis disease pathology (106.28)
Authors: Hwang Shen-An , Boyd Sydney , Kruzel Marian , Actor Jeffrey 
Published: January 2023

Abstract
Lactoferrin (LF), an iron binding protein found primarily in mucosal secretions and granules of neutrophils, possesses immune modulatory properties that include enhancement of the delayed type hypersensitivity against BCG antigens. Lactoferrin admixed to BCG enhanced host protection upon subsequent challenge with Erdman MTB, demonstrated by decreased organ CFU and reduced granuloma lesions. Splenic recall responses showed immunization with BCG/LF increased IFN-γ production. Additionally, dendritic cells cultured with BCG/LF increased expression of MHC II and CD86 compared to BCG alone. This study examines optimization of LF adjuvant to enhance efficacy of BCG by examining multiple vaccination parameters. C57BL/6 mice were immunized with or without booster at 8 weeks with BCG, BCG/bovine LF (1, 10 100μg), BCG/human recombinant lactoferrin (rhLF) sialylated (1, 10μg), or BCG/rhLF non-sialylated (1, 10μg). 12 weeks post-vaccination, mice were aerosol challenged with Erdman MTB and monitored through 24 weeks. At 6 weeks, splenic recall responses against BCG were examined. Peak LF adjuvant activity was observed at doses greater than 10μg/mouse, assessed by decreased pulmonary pathology post-MTB challenge. Splenic recall responses from BCG/bLF immunized mice showed increased IFN-γ and IL-17 with a concurrent decrease in IL-10 compared to BCG vaccinated and non-immunized controls. No significant differences observed between sialylated and non-sialylated human recombinant LF.
Intranasal vaccination with a defined live attenuated vaccine strain (ΔFTN0109) induces protective immunity against heterotypic pulmonary bacterial challenge. (106.29)
Authors: Signarovitz Aimee , Yu Jieh-Juen , Guentzel M. Neal , Klose Karl , Arulanandam Bernard 
Published: January 2023

Abstract
The need for an efficacious vaccine against the potential bioterrorism agent Francisella tularensis is a consequence of its low infectious dose, high mortality rate, and ability to be spread via aerosol, leading to pneumonic disease. FTN0109 is a novel protein that may be associated with the outer membrane of the bacterium and which is expressed across all subspecies of Francisella. In this study, we sought to determine the efficacy of ΔFTN0109 as a putative vaccine candidate. Using intramacrophage replication assays, ΔFTN0109 has been shown to be highly attenuated for growth. Moreover, the LD50 for this defined vaccine strain is &gt;105 CFU in BALB/c and C57BL/6 mice following intranasal challenge in comparison to its parental strain U112 (LD50&lt;10 CFU). Intranasal vaccination with ΔFTN0109 induces the expression of splenic antigen-specific IFN-γ and IL-2, with concurrent induction of preferential Th1 humoral responses (increased serum IgG2a over IgG1). Intranasal immunization with ΔFTN0109 confers complete protection in BALB/c mice against a subsequent pulmonary challenge with the heterotypic subspecies holarctica Live Vaccine Strain (LVS). Lungs, livers, and spleens of vaccinated and LVS-challenged mice exhibited significant reductions in bacterial burdens compared to mock-vaccinated and challenged animals. Current studies are ongoing to further clarify the mechanisms by which protection is conferred following vaccination with ΔFTN0109.
Effect of CCL1 antisense ODN on bacterial translocation in mice irradiated with whole body 137Cs γ-rays: III. Control of Enterococcus faecalis translocation (106.8)
Authors: Patel Niket , Asai Akira , Kogiso Mari , Cornforth Michael , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
In our previous studies, bacterial translocation and subsequent sepsis are demonstrated in whole body γ-irradiated mice (WBI-mice) orally infected with E. faecalis. M1Mϕ, which are major antibacterial effector cells against E. faecalis translocation, were induced by enterococcal antigen in mesenteric lymph nodes (MLN) of WBI-mice treated with CCL1 antisense ODN. Therefore, in this study, we tried to control E. faecalis translocation and subsequent sepsis in WBI-mice by CCL1 antisense ODN. WBI-mice were treated s.c. with CCL1 antisense ODN (10 μg/mouse) twice a day for 2 days starting 14 days after 5 Gy whole body γ-irradiation. From Day 1 to Day 10 after γ-irradiation, WBI-mice were decontaminated by antibiotics. One day after the final antisense ODN treatment, these mice were infected orally with 106 to 107 CFU/mouse of E. faecalis. The severities of infection were evaluated by the growth of the pathogen in MLN, kidneys and blood, as compared with those of WBI-mice treated with scrambled ODN. In the results, the great reduction of bacterial growth in MLN and kidneys of WBI-mice treated with CCL1 antisense ODN was demonstrated 1 to 3 days after infection, as compared with that of controls. Also, the pathogen was not detected in blood of WBI-mice treated with CCL1 antisense ODN. These results indicate that sepsis stemming from E. faecalis translocation in WBI-mice is controllable by CCL1 antisense ODN gene therapy.