bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural H7N9 infection in humans boosts cross-group stalk-specific antibody responses broadly cross-reactive to heterosubtypic influenza hemagglutinins from both group 1 and group 2
Authors: Liu Lu , Nachbagauer Raffael , Zhu Lingyan , Huang Yang , Xie Xinci , Jin Shan , Zhang Anli , Wan Yanmin , Hirsh Ariana , Tian Di , Shi Xiaolin , Dong Zhaoguang , Yuan Songhua , Hu Yunwen , Krammer Florian , Zhang Xiaoyan , Xu Jianqing 
Published: January 2023

Abstract

Background
The outbreak of novel avian H7N9 influenza virus infections in China in 2013 has demonstrated the continuing threat posed by zoonotic pathogens. To decipher the responses during natural infection will enlighten the vaccine development.

Methods
We assessed the induction of heterosubtypic cross-reactive antibodies induced by H7N9 infection against a large panel of recombinant hemagglutinins and neuraminidases by quantitative ELISA, and novel chimeric hemagglutinin constructs were employed to dissect the anti-stalk or head humoral response.

Results
H7N9 infection induced strong antibody responses against divergent H7 hemagglutinins. Interestingly, we also found the induction of antibodies against heterosubtypic hemagglutinins from both group 1 and group 2 and a boost in heterosubtypic neutralizing activity but not in hemagglutination inhibitory activity. Kinetic monitoring revealed that heterosubtypic binding/neutralizing antibody responses typically appeared and peaked earlier than intrasubtypic responses as stalk-specific memory responses.

Conclusions
Our results indicate cross-group binding and neutralizing antibody responses primarily targeting at stalk region could be elicited after influenza natural infection and probably with proper immunogen in the presence of preexisting responses. These data support our understanding of the breadth of the post-infection immune response that could inform the design of future, broadly protective influenza virus vaccines.
Terminally differentiated CD8 effector T cells have NK-like features and are potent mediators of HIV-specific ADCC
Authors: Lal Kerri G , Naluyima Prossy , Costanzo Margaret C , Kijak Gustavo H , Eller Leigh Anne , Creegan Matthew , Michael Nelson L , Robb Merlin L , Bolton Diane L , Sandberg Johan K , Eller Michael A. 
Published: January 2023

Abstract
Chronic viral infection and persistent antigenic stimulation is associated with a rise of late-stage differentiated CD8 T cells including a unique subset of CD8 T cells expressing FCg receptor IIIa (CD16). Expansion of CD16+ CD8 T cells is observed in other chronic diseases like HCV, but not HIV-1 infection. CD16 mediates antibody dependent cellular cytotoxicity (ADCC), most notably on NK cells, and is associated with protection from HIV-1 acquisition. Using cryopreserved PBMC from healthy and HIV-1 chronically infected donors from Uganda, we compared phenotypic, transcriptional, and functional changes in CD16+ CD8 T cells. We found that chronic, untreated HIV-1 infection is associated with elevated numbers of CD45RA+CD57+ terminal effector CD16+ CD8 T cells compared to healthy individuals, and display a distinct transcriptional profile in between conventional CD8 T cells and NK cells, characterized by high IKZF2 and KLRF1, and low expression of IL7R. This transcriptional profile translates into a NKp80+ IL-7Rα-surface phenotype and high expression of the Helios transcription factor. Additionally, CD16+ CD8 T cells are capable of mediating ADCC at levels similar to that of NK cells. These CD16+ CD8 T cells are highly activated and correlate positively with expansion of the CD8 T cell compartment and plasma levels of soluble factors of antiviral immunity and inflammation, such as IP-10, TNF, IL-6, and TNFRII. These data indicate that terminally differentiated, effector CD8 T cells acquire innate, NK cell-like characteristics during chronic HIV-1 infection, and suggest that HIV-specific ADCC is part of the repertoire of functions CD8 T cells use to combat the ability of HIV-1 to escape the TCR-specific, anti-viral effects of CD8 T cells.
“TCR transgenic, gp100 reactive T cells to target lymphangioleiomyomatosis”
Authors: Ankney Christian Mathew , Le Poole I. Caroline , Dilling Daniel F. , Eby Jonathan M. 
Published: January 2023

Abstract
Lymphangioleiomyomatosis (LAM) is a rare lung disease presenting with benign tumors, affecting premenopausal women. LAM is diagnosed by HMB45 staining. We questioned whether gp100 expression by lesional cells lends opportunities to treat LAM by adoptive T cell transfer. As LAM tumors are sparsely infiltrated by T cells, we looked to melanoma and vitiligo as sources of gp100-reactive TCRs. The gp100-reactive TCRs T4H2, R6C12 and SILv44 were cloned into retro-and lentiviral vectors and introduced into primary human CD8+ T cells. Transgenic T cells were combined with melanoma cells, melanocytes and LAM cells and responses were measured by ELISA detecting IFN-γ, IL-17, TNF or IL-4 after 48 hrs. Cytotoxicity was measured by 51Cr release and CD107a expression, and in vivo using SCID/Beige mice challenged with 106 888A2 human melanoma cells and treated twice with 106 SILv44 transduced T cells. Transgenic T cells conferred specific reactivity to HLA-A2+, gp100+ cells, including human LAM10224 cells, in vitro. The SILv44 TCR mediated most IL-17a expression whereas INF-γ secretion was greatest in T4H2 transduced cells. Surprisingly, IL17a expression decreased with increasing peptide concentrations. IL17a+, SILv44+ T cells conferred most anti-tumor protection in mice. LAM10224 cells can form tumors in immunodeficient mice, and SILv44 transgenic T cells should likewise contain such tumors. Thus, SILv44 transgenic T cells may serve as a viable treatment for LAM.
CCL3 augment antitumor immune priming in the tumor draining lymph node
Authors: Allen Frederick , Rauhe Peter , Askew David , Eid Saada , Nthale Joseph , Myers Jay , Tong Alexander , Huang Alex Yee-Chen 
Published: January 2023

Abstract
Lymph nodes (LNs) represent an area of interest for targeting metastatic tumors because they play an essential role in tumor survival in non-native tissues. The chemokine CCL3 is important in recruiting first-responder immune cells to areas of epithelial insult and orchestrating cellular contacts in the LNs of vaccinated mice that subsequently lead toward the enhancement of memory CD8+ T cell generation. We hypothesize that by introducing a continuous supply of CCL3 into the microenvironment of a metastatic tumor, we can redirect a LN destined for tumor-tolerance toward the production of greater antitumor cellular responses. To interrogate our hypothesis, we subcutaneously inoculated naïve murine recipients with a Balb/c colon metastatic tumor (CT26) that is either the wild-type (WTTUs) or WTTUs transfected to secrete CCL3 (L3TUs). Immunocompetent mice injected with L3TUs resulted in a suppression of tumor growth compared to the WTTU. In vivo analysis across 7-days post-tumor injections with WTTUs or L3TUs, revealed an enhanced accumulation of endogenous DCs, NKs, and lymphocytes in the TDLNs. In vitro analysis showed that OVA-peptide or whole-protein-pulsed bone marrow derived dendritic cells (BMDCs) cultured with CCL3, showed an enhanced capacity to induce proliferation of antigen-specific T cells. Examination of the day-5 TDLNs for direct signs of adaptive antitumor responses also revealed an enhanced production of the antitumor cytokine, IFNγ compared to WTTUs and the specific recruitment of antitumor-associated DCs to the TDLN.
IRF3 contributes to IFN-γ expression during B16F10 tumor growth and also IFN-γ-dependent reduction in B16 tumor cell growth
Authors: Petro Thomas M , Brown Deborah M , Guinn Zachary 
Published: January 2023

Abstract
Previously, we reported in C57Bl/6 (B6) and IRF3KO mice that Interferon Regulatory Factor (IRF-3) contributes to control of B16 melanoma tumor growth. Moreover we found a link between IRF-3 and expression of IFN-γ during in vitro T cell responses of B6 and IRF3KO mice. To investigate IRF3 and IFN-γ expression at growing tumors, we injected B6 and IRF3KO mice sq with B16-F10 tumor cells that constitutively express luciferase. Tumor growth was similar between B6 and IRF3KO mice at day 2 and 6, but was significantly greater at day 9 in IRF3KO mice compared with B6 mice. Using transcription factor assays of spleen extracts, IRF3 and IRF7 activation peaked at day 6 in B6 tumor-bearing mice but failed to occur in IRF3KO mice post injection. Likewise, significant induction of IFN-γ occurred in spleens and tumors in tumor-bearing B6 mice but failed to occur in tumor-bearing IRF3KO mice from day 6–9 post injection. Previous reports from other labs showed that the anti-tumor properties of IFN-γ are the result of G1/G0 cell cycle arrest. Using B16 cells or B16 cells deficient in IFN-γ receptor (B16-IRFGRKO), we found that IFN-γ decreases B16 tumor cell growth and synergizes with the TLR3/IRF3 agonists, poly I:C, in decreasing B16 cell growth. Concomitantly, IFN-γ induced interferon stimulated gene-54 (ISG54), which is IRF3 dependent and promotes apoptosis in cells. Moreover, we treated B16-SEAP and B16-SEAPIFNGRKO cells, which express secreted alkaline phosphatase (SEAP) under the control of an ISG54/ISRE promoter. We found that IFN-γ induces ISG54 promoter activity and poly I:C synergizes with IFN-γ to induce ISG54 in B16 cells. Thus an IFN-γ/IRF3/ISG54 nexus can significantly contribute to tumor cell control during anti-tumor immune responses.
GSK-J4 a potent and selective inhibitor of the H3K27 demethylase JMJD3/UTX limits acute colitis by de novo synthesis Retinoic Acid in dendritic cells
Authors: Rosemblatt Mario , Doñas Cristian , Neira Jocelyn , Osorio-Barrios Francisco , Carrasco Macarena , Pacheco Rodrigo , Loyola Alejandra 
Published: January 2023

Abstract
JMJD3 a demethylase of lysine 27 of histone H3 (H3K27) plays an important role in immune cells and inflammatory responses, and thus appears as an attractive target for the treatment of inflammatory diseases. Recently, GSK-J4, a selective and potent JMJD3 inhibitor was synthesized. We previously showed that GSK-J4 induced a tolerogenic phenotype on dendritic cells (DCs) promoting the generation and stability of induced Tregs as well as enhancing their suppressive function. However, the underlying mechanisms remain unclear.
Because GSK-J4 acts upon DCs, we evaluated RA synthesis as underlying pro-tolerogenic mechanisms affected by this drug.
Here we report that GSK-J4 treatment promoted RALDH activity on DCs and induced the expression of RALDH1 and RALDH3 enzymes in DCs, resulting in an increase in the expression of Foxp3, CCR9 and α4β7 in CD4+ T cells.
The increased RALDH1 and RALDH3 expression correlated with changes on the ratio of repressive (H3K27me3) versus active marks (H3K4me3) on RALDH1 and RALDH3 promoters in GSK-J4-treated DCs. Moreover, we demonstrated that systemic administration of GSK-J4 ameliorates the severity of DSS-induced acute colitis in mice.
Collectively this study demonstrates that GSK-J4 attenuates DSS-induced acute colitis, an effect that may be attributed to the de novo RA synthesis on DCs.
This drug may be a promising approach for the treatment of inflammatory diseases.
Amelioration of neuropsychiatric systemic lupus erythematosus by fingolimod-mediated sphingosine-1 phosphate receptor modulation.
Authors: Mike Elise V , Putterman Chaim 
Published: January 2023

Abstract
Approximately 40% of SLE patients suffer from neuropsychiatric manifestations, including cognitive dysfunction and depression. While the pathogenesis of neuropsychiatric lupus (NPSLE) is not fully understood, critical aspects of disease development include neuroinflammation and the loss of blood-brain barrier (BBB) integrity. Fingolimod is an FDA-approved sphingosine-1 phosphate (S1P) receptor modulator that has been shown to reduce CNS lymphocytic infiltration and prevent BBB disruption in multiple sclerosis. In this study, we investigated the effects of fingolimod in MRL-lpr/lpr mice, a classic spontaneous SLE model. Ten-week-old mice were treated prophylactically three times weekly with vehicle alone or fingolimod (3mg/kg, n=16/group). After 4 weeks of treatment, mice were assessed for alterations in cognitive function or affective behaviors.
Fingolimod-treated mice exhibited significantly improved preference for novel objects (p=0.019) and objects in novel placement (p=0.007) when compared with control-treated mice, thereby demonstrating maintenance of recognition memory and visual memory, respectively. Mice treated with fingolimod also displayed less despair-induced immobility during the forced swim test (p=0.017), which indicates that fingolimod may mitigate depression. Preliminary histological assessment suggests decreased perivascular and periventricular leakage of serum albumin in fingolimod-treated mice. A reduction in lymphocytic infiltration of the choroid plexus in the lateral ventricles was also observed.
Our results highlight the important role of S1P in the pathogenesis of neurocognitive manifestations of SLE and receptor modulation as a potential therapeutic target for NPSLE.
Using social media platforms Twitter and Pinterest to engage undergraduate students in vaccinology and immunology.
Authors: Gorski Stacey A 
Published: January 2023

Abstract
Recent studies have shown that biomedical scientists and healthcare professionals are increasingly more likely to use social networking sites such as Twitter for professional correspondence and to remain informed of advancements in their fields. For this reason, pre-professional health students in vaccinology and immunology courses engaged in out-of-class social media assignments using Twitter and Pinterest, respectively. The objectives of these assignments were to demonstrate appropriate social media etiquette, enhance scientific communication skills, and provide a channel for students to relate in-class material to current events. Students in the vaccinology course were tasked with maintaining an active presence on Twitter to share accurate and personal experiences regarding vaccines and immunizations. At the end of the course, 20/20 students (100%) reported that participating on Twitter “enhanced their familiarity with current events in vaccinology,” while 90% reported that it also enhanced scientific communication skills and social media skills. Additionally, &gt;95% of students felt that the assignment was worthwhile for teaching others, perhaps increasing their feelings of contributions to the field. Students in the immunology course used Pinterest to collect information regarding immunology-related study tools, prominent immunologists, current events in immunology, and immunotherapies. Students reported that the Pinterest assignment helped them learn in-class material (40%) and felt that it helped them relate in-class material to ‘real-world’ issues (60%). The majority of students in both classes reported that they were willing to continue to use the respective social media platform for professional use.
Determinants of phagocytic receptor mobility: cytoskeletal picket fences and the pericellular glycocalyx coat.
Authors: Freeman Spencer A , Riedl Magdalena , Vega Anthony , Johnson Pauline , Lidke Diane , Mayor Satyajit , Tammi Markku , Jaqaman Khuloud , Grinstein Sergio 
Published: January 2023

Abstract
Phagocytosis is initiated by clustering of receptors upon exposure to target particles bearing multiple ligands. Clustering depends on the ability of receptors to move laterally in the plane of the membrane. Intrinsic proteins were originally thought to diffuse freely along the fluid mosaic of the membrane, but more recent observations indicate that mobility can be severely restricted by the existence of a cytoskeletal fence anchored to the plasmalemma via transmembrane “pickets”. However, the molecular nature of these putative pickets, the manner whereby they associate with the cytoskeleton, and their role in phagocytosis have not been investigated. Based on its abundance and structural features, we surmised that CD44 may serve as a picket in macrophages. We used single-molecule tracking to study its behavior and how it affects the mobility of phagocytic receptors. In addition, because its extracellular domain can bind hyaluronic acid, we found that CD44 serves as a transmembrane connector between the pericellular (glycocalyx) coat and the cytoskeleton. The pericellular coat curtails access of particles to the comparatively short phagocytic receptors. The implications of this transmembrane framework to phagocytosis were investigated and will be discussed.
A systems approach to the characterization of Toll-like receptor response to different ligand stimulation in macrophages.
Authors: Nita-Lazar Aleksandra , Sjoelund Virginie Helle , Koppenol-Raab Marijke , Manes Nathan P. , Fraser Iain D , Benet Zachary , Dutta Bhaskar , Khan Mohd M. 
Published: January 2023

Abstract
One of the major questions in innate immunity is: How do the multiple TLRs stimulated during pathogen challenge act in concert to promote an appropriate host response? To begin to develop a comprehensive proteomic interrogation of TLR signaling under varying conditions, we used quantitative mass spectrometry to analyze the phosphoproteome, proteome and secretome changes in mouse macrophages. The cells were activated with each of three selective TLR ligands (LPS, P3C and R848) and with intact pathogens. We have identified and quantified on average more than 500 phosphosites per ligand after TLR stimulation at five time points within a time frame of 30 minutes. We have characterized the differences and similarities in the phosphoproteome dynamics between the three TLR stimulations, and we identified key differences between the phosphorylation profiles induced by the three TLR stimulations. The pathways most affected by the treatments were cytoskeletal signaling, endocytosis and phagocytosis. Furthermore, we compared the intracellular (proteome) and extracellular (secretome) responses of macrophages to TLR ligands. Comparison to the transcriptome yielded a significant number of proteins regulated at the post-transcriptional level, emphasizing the importance of systematic and global studies that reach beyond gene expression profiling. We have also generated preliminary data of the absolute quantification of the number of molecules per cell for the core TLR signaling pathway using targeted mass spectrometry. This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases.
Identification of novel and potent synthetic TLR agonists
Authors: WANG YING , Su Lijing , Morin Matthew , Jones Brian , Whitby Landon , Surakattula Murali , Huang Hua , Shi Hexin , Choi Jin Huk , Wang Kuan-wen , Moresco Eva Marie Y , Berger Michael , Zhan Xiaoming , Zhan Hong , Boger Dale , Beutler Bruce 
Published: January 2023

Abstract
Agonists and antagonists of Toll-like receptors (TLRs) may be useful as vaccine adjuvants or suppressors of inflammation, respectively. In an effort to identify compounds capable of activating macrophages via TLRs or other sensors, a synthetic compound library was screened using mouse peritoneal macrophages and human THP-1 cells. Through extensive SAR studies of initial hits, we developed two strong synthetic agonists: Neoseptin-3 and Diprovocim. Genetic studies established that neoseptin-3 is a mouse TLR4/MD-2 agonist with no structural similarity to LPS. It activates mTLR4/MD-2 independently of CD14 and triggers canonical MyD88- and TRIF-dependent signaling. Diprovocim was found by a combination of genetic and antibody blockade analyses to be a TLR1/2 agonist, active on both mouse and human receptors. Its EC50 in human THP-1 cells is 110 pM. Diprovocim showed TLR1/2 dependent adjuvant activity when co-administered with ovalbumin (OVA). It not only promoted antigen-specific humoral responses but also activated cytotoxic T lymphocyte responses in a TLR1/2 dependent manner. Since neither Neoseptin-3 nor Diprovocim resemble the natural ligands for TLR4/MD-2 nor TLR1/2, respectively, we surmise that other “unconventional” ligands for these TLRs may exist in nature. However, the exquisite SAR of both compounds makes it clear that TLRs are not highly promiscuous receptors; on the contrary, they are activated only by compounds that fulfill strict structural rules. In finding these agonists, we also identified antagonists that bind the TLR complexes but do not activate them. The parent compounds Neoseptin-3 and Diprovocim will be used to develop new agonists and antagonists optimized for clinical application.
2′-5′ Oligoadenylate like (OASL) inhibits interferon induction by inhibiting cGAS activity during DNA virus infection.
Authors: Ghosh Arundhati , Shao Lulu , Sampath Padmavati , Patel Nidhi , Zhu Jianzhong , Hornung Viet , Thorne Stephen , Sarkar Saumendra N 
Published: January 2023

Abstract
Oligoadenylate Synthetases-like (OASL) is a type I interferon (IFN)-stimulated gene (ISG). During RNA virus infection OASL promotes IFN induction by augmenting RIG-I activation and inhibits virus replication. Here we report a completely new role of OASL in the context of DNA virus infection. Unlike RNA viruses, human OASL or mouse Oasl2 knockout cells showed reduced replication when infected with DNA viruses such as Vaccinia (VV) and Herpes simplex virus (HSV). Consequently, Oasl2 knockout mice showed delayed and reduced VV spread and mortality as opposed to enhanced virus multiplication and spread with RNA virus such as Vesicular Stomatitis virus. Mechanistically, OASL negatively regulates DNA-sensor-mediated IFN induction in vitro and in vivo. Stimulation of both mouse and human OASL-deficient cells with intracellular DNA showed increased induction of IFN and ISG compared to the Wt cells. However, OASL-deficient cells did not exhibit any difference in IFN induction compared to Wt cells when stimulated with the STING ligand cGAMP, indicating the upstream effect of OASL on cGAS and not on STING stimulation. In vitro immunoprecipitation experiments showed OASL specifically interacted with cGAS, and this interaction is mediated by the OAS domain of OASL protein. Furthermore, this OASL-cGAS interaction led to the inhibition of cGAS enzyme activity and reduced cGAMP production. Together these results establish the unique ability of OASL to differentially modulate RNA and DNA virus replication and IFN induction.