bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host Resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression
Authors: Foreman Taylor W , Sallin Michelle , Kauffman Keith D. , Riou Catherine , Bruyn Elsa Du , Sakai Shunsuke , Hoft Stella , Nelson Christine , Myers Timothy , Gardina Paul , Sher Alan , Moore Rashida , Wilder-Kofie Temeri , Moore Ian N , Sette Alessandro , Lindestam Arlehamn Cecilia S , Wilkinson Robert , Barber Daniel L 
Published: January 2023

Abstract
Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with Tnfsf8−/− CD4 T cells, similar to Ifng−/− CD4 T cells, fails to rescue mice from early mortality. In Mtb-infected non-human primates, Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with latent Mtb infection compared to those with active tuberculosis. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule.
B7x expression on the bronchial epithelium delays CD4 T cell priming after Mycobacterium tuberculosis infection
Authors: Sakai Shunsuke , Kauffman Keith D. , Kamenyeva Olena , Zang Xingxing , Barber Daniel L 
Published: January 2023

Abstract
The priming of CD4 T cell responses after Mycobacterium tuberculosis (Mtb) infection is delayed compared to other pathogens. Although it has been thought that the slow replication rate of the bacteria is responsible for the lag in T cell priming, it is possible that negative regulatory pathways that control inflammation in the lung also contribute to this slow T cell response. Here we show that the orphan co-inhibitory ligand B7x contributes to the delay in T cell priming following Mtb infection. We find that B7x is expressed on bronchiolar epithelial cells, and B7x−/− mice display enhanced bacterial control and survive longer than WT mice after pulmonary Mtb infection. The enhanced resistance of B7x−/− mice to Mtb infection is completely dependent on CD4 T cells, but at day 28 post-infection, the peak of the T cell response, there is little difference in the number or function of Mtb-specific effector CD4 T cells. Instead, we find that Mtb-specific CD4 T cells are primed in the mediastinal lymph nodes (mLNs) and accumulate in the lungs much earlier in B7x−/− mice compared to WT mice. B7x blockade is also able to enhance Mtb-specific T cell priming even after inoculation of non-replicating irradiated Mtb into the lungs. Moreover, after ESAT-6/CpG lung immunization, B7x blockade reduces the amount of adjuvant needed to drive T cell expansion in the mLNs by ~50 fold. Collectively, our results indicate the expression of the immune checkpoint molecule B7x by the bronchial epithelium contributes in part to the notorious lag in CD4 T cell responses during tuberculosis by increasing the threshold of innate stimuli needed for the induction of T cell priming.
Increased duration of antibiotic treatment progressively alters gut microbiota and revokes protection from ocular autoimmunity
Authors: Salvador Ryan S. , Horai Reiko , Jittayasothorn Yingyos , Tang Jihong , O’Huigin Colm , Thovarai Vishal , Yuan Wuxing , Caspi Rachel 
Published: January 2023

Abstract
Autoimmune uveitis, thought to be driven by retina-specific T cells, is a major cause of blindness. Using a model of experimental autoimmune uveitis (EAU), we showed that long-term elimination of commensals by oral antibiotic treatment (ABX) did not affect susceptibility to EAU, but others reported that short-term ABX was protective. To reconcile these contradictory findings, we studied whether duration of ABX differentially affected EAU development, gut microbiota and host-immune responses.
B10.RIII mice were treated orally with a broad-spectrum antibiotic cocktail, starting 12-weeks (long-term) or 1-week (short-term) before IRBP immunization for EAU induction, and continuing until the end of the experiment. Short-term ABX delayed the onset of EAU, whereas long-term ABX showed a pattern of EAU kinetics and severity similar to untreated SPF controls. Metagenomic analyses revealed ABX duration-dependent depletion of gut microbial communities. Interestingly, ABX also resulted in progressive depletion of CD4+ and CD4+CD8+ T cells from the gut intraepithelial lymphocyte (IEL) compartment. Notably, these IELs showed some cytotoxic activity in vitro, and are thought to help preserve gut mucosal barrier integrity.
We propose that microbiota play dual roles in uveitis development: they provide a stimulus for uveitogenic effector cells, but also maintain a “regulatory” IEL population, whose progressive loss reverses the temporary protection seen with short-term ABX. Further understanding of the role of IELs in the microbiota-gut-eye axis may lead to novel treatments for autoimmunity through manipulation of the commensal microbiome and gut epithelium.
Control of mucosal barrier functions and gut microbiome homeostasis by DUSP6 in colitis
Authors: KAO CHENG-YUAN , Chang Cherng-Shyang , Liao Yi-Chu , Huang Chih-Ting , Ruan Jhen-Wei , Lin Chiao-Mei , Tan Tse-Hua , Liao Yu-Chieh 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) is a common intermittent gastrointestinal condition and the incidence and prevalence of IBD are usually high in industrialized countries in North America and Europe. Several gut microbiome studies have been conducted in different IBD cohorts and certain specific taxonomic shifts have been associated with IBD. Although there is a relative escalation in the abundance of Enterobacteriaceae, including Escherichia coli and Fusobacterium, so far no single microbe has been demonstrated to cause IBD. It is plausible that intestinal microbiota dysbiosis may contribute to IBD pathogenesis by loss of health-promoting commensal symbionts or gain of pathobionts. We applied phosphoproteomics profiling and RNA-seq analysis in DUSP6-deficient Caco-2 cells. Our results suggested that DUSP6 could affect gut barrier functions and this is further confirmed with a dextran sulfate sodium (DSS)-induced colitis mouse model. Interestingly, with 16S rRNA gene sequencing we found that the gut/fecal microbiota in Dusp6-deficient mice was more resistant to DSS-induced dysbiosis compared with wild-type mice. In summary, these findings indicate that Dusp6-deficiency is a novel host genetic factor that could modulate gut barrier functions and mucosal immunity and inhibiting DUSP6 might be a novel strategy to shape the homeostasis of microbiota and beat IBD.
PLGA-encapsulated Chlamydia recombinant MOMP enhances serum and mucosal Th1 antibodies including memory and effector T-cells via subcutaneous prime-boost as compared to the intramuscular priming route immunization of mice
Authors: Sahu Rajnish , Verma Richa , Dixit Saurabh , Duncan Skyla , Ipinmoroti Ayodeji , Singh Shree R , Dennis Vida A 
Published: January 2023

Abstract
Vaccine developmental efforts are rapidly targeting biodegradable nanoparticles-based vaccines with encapsulated antigen. We have developed a PLGA 85/15 (poly (lactic-co-glycolic acid) Chlamydia nanovaccine by encapsulating its recombinant MOMP (major outer membrane protein) that induced robust adaptive immune responses and provided enhanced protection against C. muridarum (Cm) challenge in subcutaneously immunized mice. In the current study, we compared the immunogenicity and efficacy of priming routes; subcutaneous (sc) or intramuscular (im) followed by two sc-boosts to evaluate serum and mucosal antibodies [Th1 (IgG2a, IgG2b), Th2 (IgG1)] as well as memory and effector T-cells activation after immunization and Cm challenge of mice. We observed significantly high levels of MOMP-specific serum and mucosal antibodies with high avidity especially for Th1 antibodies. A significant increase in Th1 serum and mucosal antibodies with even higher avidity was observed after genital tract Cm challenge in the sc-prime-boost immunized mice. Evaluation of the Th1/Th2 antibody titer ratio revealed that the nanovaccine evoked a higher Th1 and lower Th2 response, which skewed to a dominated Th1 antibody response after bacterial exposure to sc-prime mice. In addition, CD4+ memory (CD44highCD62Lhigh) and effector (CD44highCD62Llow) T-cells proliferation was about two-fold higher in the sc-prime mice. Herein, we reveal that the subcutaneous prime-boost immunization with the nanovaccine was more effective in enhancing the Th1 antibody response and memory and effector T-cell responses against a chlamydial genital tract challenge of mice.
Effects of high affinity engineered class II-restricted full length and single chain CAR-format T cell receptors specific for a naturally occurring Listeria monocytogenes epitope on T cell activation and specificity
Authors: Johnson Deborah , Myers Sheldon , Magoffin Wyatt , Orton Taylor , Tellez-Frietas Claudia M , Christensen Ken , Weber K. Scott 
Published: January 2023

Abstract
High affinity T cell receptors (TCRs) are absent from the native T cell repertoire. While current hypotheses propose that high affinity TCRs are more sensitive to antigen and have a competitive advantage in immune responses, emerging evidence suggests that higher affinity T cells may reach a threshold where they experience decreased functionality, loss of binding specificity, and become prone to anergy. High affinity TCRs are especially attractive to facilitate immunotherapies as native TCR binding affinity may be too low to effectively initiate activation. However, the effects of increased TCR affinity for CD4+ T cells specific for naturally occurring epitopes is poorly understood. To address this question, we engineered via yeast display several class II-restricted high affinity TCRs specific for a naturally occurring peptide from Listeria monocytogenes protein listeriolysin O. Our high affinity clones have KD values as low as 8.7 nM and half-lives as long as 174 minutes when measured by tetramer dissociation assays. This panel of class II restricted high affinity TCRs specific for a naturally occurring Listeria monocytogenes epitope provides a novel means of testing the role of affinity and CD4+ T cell activation responses in the context of an infection.
Enhancement of antigen-specific responses following protein vaccination by Albumin- Flt3L expanded dendritic cells: Potential implications
Authors: Esquivel Daniel , Lam Brandon Krishna , Lee Brandon , Tan Marietta , Wu T.C. , Hung Chien-Fu 
Published: January 2023

Abstract
Due to the crucial role that dendritic cells (DCs) play in uptaking antigens following vaccination and cross presenting these antigens for the activation of antigen-specific immunity, a strategy that can induce potent expansion and activation of cross-presenting DCs may serve as a potential strategy to enhance the efficacy of therapeutic and prophylactic vaccinations. Flt3L is a cytokine known to expand cross-presenting DCs, but is limited by its global distribution and short half-life in vivo. To overcome these shortcomings, we generated a novel immunostimulatory molecule by fusing Flt3L to Albumin; a protein known for its long half-life and trafficking to lymph nodes. Our results revealed that Albumin-Flt3L (Alb-Flt3L) retains Flt3L’s endogenous capabilities to increase total CD11c+MHCII+, CD11c+MHCII+B220+SiglecH+, and CD11c+MHCII+CD8a+ DC populations in vitro, and in vivo following a single injection, compared to Flt3L. Our data also demonstrates that following vaccination with whole Ovalbumin protein (OVA), Alb-Flt3L treated mice saw an increase in antigen-specific immunity, measured by OVA-tetramer-positive CD8+ T cells, CD4+ and CD8+ cells producing IFN-g following ex vivo restimulation, and serum OVA specific IgG2a. When vaccinated with HPV-associated antigen E7 as a long peptide that requires uptake and cross-presentation to effectively load on MHCI and subsequently activate CD8+ T cells, E7-specific T cell populations significantly increased in Alb-Flt3L treated mice compared to controls. Further investigation is underway to study the ability of Alb-Flt3L to enhance vaccination induced immune responses as well as to study the mechanism by which these phenomena occur.
Oral R848 Reduces Host Susceptibility to Enteric and Systemic L. monocytogenes Challenge
Authors: Kayraklioglu Neslihan , Horuluoglu Begum Han , Elango Madhivanan , Turan Aslihan , Klinman Dennis M 
Published: January 2023

Abstract
Toll-like receptors (TLR) trigger the immune system to mount a rapid innate response capable of protecting the host from a wide variety of bacterial and viral pathogens. There is interest in harnessing TLR agonists to reduce the susceptibility of at-risk populations to infection. Yet the widespread prophylactic use of TLR agonists is compromised by the need to administer most of them by parenteral injection. An exception is the TLR7/8 agonist R848 which can boost GI and systemic immunity when administered orally. This work examines the effect of R848 on host susceptibility to L. monocytogenes in a murine challenge model. Results show that prophylactic administration of R848 significantly reduced susceptibility to infection over the ensuing 1–7 days in Balb/C mice. Oral R848 led directly to B cell stimulation and accelerated the response of T cells to subsequent L. monocytogenes challenge. Oral R848 may thus be of use in reducing the susceptibility of at-risk individuals to infection.
A potently neutralizing site III-specific human antibody prevents human metapneumovirus replication in vivo
Authors: Mousa Jarrod , Diaz Darren , Crabtree Jackelyn , Pena-Briseno Alma , Bar-Peled Yael , Tripp Ralph A. 
Published: January 2023

Abstract
Human metapneumovirus (hMPV) is a leading cause of lower respiratory tract infection in infants and children, yet there is currently no vaccine available for prevention of hMPV disease. hMPV has three surface proteins: the small hydrophobic, the attachment, and the fusion (F) protein. The hMPV F protein is the sole target of neutralizing antibodies. To develop new therapeutics for disease intervention and to inform the development of an effective vaccine, we isolated several new human monoclonal antibodies (mAbs) to the hMPV F protein. A subset of these mAbs were determined to be neutralizing by a plaque reduction assay. The neutralizing mAbs bind to all four subgroups of the hMPV F protein, and neutralize viruses from both the A and B genotypes. We conducted epitope binning assays on the OctetRED384 system to determine the antigenic targets of each mAb. Three of the four mAbs (196, 314, 201) bind near the previously discovered mAb DS7. One mAb, MPV364, competes with the site III mAbs MPE8 and 25P13, yet unlike these mAbs, MPV364 does not cross-react with the respiratory syncytial virus F protein. MPV364 exhibits potent and broadly neutralizing activity below 20 ng/mL. We examined the therapeutic efficacy of MPV364 to prevent replication of hMPV in vivo and found a reduction in lung viral titers. These data suggest antigenic site III on the hMPV F protein elicits potently neutralizing mAbs, and should be incorporated into future vaccine candidates. Furthermore, MPV364 should be further examined for protection from hMPV disease in additional animal models of infection.
Immunoprotection versus immunopathology by type I and III interferon against human metapneumovirus
Authors: Zhang Yu , Xu Jiuyang , Miranda-Katz Margot , Rich Helen E , Manni Michelle L , Tollefson Sharon , Sarkar Saumendra N , Alcorn John F , Williams John 
Published: January 2023

Abstract
Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in infants and children. The disease outcome of HMPV infection ranges from mild infection to severe bronchiolitis and fatal pneumonia. HMPV was discovered in 2001 and its disease mechanisms are not fully understood.
To study HMPV pathogenesis, we tested nine HMPV clinical isolates in an established C57BL/6 mouse model. HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Mice infected by non-virulent strain TN/94-49 did not show significant weight loss, but mice infected with virulent isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection. These findings were confirmed in other inbred mouse strains. C2-202 infected mice also suffered from impaired pulmonary function post-recovery. Lung virus replication did not correlate with disease severity, suggesting immune-mediated pathogenesis. Further investigation revealed increased type I and III interferons, pro-inflammatory cytokine production, and neutrophil infiltration in C2-202 infected mice. HMPV C2-202 infection also inhibited dendritic cell recruitment and down-regulated MHC-II surface expression on macrophages. Stat1/Stat2 double knockout mice lacking interferon signaling exhibited reduced weight loss, lessened disease severity, and increased dendritic cell recruitment after C2-202 infection.
Our results indicate that severe disease caused by HMPV clinical isolates was due to exuberant interferon response leading to immuno-pathological tissue damage. These data suggest interferon signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target.
Improved level and longevity of protective immune responses in measles virus with efficient replication in blood and lymphoid tissue
Authors: Lin Wen-Hsuan Wendy , Adams Robert J , Griffin Diane E 
Published: January 2023

Abstract
Infection with wild type measles virus (wt-MV) is an important cause of childhood mortality and is also known to induce remarkable life-long protective immunity. Despite the antigenic similarities between wt-MV and live-attenuated measles virus vaccine (LAMV), the protective immunity after measles vaccination is not as robust or long-lived. To identify mechanisms that contribute to the longevity of immune responses induced by wt-MeV infection, we compared parameters of virologic and immunologic responses after respiratory infection with wt-MeV and LAMV in rhesus macaques. Analysis of viral RNA in various tissues revealed distinct in vivo tropisms between the two strains of virus. Wt-MeV caused efficient hematogenous spread and prolonged presence of viral RNA, while LAMV caused transient localized infection in the respiratory tract. Plasma levels of cytokines IL-1β, IL-12 and interferon (IFN)-γ and chemokines CCL2, CCL11, CXCL9 and CXCL11 were increased after wt-MeV, but not LAMV infection. Infection with wt-MeV or LAMV induced comparable levels of viral-specific T cells, but significantly higher levels of protective antibody and more long-lived plasma cells were observed after wt-MeV infection. Therefore, distinct patterns of in vivo virus replication, efficiency of hematogenous spread and persistence of viral RNA are associated with the altered virulence and the level and longevity of the humoral response. Our results establish a link between life-long protective immunity and the ability of wt-MeV to spread efficiently in lymphocytes and to be cleared slowly.
The utility of Benzathine Penicillin G for Rheumatic Fever prevention in the Solomon Islands
Authors: Sika-Paotonu Dianne , Liligeto Urijah 
Published: January 2023

Abstract
Acute Rheumatic Fever (ARF) frequently affects children and young adults and is an autoimmune condition caused by untreated Group A Streptococcal (GAS) infection of the upper respiratory tract (and skin). Repeated or very severe ARF attacks that are left untreated, can lead to Rheumatic Heart Disease (RHD) - permanent cardiac damage. RHD is rare in developed countries and yet remains a significant cause of morbidity and mortality worldwide. Unfortunately the disease burden of ARF and RHD amongst Indigenous and Pacific communities in New Zealand, Australia and the Pacific Region are amongst the highest in the world. In the absence of a GAS vaccine, the recommended preventative measure for ARF/RHD consists of painful monthly injections of a type of Penicillin known as Benzathine Penicillin G (BPG). Otherwise known as secondary prophylaxis (SP), the purpose of these injections is to prevent GAS infections that can trigger recurrence of ARF and either lead to or worsen RHD. The adherence to SP remains challenging across many settings and it is recognised that a new Penicillin that is more appropriate is needed. To support the drug design efforts and development of a new BPG formulation, this work sought to explore BPG SP for Rheumatic Fever in the Solomon Islands by engaging with health professionals, researchers and community leaders and sourcing local information. Access and other issues connected with BPG SP for those having received a previous diagnosis of ARF were identified. Information concerning these challenges are relevant for drug design efforts and SP schedules for ARF/RHD prevention.
Role of acetylcholine receptors in cholinergic pathway-mediated protection against autoimmune diabetes
Authors: Al-Ramadi Basel K , George Junu A , Bashir Ghada , Qureshi Mohamed M. , Mohamed Yassir A , Elsayed Nourhan , Fernandez-Cabezudo Maria J 
Published: January 2023

Abstract
Type I diabetes (T1D) is a T cell-driven autoimmune disease that results in the killing of pancreatic β-cells and, consequently, loss of insulin production. Using the multiple low-dose streptozotocin (MLD-STZ) model of experimental autoimmune diabetes, we previously reported that pretreatment with a specific acetylcholinesterase inhibitor (AChEI), paraoxon, prevented the development of hyperglycemia in C57BL/6 mice. This correlated with an inhibition of T cell infiltration into the pancreatic islets and a reduction in proinflammatory cytokines. The cholinergic anti-inflammatory pathway utilizes nicotinic and muscarinic acetycholine receptors (AChR) expressed on a variety of cell types. In this study, we carried out a comparative analysis on the effect of specific antagonists of the nicotinic- or muscarinic-AChR on the development of autoimmune diabetes. Co-administration of nicotinic-AChR antagonist (mecamylamine) maintained the protective effect of AChEI on the development of hyperglycemia. In contrast, co-administration with muscarinic-AChR antagonist (atropine) mitigated AChEI-mediated protection. Mice pretreated with mecamylamine had an improved response in glucose tolerance test than mice pretreated with atropine. These findings correlated with the extent of islet cell infiltration and with the structure and functionality of the β-cells. Taken together, our data suggest that muscarinic receptors are essential for the protective effect of cholinergic stimulation on autoimmune diabetes.