bluuebunny/crossref_metadata_2025_split huggingface dataset:
IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages
Authors: John Sinu P , Sun Jing , Carlson Rebecca , Cao Binh , Fraser Iain D 
Published: January 2023

Abstract
Activation of the TLR4 signaling pathway by LPS leads to activation of both inflammatory and interferon stimulated genes, however the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remains poorly understood. In a genome-wide siRNA screen of the LPS-induced TNF-a response in macrophages, we identified the interferon-stimulated protein IFIT1 as a negative regulator of the inflammatory gene program. Transcriptional profiling further identified an unexpected positive regulatory role for IFIT1 in type I interferon expression, implicating IFIT1 as a reciprocal modulator of LPS-induced inflammatory and interferon gene expression. We demonstrate that these effects of IFIT1 are mediated through modulation of a Sin3a-HDAC2 transcriptional regulatory complex at LPS-induced gene loci. Beyond the well-studied role of cytosolic IFIT1 in restricting viral replication, our data demonstrate an unappreciated function for nuclear IFIT1 in differential transcriptional regulation of separate branches of the LPS-induced gene program. IFIT1 depletion led to a significant increase in the replication of B. cenocepacia. Prior treatment of IFIT1 depleted cells with recombinant IFN-β reversed the enhanced replication of B. cenocepacia, indicating a role for autocrine IFN-β in controlling B. cenocepacia infection and a requirement for IFIT1 in interferon induction in response to bacterial infection. We also observed reduced expression of IFNβ1 in response to viral and bacterial infection in IFIT1 depleted cells, suggesting a broad role for IFIT1 in supporting IFNβ1 expression.
CD36 regulates malaria-induced innate immune responses
Authors: Puttalingaiah Ramesh Thylur , Wu Xianzhu , Gowda Nagaraj M , Punnath Kishore , Gowda Channe D 
Published: January 2023

Abstract
Malaria causes enormous morbidity and mortality worldwide. However, an effective vaccine is not yet available due to the knowledge gap in various molecular and cellular processes involved in protective immunity development. CD36, a multifunctional scavenger receptor, plays several important roles in malaria, including sequestration of parasites in host organs, parasitemia control, and protective immunity. Although the role of CD36 in the former two processes has been well understood, less is known about the function of CD36 in the latter. We studied the role of CD36 in host survival and immune responses in non-lethal Plasmodium yoelii infected WT and CD36−/− mice. WT mice showed lower parasitemia and higher survival rate compared to the CD36−/− mice. At early but not at later stages of infection, the circulatory pro-inflammatory cytokines were higher and anti-inflammatory cytokines were lower in WT mice than in CD36−/− mice. DCs, NK and T cells of WT mice had higher frequencies of pro-inflammatory and lower frequencies of anti-inflammatory cytokine-producing cells than CD36−/− mice. Additionally, Th1 response was decreased, whereas Th2 response was increased in CD36−/− mice. Compared to CD36−/− mice, macrophages and neutrophils of WT mice showed higher phagocytic activity and phagocytic receptors expression in an IFN-g dependent manner. However no difference in the malaria-induced humoral responses between WT and CD36−/− mice was observed. Our data demonstrated that CD36 plays an important role in parasitemia control and protective immunity by upregulating pro-inflammatory cytokine responses by DCs and NK cells, promoting Th1 response, and contributing to phagocytic receptor expression and phagocytic activity.
Recruitment of inflammatory monocytes during influenza infection predisposes host to secondary S. aureus infection
Authors: Sun Keer , Fischer Karl Jacob , Yajjala Vijaya Kumar , Bauer Christopher , Bansal Shruti 
Published: January 2023

Abstract
Staphylococcus aureus has emerged as a leading contributor to morbidity and mortality during recent influenza pandemics and epidemics. The mechanism for this influenza-induced susceptibility to secondary bacterial infection is incompletely understood. We have previously reported that innate antibacterial immunity is suppressed during the recovery stage of influenza infection. This impairment of bacterial control coincides with airway accumulation of inflammatory monocytes, and therefore, we investigated in this study a novel hypothesis of influenza-induced suppression of antibacterial immunity: recruitment of monocytes. C-C chemokine receptor type 2 (CCR2) is responsible for the recruitment of Ly6C+ monocytes into lungs after influenza infection. Here we demonstrate that CCR2−/− mice were more resistant than wild-type mice to influenza and S. aureus coinfection. CCR2 deficiency not only resulted in diminished monocyte recruitment but also reduced proinflammatory cytokine response to coinfection. Importantly, despite a delay in viral clearance, CCR2−/− mice exhibited significantly improved lung bacterial control, in agreement with their increased survivals from influenza and S. aureus coinfection. Furthermore, we show that CCR2-recruited monocytes served as reservoirs to protect bacteria from killing by antibiotics and more potent neutrophils. Collectively, our findings indicate that inflammatory monocytes constitute an important and hitherto underappreciated mechanism of the conflicting immune requirements for viral versus bacterial control by hosts, which subsequently leads to the worsen outcome of influenza and S. aureus coinfection.
Suppression of NFAT5-mediated inflammation and chronic arthritis by novel κB-binding inhibitors
Authors: Lee Naeun , Yoo Seung-Ah , Choi Susanna , Kim Yumi , Kim Wan-Uk 
Published: January 2023

Abstract
Nuclear factor of activated T cells 5 (NFAT5), also known as the tonicity-responsive enhancer-binding protein, is a transcription factor whose DNA binding domain shares structural homology with NF-kB and other members of the NFAT family. Evidence is emerging that NFAT5 is crucial to the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents specifically inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, we screened a library of &gt;40,000 chemicals for the suppression of nitric oxide, a NFAT5 target, through high-throughput screening. We validated anti-NFAT5 activity of the primary hit compounds using an NFAT5-specific reporter and identified the novel NFAT5 inhibitor KRN2, 13-(2-fluoro)-benzyl-berberine and its oral derivative, KRN5. KRN2 suppressed the transcriptional activation of NFAT5 by blocking NF-κB binding to the NFAT5 promoter region, inhibiting NFAT5 mRNA and protein expression in macrophages stimulated with lipopolysaccharide. Interestingly, KRN2 selectively inhibited the expression of pro-inflammatory genes, including Nos2, Tnf, and Il6 without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5 ameliorated experimentally induced arthritis in mice, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was more potent in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis.
Inducing Immunological Tolerance with Synthetic Nanoparticles
Authors: Maldonado Roberto A , LaMothe Robert , Ferrari Dan , Griset Aaron , O’Neil Conlin , Johnston Lloyd , von Andrian Ulrich H , Kishimoto Takashi Kei 
Published: January 2023

Abstract
Here we describe the use of synthetic, biodegradable tolerogenic nanoparticles carrying rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor (TLR) agonists. Treatment with these synthetic vaccine particles (SVP) and antigen (inside the particles or admixed) results in the inhibition of CD4+ and CD8+ T cell activation, differentiation of T and B regulatory cells, durable B cell tolerance resistant to multiple immunogenic challenges, the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis (R-EAE) and tolerance to biologic drugs such as the coagulation factor VIII (in hemophilia A animals), adalimumab (Humira in TNFa-transgenic animals), pegylated uricase (in uricase deficient animals), even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. SVP therapy represents a potential novel approach for the treatment of treatment of allergies, autoimmune diseases, and prevention of anti-drug antibodies (ADA) against biologic therapies. Tolerogenic nanoparticle therapy for the prevention of ADAs against pegylated uricase in the treatment of hyperuricemia is currently being evaluated in Phase 2 clinical trials. Data from our Phase 1 clinical trial will be presented.
IRAK1 attenuates TLR signaling and activates the inflammasome in response to dual-TLR stimulation
Authors: Vayttaden Sharat Jacob , Smelkinson Margery , Ernst Orna Rabinovich , Carlson Rebecca Joy , Sun Jing , Gottschalk Rachel A , Oh Kyu Seon , Pegoraro Gianluca , Meier-Schellersheim Martin , Germain Ronald N , Varma Rajat , Fraser Iain D.C. 
Published: January 2023

Abstract
Macrophages encounter many kinds of pathogen-associated molecules and a coherent immune response involves crosstalk among various immune pathways. How can a cogent response form in the face of crosstalk between various pathways? We address this in the context of combinatorial stimulation of multiple TLRs to assess TLR pathway crosstalk.
We find that IRAK1 forms cytoplasmic clusters that sequester downstream signaling proteins upon dual TLR stimulation. This could explain the less-than additive gene response on dual TLR activation. Accordingly, IRAK1 deficient IMMs and BMDMs have higher phosphoprotein, cytokine and transcriptional responses to dual TLR ligands than WT cells, but their single TLR ligand responses are comparable to WT cells. This suggests that IRAK1-dependent sequestration of key TLR signaling proteins might be a mechanism of modulating the innate immune response to high pathogen load.
We also find that IRAK1 cluster-enriched cells exhibited higher ASC nucleation and increased IL1α/β secretion, which are hallmarks of an active inflammasome. The colocalization of ASC suggests a possible role for dual TLR-induced IRAK1 clustering in diversifying signaling to multiple innate immune signaling pathways.
We conclude that IRAK1 aids in tuning the TLR arm of signaling in response to multi-TLR ligands, allowing the engagement of other PRR pathways like the inflammasome. Thus, the rerouting of immune signals by IRAK1 clusters allows the cell to diversify the immune response to complex microbial signals through activation of multiple host response pathways, and improve the quality of the immune response during an infection.
This work was supported by the Intramural Research Program of NIAID, NIH.
Evaluation of Serum Cancer Antigens (CA15-3 and CA27.29) and Circulating Immune Complexes as Important Tools in the Management of Breast Cancer in Nigeria
Authors: Emele Felix Emele , Chukwurah Ejike Felix 
Published: January 2023

Abstract

Background
Increasing reports suggest a world-wide increase in the incidence of breast cancer. Breast cancer can be affected by racial/ethnic, environmental, and other variables. Serum bio-markers, such as cancer antigens (CA 15-3 and CA 27.29) and circulating immune complexes (CIC), are recognized as important tools in the evaluation and management of breast cancer, although conflicting reports and opinions exist regarding the clinical utility of these markers. In our locality, there is paucity of information in this regard, despite increasing incidence of the disease. We, therefore, saw the need for this study.

Methodology
A total of 42 treatment naïve females with clinically and pathologically confirmed breast tumour were recruited, along with control subjects. Patients with malignant tumours were further grouped into early stage and advanced stage. Serum from patients and controls were investigated for CA 15-3, CA 27.29, and CIC. The patients were subsequently subjected to standard treatment modalities. Follow-up investigations for the markers were carried out at intervals after treatment. Assays for serum tumour markers were by immunoenzymatic methods.

Results
Tumour of all forms recorded significantly higher pre-treatment mean values for CA 15-3 and CA 27.29, compared with the control group (P&lt;0.05). Therapeutic interventions significantly reduced the values for CA 15-3 and CA 27.29 (P&lt; 0.05) but had no consistent effect on the level of CIC.

Conclusion
Tumour markers CA 15-3 and CA 27.29 showed promising diagnostic and prognostic potentials, while CIC appears to be of limited utility in the management of breast cancer in our environment.
Quadruple Negative Breast Cancers in African American women have an enriched Basal and Immune signature.
Authors: Tripathi Shweta , Davis Melissa B. , Hughley Raymond , He Qinghua , Bae Sejong , Grizzle William E. , Karanam Balasubramanyam , Marini Rachel , Colomb Windy D. , Yates Clayton 
Published: January 2023

Abstract
There is increasing evidence that Androgen Receptor (AR) expression has prognostic usefulness in breast cancer suggesting that Triple negative breast cancer (TNBC) which lack AR expression are Quadruple Negative Breast Cancers (QNBC). However, a comprehensive analysis of AR expression within all breast cancer subtypes or stratified by race has not been reported. We assessed AR RNA expression in 925 tumors from The Cancer Genome Atlas, and 136 tumors in 2 confirmation sets. AR protein expression was determined by immunohistochemistry in 197 tumors from a multi-institutional cohort, for a total of 1258 patient analyzed. We used Cox hazard ratios to determine correlations to PAM50 breast cancer subtypes, and TNBC-QNBC subtypes. K-means clustering distincted immune-related gene expression signature in QNBC tumors. AA tumors express the AR at both the RNA and protein levels at lower rates than tumors of White women which is independent of ER and PR expression (p&lt;0.0001). TNBC tumors from both racial groups demonstrate the lowest expression of AR. AR-negative tumors have odds ratio (66.60; 95% CI, 32–146) of being basal-like. QNBC tumors have odds ratio (4.01; 95% CI, 0.88–38.60) of being BL1 subtype. K-means clustering demonstrated that AA patients had a distinctive gene signature that could be subdivided into five signatures; AR pathway, T cell &gt;response pathway, Cancer B cell response, stem cell pathway, and hormone receptors enriched pathways. These observations indicate that AR expression should be included with traditionally used markers and that QNBC should be used as a prognostic marker for breast cancer patients. Further, AR-negative tumors have a characteristic immune signature that could be exploited by targeted immune therapy.
The role of interferon lambda during influenza, Staphylococcus aureus super-infection.
Authors: Rich Helen , Robinson Keven M , McHugh Kevin J. , Clay Michelle E , Alcorn John F 
Published: January 2023

Abstract
While pandemic influenza A H1N1 infection causes significant morbidity and mortality on its own, it also renders an individual more susceptible to secondary infection with bacterial pathogens such as Staphylococcus aureus. We have previously shown that type I interferons produced by influenza impair bacterial defense six to seven days post-influenza infection. However, the role of the predominant type III interferons (interferon lambda/IFNL, IL-28A/B) in bacterial super-infection is less clear. Thus, we explored the role of IFNL in influenza, S. aureus super-infection. First, we examined the impact of attenuating IFNL signaling directly before bacterial challenge. We found that treatment with the IFNLR1 Fc protein significantly increased bacterial burden in the lung compared with controls. However, when we challenged mice with super-infection that have constitutively attenuated IFNL, we found reduced bacterial burden compared to controls, which was significantly correlated with the degree of IFNL expression. While cellular inflammation was not altered, preliminary results suggest that higher bacterial burden is significantly correlated with higher weight loss, suggesting that mice with constitutively attenuated IFNL are protected from both influenza infection and bacterial super-infection. It has been published that mice lacking IFNL receptor 1 have lower bacterial burden during super-infection, which is corroborated by data from our constitutively attenuated IFNL mice. However, attenuation of IFNL signaling directly prior to bacterial challenge increases bacterial burden, suggesting that the timing of IFNL production regulates susceptibility to secondary bacterial infection.
HIV-induced modifications of TIGIT expression impair CD8 T cell polyfunctionality
Authors: Scharf Lydia , Tauriainen Johanna , Frederiksen Juliet , Naji Ali , Ljunggren Hans-Gustaf , Sönnerborg Anders , Lund Ole , Reyes-Terán Gustavo , Hecht Frederick M , Deeks Steven G , Betts Michael R , Buggert Marcus , Karlsson Annika C 
Published: January 2023

Abstract
HIV-specific CD8 T cells display an accumulation of inhibitory receptors that are associated with poor effector functions. Expression of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), its co-stimulatory receptor CD226 and their ligand poliovirus receptor (PVR) are altered during chronic viral infections and cancer. Here we show that the TIGIT/CD226/PVR axis is dysregulated during HIV infection and linked to poor polyfunctional activity, increased expression of inhibitory receptors and an altered effector transcriptional programming. We report that TIGIT expression is increased on CD8 T cells in untreated HIV infection. Additionally, a longitudinal increase in TIGIT expression was demonstrated despite early initiation of antiretroviral therapy during acute HIV infection. The HIV-specific TIGIT+ CD8 T cells co-expressed PD-1, CD160 and 2B4 and had an inverse expression profile of the T-box transcription factors T-bet and Eomes. The HIV-specific CD8 T cells were almost exclusively TIGIThiCD226neg/dim and the frequency of TIGIThi cells was inversely correlated with polyfunctionality. Furthermore, the TIGIT/CD226 ligand PVR was increased on CD4 T cells, especially T follicular helper (Tfh) cells in HIV-infected lymph nodes. These results demonstrate a preferential skewing of the TIGIT/CD226 axis towards the inhibitory receptor TIGIT on CD8 T cells during HIV-1 infection, which is linked to severe T cell dysfunction. The findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that potentially could hinder future therapeutic “cure” strategies that require potent HIV-specific CD8 T cells and/or the clearance of HIV-1 infected Tfh cells.
Harnessing innate anti-tumour immunity using a Klebsiella-derived therapeutic to reduce tumour burden and improve outcomes in mouse models of lung cancer
Authors: Bazett Mark , Costa Amanda L , Bosiljcic Momir , Alexander Matthew P , Anderson Rebecca M , Wong Stephanie WY , Gunn Hal , Kalyan Shirin , Mullins David W 
Published: January 2023

Abstract
Tumour regression and increased survival has been associated with certain acute microbial infections. Immune dysfunction contributes to the development and progression of lung cancer, and therapies that re-constitute anti-tumor immune responses provide an important means to effectively treat malignancies and improve health outcomes. We hypothesized that stimulating the innate immune system with bacterial-derived immunomodulators could induce protective anti-cancer immune responses. A Klebsiella-derived drug product, QBKPN (Qu Biologics), was used to specifically stimulate the innate immune niche in the lungs in established mouse models of lung cancer. Repeated subcutaneous administration with QBKPN significantly reduced lung tumor burden and increased survival. The protective action of QBKPN required prior exposure to Klebsiella through either environmental exposure or lung infection. However, this QBKPN-mediated anti-tumour response was independent of adaptive immunity, as the protective effect remained in RAG2-knockout mice. QBKPN intervention was characterized by a rapid, acute-like systemic immune response, including increased circulatory inflammatory cytokines and innate immune cells, leading to recruitment of immune effector cells into the lung tissue, including macrophages and natural killer (NK) cells. In addition to recruitment of innate immune cells, QBKPN increased markers of classically activated macrophages and increased production of NK cell effector molecules. Together, these data suggest that QBKPN, a Klebsiella-derived immunomodulator, causes activation and recruitment of macrophages and NK cells into the lungs, reducing cancer tumour burden and improving survival outcomes.
Improving immunotherapeutic efficacy against metastatic tumors in a pre-clinical model of murine renal cell carcinoma.
Authors: Boi Shannon Kathryn , Orlandella Rachael M , Norian Lyse A 
Published: January 2023

Abstract
Renal and pelvic cancers are the ninth most common cancer in the U.S., and although five-year survival rates for localized renal tumors are &gt;90%, those for metastasized tumors are &lt;12%. Metastatic renal cell carcinoma (RCC), the most common type of renal neoplasm, is resistant to radio- and chemotherapies. Immune-based therapies, including checkpoint blockade, are being pursued in an attempt to amplify protective adaptive immunity but overall response rates remain at 20–30%. We hypothesized that a therapeutic strategy employing T cell priming plus checkpoint blockade would result in improved clearance of renal tumors verses checkpoint alone. Utilizing our previously described in vivo T cell priming therapy, adenovirus-encoded tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (AdTRAIL) with class B oligonucleotides (CpG), we evaluated therapeutic effects on primary tumor outgrowth and metastatic burden in a pre-clinical model of orthotopic murine RCC. We report here that administration of intra-renal AdTRAIL/CpG in combination with α-CTLA-4, but not α-PD-1, causes significant decreases in primary tumor burdens. Strikingly, we observed that this therapeutic strategy caused significant reductions in metastatic lung burdens – equating to a 98% reduction over no therapy controls. Flow cytometric analysis revealed increases in CD8+ T cells in AdTRAIL-treated groups over no therapy/checkpoint alone; results were further supported by immunosuppressive CD4+ to CD8+ T cell ratios that were in favor of anti-tumoral responses. Our results suggest AdTRAIL/CpG can be used as an effective upstream therapeutic approach to enhance the efficacy of α-CTLA-4 checkpoint blockade in a pre-clinical model of murine RCC.