bluuebunny/crossref_metadata_2025_split huggingface dataset:
West Nile virus infection in the Collaborative Cross mouse model recapitulates unique human disease states
Authors: Graham Jessica B , Swarts Jessica , Thomas Sunil , Wilkins Courtney , Ferris Martin , Gale Michael J , Lund Jennifer M 
Published: January 2023

Abstract
West Nile Virus (WNV) is a cytopathic neurotropic flavivirus that causes a wide range of infection states in humans, ranging from asymptomatic to severe neuroinvasive disease. This variation supports the idea that host genetics play an important role in immunity to WNV infection. The significant individual to individual variation in immune responses within the human population can not be fully captured in single laboratory inbred strains, so a systems genetic approach requires the use of the Collaborative Cross (CC) mouse system to identify polymorphic host genes and networks that control the regulation of adaptive immunity to WNV infection. The CC is a panel of lines with over 40 million single nucleotide polymorphisms evenly distributed throughout the genome, providing the statistical power to map multiple genetic factors with small to moderate effect. In the CC model we have identified lines with unique human phenotypes that have not previously been captured in laboratory inbred strains, such as severe neuroinvasive disease and chronic WNV infection. Our use of the CC model shows differing immune responses to WNV in terms of T cell frequency and activation, antigen-specific CD8 T cell frequency, memory precursor cells, and T cell cytokine production between CC strains after WNV infection. A distinct immune signature is present in the chronic line, characterized by a strong systemic regulatory T cell response and late virus-specific response in the CNS due to viral persistence. Microarray analysis on spleen and CNS tissue reveals expression changes correlated with extreme immune phenotype responses within and between organ compartments, allowing for identification of correlates of protection and susceptibility to WNV infection.
HVEM regulates effector versus memory cell fate decisions following respiratory poxvirus infection
Authors: Desai Pritesh , Abboud Georges , Dastmalchi Farhad , Stanfield Jessica , Ware Carl F , Croft Michael , Song Jianxun , Hutchinson Tarun E , Salek-Ardakani Shahram 
Published: January 2023

Abstract
During an acute respiratory viral infection, effector CD8 T cells differentiate into short-lived effector cells (SLECs) that are destined to die and memory precursor effector cells (MPECs) that give rise to long-lived memory cells. Defining the precise molecular cues that regulate the survival of MPECs is of great interest. HVEM (Herpes Virus Entry Mediator) is a member of tumor necrosis factor receptor (TNF) superfamily that acts as a molecular switch between pro-inflammatory and inhibitory signaling by respectively binding with its endogenous ligand (LIGHT) from the TNF family and with (BTLA) from the Ig like CD28/B7 family. Using respiratory vaccinia virus (VACV) infection in mice, we found that HVEM was selectively expressed on MPECs but not on SLECs. Lack of HVEM on Ag-specific CD8 T cells resulted in an altered SLEC/MPEC ratio, with effector cells skewing more towards SLEC phenotype. Adoptive transfer of HVEM-deficient MPECs showed markedly increased contraction after viral clearance, leading to nearly complete loss of lung-resident CD8 memory T cells. Similar to CD8 T cells lacking HVEM, WT CD8 T cells failed to accumulate in LIGHT-deficient host but not BTLA-deficient host upon VACV infection. Collectively, these results reveal that HVEM expression on MPECs is critical for the development of long-lived memory cells and suggests that strategies targeting HVEM signaling might be beneficial in augmenting CD8 T cell immunity against respiratory viruses.
The influence of genetic diversity on neonatal respiratory syncytial virus disease
Authors: Siefker David , Williams Robert W. , Lu Lu , You Dahui , Cormier Stephania 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the number one cause of lower respiratory infections in children. Although most children are infected with RSV in their first year of life, 40% have severe disease suggesting a genetic component in addition to age. This collaborative project aims to identify genetic determinants associated with RSV infectivity during the neonatal period. Recombinant inbred strains of mice such as the BXD family have been extensively typed for both genetic polymorphisms (5 million variants) and a wide range of phenotypes, including influenza and other pathogens. Here, we infected different BXD strains with RSV at five days of age and evaluated pulmonary viral load. We show a difference in viral burden in the lungs of neonatal mice between different BXD strains, suggesting a role for genetic variation in RSV infectivity. Therefore, we have a novel system to identify genetic loci involved in the development of RSV disease. These results will be critical in the development of specific antivirals and vaccines against RSV.
Membrane-based immunotherapy with immune checkpoint blockade antibodies confers protection against metastatic breast cancer
Authors: Bommireddy Ramireddy , Pack Christopher D , Bozeman Erica N , Patel Jaina M , Vartebedian Vincent F , Munoz Luis E , Shafizadeh Yalda , Menon Ashwathi P , Lakshmanan Ramana , Reddy Shaker JC , Selvaraj Periasamy 
Published: January 2023

Abstract

Objective
The 4T1 triple negative breast cancer (TNBC) model resembles many of the hallmarks of advanced TNBC in humans. In this study we investigate if combining a membrane-based immunotherapy with immune checkpoint blockade antibodies in a metastatic tumor model could effectively generate protective immunity. This personalized strategy is applicable to indications such as TNBC that exhibit a high degree of heterogeneity and do not respond to approved cancer therapies.

Methods
4T1 tumor tissue was harvested from BALB/c mice and processed to generate tumor membrane vesicles (TMVs). TMVs were then incorporated with GPI-B7-1 and GPI-IL-12 by protein transfer and used for immunization in conjunction with immune checkpoint inhibitors. Survival was assessed using a Kaplan-Meier survival curve and significance determined using a Log-rank test for comparison analysis. Metastasis was assessed by clonogenic assay. Immune response was assessed by IFN-γ ELISPOT. Cell depletion studies were performed with anti-CD4 and anti-CD8 antibodies. Significance was determined using a student’s t test to compare metastasis and immune responses.

Results
TMV-based immunotherapy in combination with anti-CTLA-4 antibody significantly improved survival, reduced pulmonary metastasis, and increased tumor-specific CD8 T cell responses. Interestingly, either treatment alone failed to have a significant impact on survival, metastasis, or immune response.

Conclusions
These results strongly suggest that a TMV-based immunotherapy in combination with anti-CTLA-4 antibody generates effective antitumor immunity. Such a combinatorial approach could potentially translate into an effective treatment for patients with metastatic TNBC.
Role of miR-142 in regulatory T cell development and regulating immune responses
Authors: Bhela Siddheshvar , Rouse Barry T 
Published: January 2023

Abstract
Regulatory T cells (Treg) are essential for maintenance of self-tolerance and prevention of autoimmune diseases. Although, Treg have been known to be regulated by the transcription factor Foxp3 but role of miRNAs that control Treg is still not yet completely understood. Here, we report that miR-142-deficient mice have reduced number of Treg, but normal development of CD4+Foxp3− T cells both in the thymus and periphery. Interestingly, reduced number of Treg was accompanied by increased frequencies and numbers of Th1 cell responses in the periphery. In addition, we found that miR-142KO T cells showed defective in-vitro Treg cell differentiation. Lastly, we compared the outcome of herpes simplex virus 1(HSV-1) induced immunopathology, Th1 cell orchestrated ocular lesions, in mice unable to express miR-142 because of gene knockout to that of wild-type mice. The miR-142KO mice developed more-severe and earlier stromal keratitis lesions than did infected wild-type animals. This increased disease severity was associated with increased Th1 cell responses in the cornea at day 7pi. Taken together our data suggests that miR-142 is required for normal Treg cell development and that proper regulation of miR-142 is crucial for immunological tolerance.
Modulation of the subcellular localization of T-bet and Eomes alters CD8 exhaustion during chronic LCMV infection
Authors: McLane Laura M , Attanasio John , Huang Alexander C. , Wherry E. John 
Published: January 2023

Abstract
Following acute viral infection, effector CD8 T-cells (TE) differentiate into long-lived memory cells (TMEM) required for secondary viral clearance. Due to persisting antigen in chronic infection, rather than differentiating into TMEM, TE progressively lose their functional abilities and become exhausted (TEX), expressing high levels of the inhibitory receptor PD1. Differentiation into TE, TMEM, and TEX is driven by transcription factors including T-bet and Eomes. In TMEM, T-bet represses PD1 while Eomes drives memory formation. In PD1+ TEX, T-betand Eomes are also expressed leading to the question of how these factors are able to play differing roles in TMEM and TEX. Using the LCMV infection model, we show that T-bet and Eomes are differentially localized during acute and chronic infection where T-bet is more cytoplasmic and Eomes is more nuclear during chronic Clone 13 infection compared to Armstrong. Additionally, nuclear T-bet in TMEM is associated with low PD1 and nuclear Eomes correlates with high PD1 in TEX. Interestingly, a higher Eomes to T-bet ratio in the nucleus correlates with TEX and blocking PD1 during chronic infection reverses this ratio. We also found that post aPD1-treated tumor-infiltrating lymphocytes from human melanoma patients have more T-bet in the nucleus compared to Eomes. Taken together, these data suggest the subcellular localization of T-bet and Eomes impacts exhaustion: nuclear Eomes is associated with high PD1 and nuclear T-bet correlates with low PD1. Importantly, these data also reveal the ratio of nuclear Eomes to T-bet influences CD8 TMEM and TEX formation and blocking PD1 signaling impacts T-bet and Eomes localization suggesting that dampening its expression might be key to reversing exhaustion.
The Influence of Genetic Diversity on Neonatal Respiratory Syncytial Virus Disease
Authors: Siefker David , Williams Robert , Lu Lu , You Dahui , Cormier Stephania 
Published: January 2023

Abstract
Respiratory Syncytial Virus (RSV) is the number one cause of lower respiratory infection in children and is linked to asthma development later in life. After acute infection, some infants develop severe lower respiratory disease that requires hospitalization and can even cause death. This collaborative project aims to identify genetic determinants associated with susceptibility to RSV infection during the neonatal period. Our laboratory has developed a neonatal mouse model of RSV infection to study immunopathology in an age-appropriate manner. Recombinant inbred strains of mice have been extensively sequenced for genetic polymorphisms and are used as a forward genetics approach to identify groups of genes involved in phenotypes of interest, such as disease susceptibility. Here, we utilize the BXD family of recombinant inbred strains of mice with our neonatal RSV infection model to discover genetic loci involved in the susceptibility of neonates to RSV. We show a difference in viral burden in the lungs of neonatal mice between different BXD strains, suggesting a role for genetic variation in RSV susceptibility. Therefore, we have a novel system to identify genetic loci involved in the development of RSV disease. These results will be critical in the development of specific antivirals and vaccines against RSV, which remain elusive despite five decades of research.
Type I interferon suppresses neutralizing antiviral B cell responses by modulating CD8+ T cell differentiation
Authors: Moseman E. Ashley , Wu Tuoqi , de la Torre Juan Carlos , Schwartzberg Pamela L. , McGavern Dorian B 
Published: January 2023

Abstract
Studies have established a role for T cells in resolving persistent viral infections, yet emerging evidence indicates that both T and B cells are required to control some viruses. During persistent infection, a marked lag or failure to generate neutralizing antibodies is commonly observed and likely contributes to an inability to control certain pathogens. Using lymphocytic choriomeningitis virus (LCMV) as a model, we have examined how a persistent viral infection can suppress neutralizing humoral immunity. By tracking the fate of virus-specific B cells in vivo, we report that LCMV-specific B cells were rapidly deleted within a few days of persistent infection, and this deletion was completely reversed by blockade of type I interferon (IFN-I) signaling. Early interference with IFN-I signaling promoted survival and differentiation of LCMV-specific B cells, which accelerated the generation of neutralizing antibodies. This marked improvement in antiviral humoral immunity did not rely on the cessation of IFN-I signaling in B cells but on alterations in the virus-specific CD8+ T cell response. Using two-photon microscopy and in vivo calcium imaging, we observed that cytotoxic T lymphocytes (CTLs) productively engaged and killed LCMV-specific B cells in a perforin-dependent manner within the first few days of infection. Blockade of IFN-I signaling protected LCMV-specific B cells by promoting CTL dysfunction. Therapeutic manipulation of this pathway may facilitate efforts to promote humoral immunity during persistent viral infection in humans. Our findings illustrate how events that occur early after infection can disturb the resultant adaptive response and contribute to viral persistence.
Antibody responses induced to the C1 region of HIV-1 gp120 in acute HIV-1 infection and after vaccination
Authors: Trinh Hung Viet , Pham Peter , Hamlin Christopher , Bose Meera , Tovanabutra Sodsai , Kijak Gustavo , Sanders-Buell Eric , Eller Leigh A. , Alving Carl R. , Kim Jerome H. , Michael Nelson L. , Robb Merlin L. , Rao Mangala 
Published: January 2023

Abstract
Based on the analysis of secondary immune correlates, the RV144 phase III trial demonstrated a reduced risk of infection in vaccine recipients with high levels of ADCC activity and low HIV-1 Env specific plasma IgA antibodies (Abs). Ab responses to the HIV-1 Env constant 1 (C1) region constituted the dominant ADCC Ab response. To further explore the binding Ab profiles and determine differences in the Ab responses to the C1 region (100 amino acids) induced by vaccine versus natural HIV-1 infection, plasma samples from an early acute HIV-1 infection Thai cohort (RV217) and a phase II clinical trial, RV135 (ALVAC prime and gp120 SF2/CM235 boost adjuvanted with MF59) were evaluated by Biacore. Based on the sequencing data from 16 RV217 individuals at 3 time points (week 1, weeks 4–6 and weeks 21–27 post infection), consensus 40-mer C1 peptides with 10-mer-overlapping amino acid sequences were initially screened for binding responses in RV217 and RV135 plasma samples. This was then followed with 16-mer peptides with 8-mer overlapping amino acid sequences to match the viral sequences in individual RV217 patients at these 3 time points. Vaccinees (RV135) induced Ab responses that recognized linear C1 peptides spanning amino acids 31-46, 55-70, 61-76, 77-92, and 85-100, whereas HIV-1 infected individuals (RV217) recognized linear C1 peptides spanning amino acids 1-16, 55-70, and 77-92. Future experiments will examine the functional role of these C1-specific Abs, in particular ADCC activity.
Docosahexaenoic acid improves the decrement in antibody production upon influenza infection in murine obesity through the production of pro-resolving lipid mediators
Authors: Guesdon William , Crouch Miranda , Kosaraju Rasagna , Armstrong Mike , Reisdorph Nichole , Shaikh Saame Raza 
Published: January 2023

Abstract
Obesity is associated with diminished antibody production against influenza infection. Therefore, therapeutic strategies are needed to enhance humoral immunity. We previously demonstrated that essential long-chain n-3 polyunsaturated fatty acids (PUFA) enhance humoral responses to a T-independent antigen. Thus, here we hypothesized that the n-3 PUFA docosahexaenoic acid (DHA) could improve antibody production upon influenza infection in obese mice. To test the hypothesis, mice were fed for 15 weeks with a control or a Western diet with or without DHA supplementation followed by infection with influenza A/Puerto Rico/8/34. The data show that DHA supplementation improved antibody titers, as measured by HAI and microneutralization assays, in obese mice after influenza infection. Mechanistically, DHA did not target B-cell PPARγ or the DHA-sensing G-protein coupled receptor 120 to boost antibody levels. Instead, DHA increased the levels of downstream D-series specialized pro-resolving lipid mediators (SPMs), which are known to increase antibody production through the generation of CD138+ antibody secreting cells. Specifically, LC/MS analyses showed 14-HDHA to be elevated upon DHA intervention, which elevated antibody levels upon infection and increased the frequency of CD138+ cells. Overall, the results suggest that DHA may have potential therapeutic applications for improving humoral immunity, potentially through an SPM mediated mechanism.
B cell response to parvovirus B19 despite abnormal splenic architecture and cytokine/chemokine profiles in patients and animal models with sickle cell disease (SCD)
Authors: Penkert Rhiannon , Hankins Jane S , Dormitzer Philip R , Settembre Ethan C , Tang Li , Sun Yilun , Thomas Paul G , Chandramouli Sumana , Hayden Randall , Wong Susan , Surman Sherri L , Sealy Robert E , Rosch Jason , Dowdy Jola , Young Neal S , Hurwitz Julia L 
Published: January 2023

Abstract
Sickle cell disease (SCD) is caused by a mutant β-globin gene and affects more than 100,000 individuals in the USA alone. Sickled RBCs and ischemic events cause tissue damage, altered splenic architecture, and inflammation. When children are infected with parvovirus B19, they can develop life-threatening aplastic crisis. Previous reports have described immune defects among patients with SCD, and their potential correlations with splenic dysfunction or inflammation. In a multi-center study involving St. Jude, NIH, Novartis, and GlaxoSmithKline, we examined (i) inflammatory cytokines/chemokines in patients with SCD, treated or untreated with hydroxyurea (HU); (ii) immune responses toward parvovirus B19 infections in children with SCD; and (iii) immune responses in a mouse model for SCD against a candidate Saccharomyces cerevisiae-derived parvovirus B19 VLP vaccine. Results showed that HU treatment reduced serum cytokines/chemokines in patients with SCD (e.g. TGFα, TNFα, and sVCAM-1). Both HU-treated and untreated children, regardless of their cytokine/chemokine profile, responded to parvovirus B19. Binding antibodies were apparent in the nasal cavity (a common point-of entry for the pathogen) and sera by day 7 post-infection, and virus-specific neutralizing antibodies were induced. In transgenic mice with SCD (expressing human α, βS, and γ globin genes), we observed normal antibody activities toward the VLP vaccine. Together, data show that parvovirus B19 -specific B cells withstand the aberrant SCD environment better than their previously-described Streptococcus pneumonia-specific B cell counterparts. Data encourage rapid development of the VLP vaccine to prevent aplastic crises in children with SCD.
Acute phase human B cell response after ZIKV infection
Authors: Bhaumik Siddhartha Kumar , Priyamvada Lalita , Kauffman Robert , Mulligan Mark , Wrammert Jens 
Published: January 2023

Abstract
Prior to its emergence in Brazil in 2015, Zika virus (ZIKV) was mainly reported to cause either asymptomatic infections or mild, self-limiting illness. However, the disease pathology of recent epidemics includes neurological complications such as Guillain-Barré Syndrome in adults and congenital microcephaly in neonates. Consequently, there is a pressing need to understand ZIKV pathogenesis and the immunology of ZIKV infections. To this end, we have studied the B cell response in acutely-infected ZIKV patients, both at the serum and at the monoclonal level. Of the several plasmablast-derived mAbs generated, most were specific to the ZIKV envelope. Given the immunological cross-reactivity between ZIKV and dengue virus (DENV), we tested the panel for reactivity against DENV1-4 and found that all ZIKV-reactive mAbs also bound DENV antigens. Interestingly, even though the patients was infected with ZIKV, more mAbs neutralized DENV than ZIKV in vitro. Patient serum showed high ZIKV and DENV IgG binding titers, illustrating that this cross-reactivity was evident at the serum level as well. At the cellular level, the plasmablasts isolated from these patients exhibited high levels of somatic hypermutation, comparable to frequencies seen in secondary dengue cases. Together, these data suggest that the patients may have previously been exposed to DENV, and that the poorly neutralizing mAbs generated after ZIKV infection could be the product of a DENV-derived memory response, suggesting evidence of original antigenic sin (OAS). These findings have important implications from a public health viewpoint, given that a majority of areas currently experiencing ZIKV outbreaks are also DENV endemic.
Autoreactive T-bet+ B-cells promote pathological anemia during infection
Authors: Rivera-Correa Juan , Pardo-Ruge Maria , Gonzalez Sandra , Rodriguez Ana 
Published: January 2023

Abstract
Malaria is still one of leading infectious diseases in the world being a great global health burden. Pathological anemia is one of the most common malaria-associated complications, which accounts to both great morbidity and mortality of the infection. Our lab has recently identified autoantibodies that target the membrane lipid phosphatidylserine (PS) on uninfected erythrocytes as a major promoter of malarial anemia both in a rodent model and correlating with P. falciparum malarial anemia in patients. The aim of this work was to identify the population of B-cells that are responsible for the production of these autoantibodies as well as characterizing the mechanism by which they arise during malarial infection. Our results have identified an atypical population of B-cells expressing the transcription factor T-bet as being major producers of anti-PS antibodies during malarial anemia. Additionally we have identified parasite DNA along with inflammatory cytokine IFNγ as essential signals that synergize to promote the development and appearance of these autoreactive T-bet+ B-cells. Similarly, the lack of any of these signals ameliorated severe anemia during a rodent malarial infection model. We have also identified both expansion of T-bet+ B-cells and production of anti-PS antibodies in ex-vivo cultures of naïve human PBMCs exposed to P. falciprum infected erythrocyte lysates. Lastly, we have also observed the expansion of T-bet+ B-cells correlating with both anti-PS antibodies and anemia during rodent trypanosoma (T. brucei) infection. These results provide mechanistic insights about the appearance of autoimmunity during infection and attribute a role for autoimmunity in contributing to pathology during parasitic infections.