bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inoculation of α-Galactosylceramide and HPV18-E1 protein promote a cytokines profile involved in the generation of central memory CD8 + T cells
Authors: Amador Alfredo , Gonzalez-Telona Ana Daniela , Lizano Marcela 
Published: January 2023

Abstract
CD8+ mediated immune response plays a major role in the clearance of Human Papillomavirus (HPV) infected cells. In the natural history of an HPV infection, the expression of HPV-E1 helicase during viral replication makes it a potential immunological target. Currently, there are no therapeutic vaccines that eliminate the lesions caused by HPV. Nevertheless, there are many studies on developing therapeutic vaccines against HPV. Vaccines and immunological therapies mostly use adjuvants, particularly α-galactocilceramide (α-GalCer) is an adjuvant that promotes a CD8+ T lymphocyte response mainly.
We demonstrate in previous work, that immunization of HPV type 18 E1 protein along with α-GalCer adjuvant elicited CD8 T cell-immune response, able to eliminate tumor cells expressing HPV18 E1 protein.
In this study, we analyzed the effect of α-GalCer in the generation of memory T CD8+ populations. We evaluated the serum levels of IL-15, IL-7, IL-4, IL-31, IL-2, TNF-α and the number of memory CD8+ T cells.
The serum levels of IL-15, IL-7, IL-4 and TNF- α are increase in mice inoculated with α-GalCer plus HPV18-E1 with respect to mice inoculated with α-GalCer or HPV18-E1 protein. These data correlate with the increase of central memory T CD8+ population in mice inoculated with α-GalCer plus HPV18-E1.
These data indicate that the administration of α-GalCer along with HPV18-E1 protein helps the generation of central memory CD8 + T lymphocytes. This adjuvant could be useful in the development of new therapeutic strategies to clearance HPV established infections.
INCAN: (017/076/17) (CEI/1076/17)
Transduction of retinoic acid-inducible gene 1 by Ebola virus-like particles enhances antigen-presentation
Authors: Martinez Osvaldo , Ngu Mee Kee Esther , Warneke Paul , burmeister Brock 
Published: January 2023

Abstract
Ebola virus (EBOV), a filovirus family member, is a highly pathogenic virus that causes Ebola hemorrhagic fever resulting in documented mortality rates in humans as high as 50%. EBOV virus-like particles (VLPs) are morphologically and biochemically similar to parental virus, yet because they lack a genome and cannot replicate, are safe enough to be used as vaccines. We hypothesize that addition of a constitutionally active retinoic acid-inducible gene 1 (RIG-I) would enhance the ability of the EBOV VLPs to induce antigen-presentation from infected antigen-presenting cells. Expression of EBOV VP40 in 293T cells induces the spontaneous production of VLPs into the media supernatant and if expressed with EBOV glycoprotein (GP), will produce VLPs studded with the attachment GP. Recombinant chimeric constitutively active (ca)RIG-I-VP40 matrix and a nonfunctional mutant L58A (mu)RIG-I-VP40 matrix genes were constructed to produce VLPs containing constitutively active and nonfunctional RIG-I, respectively. Supernatant from 293Ts transfected with caRIG-I-VP40, muRIG-I-VP40 or VP40 along with GP expression plasmids were tested for the presence of VLPs. Western blotting of purified VLPs confirmed the presence of RIG-I in caRIG-I-VP40 and muRIG-I-VP40, but not VP40 containing VLPs. Monocyte-like THP-1 reporter cells were treated with nothing, VP40+GP, caRIG-I-VP40+GP and muRIG-I-VP40+GP VLPs as well as LPS control and tested for induction of interferon signaling. CaRIG-I containing, but not muRIG-I containing VLPs induced interferon signaling as well as greater MHC I upregulation.
Daidzein and its analogs reactivate HIV replication from latently infected CD4 T cells
Authors: Liu Li , Liang Jianguo , Lu Xiaofan , Chen Zhiwei 
Published: January 2023

Abstract
Human immunodeficiency virus (HIV) persists in a latent form in infected individuals under antiretroviral therapy (ART) through integrating proviral DNA into the genome of host immune cells. In these latently infected cells, the transcription of HIV proviral DNA remains silent, which enables the infected cells to escape from the killing by anti-viral CD8+ T cells. One of the recent new therapeutic strategies for HIV eradication aims to reactivate HIV production in the latently infected cells, so that these cells could be detected and eliminated by the immune system. Here we show that small molecules isolated from Spatholobus suberectus Dunn., Daidzein and its analogues, reactivate HIV replication from latency. Daidzein reactivates HIV replication in latently infected CD4 T cell lines J lat and A72 dose dependently, but not monocytes. Moreover, by using cells that contain an integrated HIV LTR linked to the luciferase reporter gene, we found that Daidzein activates HIV replication at the level of transcription. This effect is through Akt signaling pathway, and do not induce T cell activation. Structure-activity relationships (SARs) analysis of Daidzein and its five analogues revealed that three analogues, Daidzin, Glycitein and Glycitin, reactivate HIV replication without obvious cell toxicity observed, and 4′-hydroxyisoflavone is their bio functional core structure. Therefore, Daidzein and its analogues have potential to be modified to improve their potency and developed into significant components for HIV therapy.
HIV-induced production of CCL2 may promote rapid seeding of the latent HIV reservoir
Authors: Packard Thomas Alexander , Herzig Eytan , Luo Xiaoyu , Egedal Johanne H , Grimmett Zachary W , Hasenkrug Kim J , Roan Nadia , Greene Warner C 
Published: January 2023

Abstract
Seeding of the latent HIV reservoir occurs quickly within hours to a few days after initial viral infection. It is the persistence of virus within this reservoir that thwarts an HIV cure and necessitates life-long antiretroviral therapy (ART). Central memory CD4 T cells harboring latent HIV proviruses form a major part of this reservoir. How the virus establishes latency so rapidly within this subset of CD4 T cells remains unknown.
We find that HIV infection leads to rapid production of the CCL2 chemokine in human lymphoid CD4 T cells. Cas9RNP-mediated depletion of IFI16 and STING genes significantly reduces production of CCL2 occurring in response to HIV. IFI16 was previously implicated as the key sensor triggering CD4 T cell pyroptosis. Thus, infection may also stimulate a second pathway of IFI16-mediated signaling involving STING culminating in CCL2 production. CCL2 functions a potent chemoattractant for cells expressing CCR2. Lymphoid CCR2+ CD4 T cells express the CCR5 co-receptor for HIV and markers of central memory. Additionally, these cells express many markers previously associated with the latent HIV reservoir. CCR2+ CD4 T cells are highly permissive to latent and productive infection by both R5 and X4-tropic viruses. When CCR2+ CD4 T cells are purified from HIV-infected individuals on suppressive ART, these cells are enriched up to 75-fold for HIV proviral DNA compared to naïve cells (n=10, p=0.0078).
Together, our findings support a model where HIV infection triggers the production of CCL2, leading to directed recruitment and infection of CCR2+ CD4 central memory T cells. Thus, HIV hijacks a component of the innate immune response to rapidly recruit precisely those target cells that ensure its long term persistence.
Impaired T cell activation resulting from IL-33 induced myeloid derived suppressor cells and IL-10 secreting Tregs is a major determinant of susceptibility to HSV1 infection of the central nervous system
Authors: Chandran Ramakrishna , Mendonca Stacee , Cantin E M 
Published: January 2023

Abstract
Resolution of viral infections of the central nervous system (CNS) is contingent on eliciting protective immunity with minimal pathology. C57BL/6 (B6) mice elucidate efficient innate and anti-viral T cell responses which render them resistant to infection with a virulent HSV 17+ virus strain. Virus replication is limited to ganglia and brainstem. However, susceptible mice such as 129S6 and BALB/c mice harbor increased virus in the CNS. These mice show increased myeloid derived suppressor cells (MDSC) and Tregs along with associated cytokines such as G-CSF, GM-CSF, IL-10 and IL-33 resulting in reduced numbers of virus specific CD8 T cells and effector T cells with increased expression of suppressive markers such as PD-1 and LAG-3. This impaired immune response resulted in disease and mortality. Neutralization of checkpoint inhibitors or immunosuppressive cytokines and depletion of myeloid cells or Tregs did not alter susceptibility rates. However, reducing expression of IL-33 in the CNS had a beneficial effect on T cell activation and the overall outcome of disease. Intriguingly, immunizing susceptible mice with a HSV thymidine kinase mutant virus incapable of infecting CNS induced memory T cells that suppressed MDSCs and protected from a subsequent challenge with HSV 17+. Interestingly IFNg, B cells or antibody were not essential but instead revealed the importance of the T cell myeloid interaction in determining disease outcomes. IL-33 plays critical roles as an immune-modulatory Th2 cytokine regulating immune-mediated diseases and tissue function especially in the CNS and as an alarmin in response to pathogens. This study shows that tempering IL-33 responses is essential to predicting improved outcomes to CNS viral infections.
Vaccinia virus E5 is a dominant inhibitor of the cytosolic DNA sensor cGAS
Authors: Yang Ning , Wang Yi , Shuman Stewart , Deng Liang 
Published: January 2023

Abstract
The cytosolic DNA sensor cGAS plays an important role in detecting viral nucleic acid, which leads to type I IFN production. We have previously shown that infection with conventional dendritic cells with modified vaccinia virus Ankara (MVA), a highly attenuated vaccinia strain (VACV), induces IFN production via a cGAS/STING-dependent mechanism. However, MVA or VACV infection triggers cGAS degradation and its mechanism is still unknown. VACV is a cytoplasmic DNA virus, which encodes more than 200 genes. In this study, we screened 70 vaccinia viral early genes for inhibition of cGAS/STING pathway using a dual luciferase system. We found that vaccinia E5 is a dominant inhibitor of cGAS and is the key protein mediating cGAS degradation. MVAΔE5R induces much higher levels of type I IFN than MVA in multiple cell types, including bone marrow derived dendritic cells (BMDC), bone marrow-derived macrophages (BMDM), and skin primary fibroblasts. MVAΔE5R-mediated type I IFN production is dependent on cGAS. Furthermore, MVAΔE5R gains replication capability in cGAS−/− skin fibroblasts. As a vaccine vector, skin scarification or intradermal vaccination with MVAΔE5R-OVA leads to much higher OVA-specific CD8+ T cell responses than MVA-OVA in vivo. Intratumoral injection of MVAΔE5R leads to stronger anti-tumor immune responses and better survival compared with MVA. Finally, in an intranasal infection model, VACVΔE5R is at least 100-fold attenuated compared with WT VACV. Taken together, our results provide strong evidence that E5 is a key viral virulence factor targeting the cytosolic DNA sensor cGAS and thereby inhibits type I IFN production.
Respiratory syncytial virus disease severity is associated with distinct CD8+ T cell profiles
Authors: Siefker David , Vu Luan , You Dahui , McBride Andrew , Taylor Ryleigh , Jones Tamekia L. , DeVincenzo John P. , Cormier Stephania 
Published: January 2023

Abstract
Most infants are infected with RSV by their second birthday. Despite known risk factors such as prematurity or congenital heart disease, most hospitalized infants are previously healthy. The mechanisms underlying the immunopathology of severe disease is incompletely understood. Our objective was to compare T cell profiles in nasal aspirates between infants with moderate and severe RSV disease hospitalized without immune deficiencies or congenital heart disease, during 2014–2017. Infants requiring intensive care were categorized as having severe disease, while infants maintained in the general ward were categorized as having moderate disease. The T cell profile in nasal aspirates collected 7 days after hospitalization (median 11 days after first symptom onset) was determined by flow cytometry. Nasal aspirates from patients with severe disease were characterized by a higher proportion of CD8+ T cells expressing IL-4 (Tc2) (P=0.024) and a lower proportion of CD8+ T cells expressing IFNγ (Tc1) (P=0.019) compared to patients with moderate disease. Patients with reduced frequencies of Tc1, Tc17, or Th17 cells had shorter durations of hospitalization (P=0.0023, P=0.0188, P=0.0437, respectively). Additionally, patients with severe disease had lower concentrations of IL-17 in nasal aspirates compared to patients with moderate disease (P=0.0133). These results suggest that RSV disease severity is associated with a specific T cell profile, and that Tc2 cells may play an underappreciated role in the development of RSV immunopathology.
Relative timing of type I interferon response and virus replication determines disease outcome during respiratory virus infection
Authors: Channappanavar Rudragouda , Fehr Anthony , Zheng Jian , Abrahante Juan , Mack Matthias , Meyerholz David , Perlman Stanley 
Published: January 2023

Abstract
Type 1 interferons (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I results in delays in virus clearance and impaired MERS-CoV-specific T cell responses. Administration of IFN-I within 1 day post infection (dpi) protected mice from lethal infection. In marked contrast, delayed IFN-I enhanced the inflammatory response, converting a sublethal to a fatal infection. Together, these results suggest the relative timing of IFN-I signaling and maximal virus replication is key in determining the disease outcome and that IFNab should be used cautiously to treat virus infections.
Lung-draining lymph-node-resident memory CD8 T cells mediate local protective immunity
Authors: Anthony Scott M , Van Braeckel-Budimir Natalija , Moioffer Steven , Hartwig Stacey M , Varga Steven M , Badovinac Vladimir P , Harty John T 
Published: January 2023

Abstract
Recent studies indicate tissue-resident memory CD8 T cells (Trms) form at both the sites of initial infection and in lymphoid tissues upon resolution of systemic or localized viral infections. We examined if lymph node Trms were also generated in lung-draining mediastinal lymph nodes (mLN) during intranasal infections. Both transgenic P14 cells and endogenous influenza-specific CD69+/CD103+ Trms were detected in lung-draining mLN but absent in non-draining LNs after intranasal infection with recombinant influenza or vaccinia viruses. Similar to lung Trms, which wane over time, these primary memory (1M) mLN Trms had limited persistence with continual contraction throughout the memory phase. As influenza is a seasonal virus, and we previously observed that repeated antigen exposure extended the durability of lung Trms, we investigated the effects of multiple antigen exposures on the mLN Trm population. Similar to their lung Trm-counterparts, the lung-draining LN Trms derived from repeatedly stimulated (4M) memory CD8 T cells exhibited extended survival, down-regulation of Eomesodermin and the shared IL-2/15Rβ CD122 compared to 1M LN Trms. During parabiosis, both 1M and 4M mLN Trms largely maintained residence within their respective hosts. Importantly, hosts containing 4M P14 mLN Trms provided superior early protection against LCMV challenge in the mLN compared to 1M hosts, demonstrating the functional capacity for mLN Trms to contribute to protective anti-viral immune responses. Overall, these data indicate that lung-draining lymph node Trms co-express CD69 and CD103, largely maintain LN-tissue residency and can contribute to subsequent viral infections.
The role of Exchange Proteins Directly Activated by cAMP in Respiratory Syncytial Virus-induced Pulmonary Pathogenesis
Authors: Choi Eun-Jin , Ren Junping , Wu Wenzhe , Garofalo Roberto P , Bao Xiaoyong 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in children, the elderly, and immunocompromised patients, representing a huge medical burden globally. However, a specific and effective treatment for RSV infection is not currently available, largely due to poorly understood host-RSV interaction. To facilitate the development of preventive and therapeutic approaches, continuous identification of novel host and viral molecules involved in host responses to RSV and associated pathogenesis is greatly needed. We previously have shown that modulation of cellular EPAC2 protein significantly impacts cellular responses and viral replication in both upper and lower airway epithelial cell models of RSV infection, suggesting EPAC2 could be a promising therapeutic target for RSV infection. In this study, mice deficient in EPAC2 was used to investigate the contribution of EPAC2 to pulmonary responses to RSV infection. EPAC2−/− mice showed less body weight loss and better respiratory function than wildtype mice after RSV infection, suggesting attenuated disease severity. RSV-induced cytokines/chemokines and neutrophil cells in bronchoalveolar lavage fluid (BALF) were also significantly less in EPAC2−/− mice. In addition, histopathology studies revealed less pathogenesis by EPAC2 deletion. Taken together, our data indicate that EPAC2 is a key host molecule contributing to RSV-induced inflammatory responses.
Cancer in Pacific Populations in New Zealand and ctDNA technology for early cancer detection
Authors: Sika-Paotonu Dianne , Guilford Parry 
Published: January 2023

Abstract
The burden of cancer amongst Pacific Peoples living in New Zealand and in the Pacific Region remains a public health concern. The utilization of a simple blood sample to enable the detection and monitoring of cancer growth is an attractive alternative to obtaining invasive biopsy samples from solid cancers in people. This can be achieved through the use of circulating tumour DNA (ctDNA) detection which refers to small fragments of tumour DNA found in the blood circulation that can be isolated and analysed to allow monitoring of tumour size and progression. This method of cancer monitoring and the potential for early cancer detection, will enhance the precision of cancer diagnostics and surveillance that will likely lead to improved cancer health outcomes over time. This work sought to investigate the potential utilization of ctDNA to support and improve the diagnosis, care and health outcomes of Pacific cancer patients in the New Zealand. A high degree of support and interest was expressed by health professionals, researchers, senior academics and lay persons engaged with for the development of ctDNA as a potential diagnostic tool for early cancer detection, particularly with regards to achieving reductions in adverse cancer statistics and addressing inequalities. As in the Pacific Region, one of the key features of interest was the potential for frail or remotely located patients to be monitored for their cancer without their need to travel or be transported to the Hospital setting which can create a significant source of stress for some. The applicability of ctDNA as an early cancer detection method was explored in depth and received with approval within the research, academic and clinical health care settings.
Human plasmablast migration toward CXCL12 requires glucose oxidation by enhanced pyruvate dehydrogenase activity via AKT
Authors: Nam Bora , Pak Hyo-Kyung , Park Chan-Sik 
Published: January 2023

Abstract
Migration of human plasmablast to the bone marrow is essential for the final differentiation of plasma cells and maintenance of effective humoral immunity. This migration is controlled by CXCL12/CXCR4-mediated activation of the protein kinase AKT. Herein, we show that the CXCL12-induced migration of human plasmablasts is dependent on glucose oxidation. Glucose depletion markedly inhibited plasmablast migration by 67%, and the glucose analog 2-deoxyglucose (2-DG) reduced the migration by 53%; conversely, glutamine depletion did not reduce the migration. CXCL12 boosted the oxygen consumption rate (OCR), and 2-DG treatment significantly reduced the levels of all measured tricarboxylic acid (TCA) cycle intermediates. AKT inhibitors blocked the CXCL12-mediated increase of OCR. CXCL12 enhanced the pyruvate dehydrogenase (PDH) activity by 13.5-fold in an AKT-dependent manner to promote mitochondrial oxidative phosphorylation. The knockdown and inhibition of PDH confirmed its indispensable role in CXCL12-induced migration. Cellular ATP levels fell by 91% upon exposure to 2-DG, and the mitochondrial ATP synthase inhibitor oligomycin inhibited CXCL12-induced migration by 85%. Low ATP levels inhibited the CXCL12-induced activation of AKT and phosphorylation of myosin light chains by 42%, which are required for cell migration. Thus, we have identified a mechanism that controls glucose oxidation via AKT signaling and PDH activation, which supports the migration of plasmablasts. This mechanism can provide insights into the proper development of long-lived plasma cells and is, therefore, essential for optimal humoral immunity.
Transcription factor T-bet is required for pathogenicity of GM-CSF-only Th cells in experimental autoimmune encephalomyelitis
Authors: Rasouli Javad , Ciric Bogoljub , Casella Giacomo , Yoshimura Satoshi , Zhang Guang-Xian , Rostami Abdolmohamad 
Published: January 2023

Abstract
Myelin-specific Th1 and Th17 cells play a pivotal role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, recent descriptions of a new Th subset, tentatively called “GM-CSF-only” Th cells, or ThG cells, raised the possibility that these cells also contribute to the pathogenesis of MS and other autoimmune diseases. ThG cells express GM-CSF, but lack expression of master transcription factors (TF) and hallmark cytokines of established Th cell lineages. Previous studies showed that Th17 cells switch to Th1 phenotype by upregulating T-bet, which is required for their encephalitogenicity. To test whether pathogenicity of ThG cells is also dependent on T-bet, we evaluated the role of T-bet expression by ThG cells in EAE. T-bet was not required for development of ThG cells in vitro or in vivo. Adoptively transferred ThG cells upregulated T-bet expression in the CNS of EAE mice, while they had low or undetectable levels of RORγt, GATA3 and Foxp3. Next, we adoptively transferred ThG cells that developed from WT and T-bet-deficient 2D2 mice to RAG−/− recipients. WT ThG cells were highly encephalitogenic, whereas T-bet-deficient ThG cells failed to induce disease. Taken as a whole, our data show that ThG cells, similar to Th17 cells, have plastic phenotype, upregulate T-bet and IFN-γ in the CNS of EAE mice, and that their encephalitogenicity is dependent on T-bet.