bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteogenomic characterization of the specific antibody repertoire induced by gold nanoparticles of differing shape and biomolecular surface: towards the development of nanoparticle-based vaccines
Authors: Pérez-Potti André , Giannone Valeria , Lara Sandra , Bigini Paolo , Dawson Kenneth A. , Yan Yan 
Published: January 2023

Abstract
Nanoparticles (NPs) in the size range of 1–100 nanometres (nm) present unique physical-chemical properties compared to bulk material making them suitable for a range of biomedical applications. Due to their size and shape, NPs engage in particular ways with cell receptors and by co-delivering antigens, adjuvants and immunomodulators grafter or encapsulated they can serve as new vaccine formulations for the treatment of several diseases such as cancer or HIV.
Gold NPs (AuNPs) are interesting due to their ease of synthesis and control of size and shape, being the later considered a relevant parameter driving interactions with cell receptors. Here is shown the work to study the capabilities of AuNPs with different shape to induce antibody responses in vivo. Spherical and branched AuNPs were repeatedly inoculated subcutaneously to CD rats. The levels of Immunoglobulins G and M (IgG and IgM) were analyzed by Enzyme-Linked Immunosorbent assay (ELISA) and the B cell receptor (BCR) V(D)J rearrangements were assessed by Ig-Sequencing of the BCR transcripts from different lymphoid tissues. Mass spectrometry (MS) analysis of enriched IgG from treated rats plasma revealed the functional antibody response.
In the case of branched AuNPs, the levels of total IgG and IgM appeared higher and increased autoantibody levels were found. V(D)J gene and allele usages were more diverse, showing considerable shifts in the repertoire, and B cell clonality was higher in comparison to spherical AuNPs and controls. Immune tolerance seems to be disrupted by branched NPs with particular biomolecular surfaces. These findings represent a step forwards in the development of NP-based vaccines towards motifs on the surface (e.g. tumor antigens) of such NPs.
Evaluation of the safety profile of ssRNA adjuvant derived from the IGR IRES region of CrPV
Authors: Park Hyeongjun , Kim Hye-Jung , Ko Hae Li , Kwak Hye Won , Won Dong-Hoon , Hwang Da-Bin , Shin Yoo-Sub , Yun Jun-Won , Nam Jae-Hwan 
Published: January 2023

Abstract
Adjuvants enhance the efficacy of vaccines by stimulating immune response relate gene expression and pathways. However, development of an appropriate adjuvant for a specific vaccine type is difficult, because of their unwanted systemic and local adverse effects. Despite intensive efforts for more than 80 years, there are only a few approved adjuvants. Poly I:C, a double stranded RNA was experimentally used as an adjuvant since 1970s. Although poly I:C dramatically stimulates the innate immune response, which is a prerequisite of a good adjuvant, inducing effective immune response while avoiding adverse events is a major challenge. In this study, we evaluated the safety and toxicological profile of a high-dose (200ug/mouse) single stranded RNA (ssRNA) derived from the intergenic region (IGR) internal ribosome entry site (IRES) of cricket paralysis virus (CrPV) as a novel adjuvant in a mouse model. The results indicate that there were no significant differences in body weight and food intake pattern in mice immunized with ssRNA adjuvant and the control group. Hematological parameters like ALT and AST levels appeared to be normal in both treated and control group. Histology of organs such as liver, spleen, lung, and kidney appeared to be normal. There was no evidence of tissue damage in mice treated with ssRNA adjuvant and control group. IgE levels, which is marker of autoimmune disease, is also not different compared with treated group and control group. In addition, the adjuvant effect is similar in both high-dose and low-dose (20ug/mouse) treated groups. In conclusion, novel ssRNA adjuvant exhibited a safe toxicological profile in mouse model. The results obtained may be utilized for conducting further clinical trials in humans.
Designing pathogen-like particles to augment vaccine potency through the induction of broadened and synergistic innate immune responses
Authors: Toy Randall , Pradhan Pallab , Keenum M. Cole , Jhita Navdeep , Blanchard Emmeline , Atalis Alexandra , Narang Neha , Chukwu Chinwendu , Cortes Gabriela , Suthar Mehul S , Santangelo Philip , Shayakhmetov Dmitry , Roy Krishnendu 
Published: January 2023

Abstract
Vaccines have protected against many deadly diseases, but they are less effective at defending against pathogens with weakly immunogenic or rapidly mutating antigen epitopes. Adjuvants that specifically trigger Toll-like and cytosolic receptors have been developed to enhance vaccine potency against antigens with poor immunogenicity. We hypothesized that adjuvant combinations delivered on pathogen-like particles (PLPs) could further improve the breadth and potency of the innate immune response. PLPs were synthesized by encapsulating hydrophobic adjuvants inside PLGA microparticles and nanoparticles, which were functionalized with polyethylenimine to facilitate surface loading of charged RNA or ssDNA adjuvants. The immune response of a virus PLP (TLR7/RIG-I adjuvants) and a Gram-negative bacteria PLP (TLR4/TLR9 adjuvants) was evaluated in bone marrow-derived dendritic cells (BMDCs). The viral PLP induced a broadened immune response by simultaneously inducing cytokine profiles representative of the individual adjuvants. The Gram-negative bacteria PLP induced synergistic upregulation of IFN-b and IL12-p70 at both the gene and protein level. Studies in BMDCs from knockout mice revealed that TRIF signaling cooperates with MyD88 signaling and IRF5, not IRF3 or IRF7, is the primary interferon regulatory factor driving synergistic cytokine responses. Moreover, the Gram-negative bacteria PLP could induce upregulation of pro-inflammatory genes and synergistic DC activation in vivoafter IM injection. Ongoing work will evaluate the molecular mechanisms governing adjuvant synergy with PLPs and assess if PLPs can enhance flu vaccine potency in challenge studies
New role of Epstein-Barr virus in pathogenesis of acute and chronic lymphocytic leukemia
Authors: Laurynenka Viktoryia , Carter Martha , Parameswaran Sreeja , Chen Xiaoting , Kottyan Leah C. , Weirauch Matthew T. , Harley John B 
Published: January 2023

Abstract
Acute lymphoblastic leukemia (ALL) is the most common mortal cancer in children. Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia in western countries. B lymphocytes dominate the origin of both diseases. We have found a possible role for Epstein-Barr virus (EBV) in the origins of both ALL and CLL.
We applied our strategy (Nat Genet 50:699, 2018) to determine whether the binding of EBV transcription factors (TFs) was concentrate at the 84 known risk loci for CLL and 16 loci for ALL. We evaluated 52 virally encoded TF ChIP-seq (chromatin immunoprecipitation with DNA sequencing) datasets and complemented this analysis with the results from 1535 human TF ChIP-seq datasets.
We found that Epstein-Barr nuclear antigen leader protein (EBNALP), EBNA3C and EBNA2 were concentrated in the CLL loci by 3.7, 3.7 and 3.5-fold with p=4.89*10−19, p=2.74*10−11 and p=1.07*10−8, respectively. The viral (n=3) and human TFs (n=40) cluster together in an optimal subset of ~15 of the 84 known loci in CLL at p&lt;10−6. Eighty percent of the most highly associated viral and human TF ChIP-seq datasets were collected from EBV transformed B cell lines in the Latency III program of viral expression, for which EBNALP, EBNA3C and EBNA2 are viral gene products.
In ALL 3 of 16 loci were occupied by EBNA3ABC by a 17.7-fold enrichment with p=2.0*10−10. Among human TFs only c-MYC reached statistical significance binding 2 non-overlapping risk loci with 28.4-fold enrichment with p=2.9*10−10.
These results nominate EBV for a role in the pathogenesis of CLL and ALL by a mechanism operating in transformed B cells through the EBV Latency III program of viral expression.
Axl promotes ZIKV entry and modulates antiviral state of human Sertoli cells
Authors: Strange Daniel P , Jiyarom Boonyanudh , Zarandi Nima Pourhabibi , Xie Xuping , Sadri-Ardekani Hooman , Shi Pei-Yong , Verma Saguna 
Published: January 2023

Abstract
Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. The ability of ZIKV to establish persistent infection in the testes clearly suggests involvement of unique immune suppressive pathways, however the underlying mechanisms are not defined. We demonstrated that human Sertoli cells (SC), the major cell type of seminiferous tubules, an immune privileged compartment of the testes, support prolonged ZIKV replication without compromising cell survival. Our recent study also provides evidence that human testicular organoids (HTO) can be used as a tool to study ZIKV immunopathogenesis. Recent reports have identified the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase Axl, a critical regulator of innate immunity and apoptosis, as an entry receptor and/or immune modulator for ZIKV infection depending on cell type. Interestingly Axl receptor is highly expressed in the testes, however, the role of Axl in ZIKV infection of SC has not been determined. In this study, we show that Axl was highly expressed in SC as compared to Leydig cells that correlated with robust infection of ZIKV only in SC. Further, neutralizing Axl receptor and its ligand Gas6 strongly attenuated virus entry and replication in SC. Blocking of Axl kinase and downstream signaling was associated with decrease in the negative regulators of antiviral immunity including pSTAT1 and SOCS1 that led to increased expression of IFIT1 and MxA, and reduced virus replication in the SC and HTO. Together, our data demonstrates that Axl promotes ZIKV entry and negatively modulates antiviral state of SC to augment long-term infection of the testes and provides new insights into testis immunology in the context of ZIKV persistence.
Quantifying Virus Escape from T Cells in the Latent HIV Reservoir
Authors: Warren Joanna A , Zhou Shuntai , Xu Yinyan , Moeser Matthew , Kirchherr Jenn , Sung Julia , Roan Nadia , Adimora Adaora , Kuruc JoAnn , Gay Cindy , Margolis David , Archin Nancie , Swanstrom Ronald , Goonetilleke Nilu 
Published: January 2023

Abstract
There is no cure for HIV, largely because HIV establishes a small but sustained pool of latently infected cells that are not cleared by antiretroviral therapy (ART). Current strategies include firstly reactivating the latent HIV reservoir and then using T cell immunotherapy to clear reactivated cells. However, pre-ART CD8 T cell escape variants have been reported in the HIV reservoir, which may limit CD8 T cell recognition and clearance of HIV-infected cells. The extent of virus escape from T cells in the latent reservoir is unclear.
HIV-specific T cell responses were comprehensively mapped across the Clade B HIV proteome by IFN-g ELISpot in 25 ART-suppressed participants. In parallel, replication competent viruses derived from supernatants of autologous resting CD4 T cells following mitogenic reactivation were sequenced. Peptides spanning virus variants within reactive T cell epitopes were synthesized and examined by ELISpot for evidence of escape, defined as ≥50% difference in T cell magnitude between peptide variants.
No correlations were observed between the size of the latent HIV reservoir and either HIV-specific T cell breadth (1–19 epitopes) or magnitude (156–2855 SFU/M PBMCs). T cell escape was assessed in 17 participants. 39% of reactive T cell epitopes (48/124) harbored ≥1 amino acid variants in the sequenced latent reservoir. Of those 48, 20 afforded T cell escape, providing an overall escape frequency in the reservoir of 16% (20/124).
These data show that the majority of replication competent latent HIV viruses do not harbor CD8 T cell escape mutants, suggesting that immunotherapy approaches that boost CD8 T cell responses can successfully target the latent reservoir in HIV curative and or remission strategies.
Stochastic HIV Gene Expression is a Novel Mechanism for HIV Persistence
Authors: Matus Nicodemos Rodrigo A , Douek Daniel , Koup Richard 
Published: January 2023

Abstract
In HIV-infected people, the virus persists in resting memory CD4 T cells as a latent provirus integrated into transcribed genes. HIV has 9 gene products that are generated from 7 alternatively spliced mRNAs whose expression is regulated by the cell’s transcriptional state. Furthermore, transcription of genes accessible by RNA pol II occurs in bursts, giving rise to the stochastic expression of mRNAs in cells.
The HIV protein Nef allows infected cells to evade CD8 T cell recognition through the downregulating of peptide-MHC complexes (pMHCs). The precise kinetics of pMHC downregulation by Nef upon reactivation of a latent provirus remains unclear. We explored this question by direct infection and longitudinal analysis of primary resting CD4 T cells with a CCR5-tropic intact replication-competent virus in which GFP reports the expression of Nef.
We detected GFP+ cells 3 to 4 days after infection. These GFP+ cells were resting memory CD4 T cells and had downregulated CD4 and pMHCs. We then performed single-cell RNA-seq on sorted GFP+ cells to examine both cellular and virus gene expression, as well as HIV integration sites. Our dataset identified various transcribed host genes that had an integrated provirus. Strikingly we found GFP+ cells either (1) had no HIV mRNAs or (2) had HIV mRNAs encoding Nef, Vpr, Vif or Vpu-Env, but never HIV mRNAs encoding Gag-Pol, Tat or Rev.
We conclude that in resting memory CD4 T cells, an integrated HIV genome is transcribed and alternatively spliced for mRNAs encoding Nef, Vif, Vpr or Vpu-Env. HIV expression is stochastic because infected cells didn’t always express HIV mRNAs. Therefore we propose stochastic HIV gene expression is a novel mechanism for HIV persistence by hiding the infected cells from the immune system.
Age-dependent Susceptibility To Virus Infection Is Governed by Host Genetics
Authors: Menachery Vineet D , McAnarney Eileen T , Ferris Martin T 
Published: January 2023

Abstract
While improved sanitation and medical care have reduced the burden of infectious disease, it remains the 4th leading cause of death in the elderly. Coupled with the expansion of the aged population over the next two decades, understanding the interplay between infection and the senescent host is critical. Both the microbiome and host genetics have been predicted to play critical roles in aging immunity. In this work, we explore the role of each in age-dependent susceptibility to virus infection. Severe acute respiratory syndrome coronavirus (SARS-CoV), the first outbreak virus of the 21st century, produces increased disease in aged patients as compared to the young. Importantly, age-dependent susceptibility is observed in mouse models of SARS-CoV infection. Our results indicate that despite microbiome variation between young and aged animals, limiting these differences had only a marginal effect on disease in the aged following infection. In contrast, age-dependent susceptibility was not fully conserved across genetically diverse Collaborative Cross (CC) mice. We found that while the majority of CC lines maintained increased disease as they aged, several lines showed no distinction between young and aged animals. In one CC line, we found that aged mice were more resistant to SARS-CoV infection than their younger equivalent. Notably, age-dependent susceptibility was not simply associated with higher viral loads driving augmented disease. Instead, the results suggest that host factors including tissue and inflammation responses govern disease in the senescent host. Together, the work highlights the importance of genetic elements in driving age-dependent disease following infection.
Respiratory syncytial virus strains differentially activate the inflammasome eliciting a pathogenic Th17 response
Authors: Waldstein Kody , Weiss Kayla A. , Hartwig Stacey , Quick Hannah , Poudel Barun , Gurung Prajwal , Varga Steven M 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children worldwide with no licensed vaccine available. RSV-induced disease ranges from mild to severe, with severe disease correlated with elevated levels of pro-inflammatory cytokines, including the Th17-associated cytokine IL-17. To better understand the virus factors that influence the induction of a Th17 response, we compared the inflammatory responses elicited by different RSV strains. In contrast to the commonly used RSV A2 strain, RSV 2–20 infection resulted in increased levels of IL-6 and IL-1β, which were required to induce a pathogenic Th17 response. Th17 induction was associated with increased mucus production and airway hyperreactivity following RSV 2–20 infection indicating a strain-dependent increase in disease severity. A recombinant RSV A2 virus expressing the 2–20 fusion (F) protein induced IL-1β to similar levels as wild-type RSV 2–20 suggesting that the 2–20 F protein is necessary for increased pro-inflammatory cytokine production. Sequencing of the RSV A2 and 2–20 F protein genes revealed three point mutations in a region likely to interact with host cells. Reversion of these three amino acids in the RSV A2/2–20 F recombinant virus to the A2 sequence significantly reduced RSV-induced IL-6 and IL-1β protein production. Together our results demonstrate that the RSV F protein plays an essential role in the induction of pro-inflammatory cytokines which are critical for CD4 Th17 cell differentiation. Genetic variations in the RSV F protein between RSV strains play a crucial role in modulating RSV-induced disease severity in the animal model and may contribute to the differential RSV pathogenesis observed in humans.
Evaluating the role of candidate gene, csf3r, for sex-linked susceptibility to lupus-like disease in mice
Authors: Gubbels Bupp Melanie R , Woodfin Anne E. 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects women and this trend is also observed in BWF1 lupus-prone mice. Although the factors that contribute to sex-specific lupus incidence are complex, evidence suggests that sex hormone regulation of genetic targets likely play a role. Several candidate genes have been identified by their disproportionate expression within splenocytes isolated from male and female BWF1 mice and because their expression is regulated by the sex hormone, testosterone. One candidate gene in particular, csf3-r, is predominantly expressed in CD11b+ cells and is the focus of our current studies. Previous research has indicated that Gr1low CD11b+ cells accumulate in male lupus-prone mice, and are associated with disease suppression. We hypothesize that sex-specific expression of csf3-r contributes to the different frequencies of specific neutrophil subpopulations in BWF1 lupus prone mice and may contribute to disease protection in male mice. To test this hypothesis, we are examining the expression levels of csf3r in neutrophils in lupus-prone and nonautoimmune-prone male and female mice and assessing potential correlations between sex-specific expression of csf3r and the frequencies of particular neutrophil subpopulations. The elucidation of testosterone-regulated pathways that contribute to lupus-like disease may point to new therapies that may be beneficial in autoimmune diseases with sex-specific incidences.
Educational Program Impacts Suicidal Thoughts of Individuals with Autoimmune Conditions
Authors: Ramirez Francisco E , Nedley Neil , Queva Timothy 
Published: January 2023

Abstract

Rationale
Some research has suggested a relationship between suicidality and autoimmune diseases. This study documents the effects of an 8-week community educational program on suicidal ideation severity in participants with autoimmune conditions.

Methods
Participants were educated in healthy lifestyle habits during a once a week for 8 weeks program, each program lasted 2 hours. Instruction included control of thoughts, benefits of a plant-based diet, proper exercise, adequate sunlight, and sleep hygiene. No patient-doctor relationship was established. Each individual took the depression and anxiety test before and after the program which measures depression, symptoms of depression, suicidal ideation, demographics and autoimmune conditions. Suicidal thoughts were reported as None or rare, About 1/4 of the days of week, 1/2 of the days of a week and almost every day.

Results
From n=431 participants that had an autoimmune condition and finished the 8 week program, at baseline 62% (n=267) participants reported no suicidal thoughts. Those with suicidal thoughts, 15% (n=65) reported suicidal thoughts 1/4 of the days, 13% (n=56) reported suicidal thoughts 1/2 of the days, and 10% (n=43) reported suicidal thoughts almost every day.
Upon completion of the 8 week program: 85% (n=368) had no suicidal thoughts, 8% (n=36) had suicidal thoughts 1/4 of the days, 4% (n=17) had suicidal thoughts 1/2 of days, and 2% (n=10) had suicidal thoughts almost every day.

Conclusion
The program was effective in decreasing quantity and quality of suicidal thoughts. Only a small number of participants did not improve (6%) and only 3% became worse.
Modulation of ILC2 trafficking and effector functions in ILC2-driven airway hyperreactivity
Authors: Hurrell Benjamin P , Galle-Treger Lauriane , Howard Emily , Jahani Pedram Shafiei , Santosh Swetha , Soroosh Pejman , Akbari Omid 
Published: January 2023

Abstract

Background
Asthma is a heterogeneous disease of the airways characterized by increased airway hyperreactivity (AHR) to specific and unspecific stimuli. Group 2 innate lymphoid cells (ILC2s) are type 2 secreting cells that are sufficient to induce eosinophilic lung inflammation and AHR independent of adaptive immunity in murine models. Identifying pathways that modulate ILC2 homeostasis and function are therefore an important step towards treating ILC2-dependent asthma.

Objective
We examined the expression of adhesion molecule lymphocyte-associated antigen 1 (LFA-1) and ligand intercellular adhesion molecule (ICAM)-1 on ILC2s and their effect on the development of lung inflammation and AHR in murine models.

Methods
Genetically modified mice constitutively lacking LFA-1 or ICAM-1 were assessed for the development of lung inflammation and AHR. We further generated mixed bone marrow chimeras and performed transcriptomic analysis to characterize their role on ILC2 homeostasis and function.

Results
LFA-1 is expressed on murine naïve and IL-33-activated ILC2s, while ICAM-1 is surprisingly expressed – and upregulated – upon activation. Compared to WT mice, both LFA-1−/− and ICAM-1−/− mice develop less lung inflammation and AHR in response to intranasal IL-33 challenge. Furthermore, experiments with chimeric mice revealed that LFA-1−/− ILC2s significantly traffic less to the lungs, unlike ICAM-1−/− ILC2s. Strikingly, ICAM-1−/− ILC2s however show a defect in proliferation and cytokine production, ultimately affecting lung inflammation.

Conclusions
The LFA-1-ICAM-1 interaction is involved in lung ILC2 trafficking, homeostasis and function. Such findings could lead to the development of new therapeutic targets.