bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary tryptophan alters CD4+ T cell function in the lupus-prone B6. Sle1.Sle2.Sle3 (TC) mouse model
Authors: Brown Josephine Michelle , Choi Seung-Chul , Morel Laurence 
Published: January 2023

Abstract
Tryptophan (Trp) metabolism is altered in lupus patients with higher production of kynurenine (Kyn). We show that TC mice have the same alterations. To ascertain whether Trp plays a role in autoimmune pathogenesis, TC and B6 control mice were fed with either high or low Trp. High Trp exacerbated disease in TC mice while low Trp was protective. Expression of IDO1, the enzyme producing Kyn from Trp, was similar between TC and B6 mice, and its inhibition by 1MT did not change disease outcomes with and without dietary Trp variations. To identify the mechanism by which Trp plays a role in this process, we analyzed CD4 T cell phenotypes. Regulatory T cell (Treg) functional markers were altered by dietary Trp. Further, Tregs from TC mice consuming high Trp lost their suppressive capacity in vitro, whereas Tregs from TC mice on low Trp were as suppressive as that of B6 controls. Additionally, increasing Trp concentrations affected B6 and TC T cell polarization in vitro differently. A high Trp concentration increased the percentage of IFNg+ and FoxP3+ CD4+ T cells from B6 and TC mice under Th1 and Treg polarizing conditions, respectively. On the other hand, B6 Treg polarization increased with a higher Kyn concentration while TC Treg polarization decreased. These findings suggest that Trp and some of its metabolites modulate lupus pathogenesis in TC mice potentially by altering T cell phenotypes. Thus, these data emphasize a novel pro-inflammatory role for Trp metabolism in lupus.
Supported by a grant from the NIH (RO1 AI143313) to LM.
NLRP3 inflammasome activation profile in CD4+ T and CD19+ B lymphocytes from HIV-infected patients
Authors: Leal Vinícius Nunes Cordeiro , Reis Edione Cristina , Fernandes Fernanda Pereira , Pontillo Alessandra 
Published: January 2023

Abstract

Background
HIV-1 triggers inflammasome activation in myeloid cells, through NLRP3, which contributes to the first line defense against infection. However, it was postulated that NLRP3 activation could be involved in chronic inflammation and immune exhaustion in HIV-infected patients. But whether its activation occurs only in myeloid cells or also in lymphocytes is not yet understood. Considering that NLRP3 inflammasome was recently described in CD4+ T and CD19+ B lymphocytes, we hypothesize that NLRP3 inflammasome could be activated also in lymphoid cells during chronic HIV infection.

Aim
To evaluate NLRP3 activation in peripheral blood lymphocytes from HIV-infected patients.

Methods
NLRP3 inflammasome activation was evaluated in Antirretroviral-treated HIV-infected patients and healthy donors (HD) peripheral blood lymphocytes by the meaning of caspase-1 cleavage, IL-1β and IL-18 production and NLRP3+ASC+ “specks” formation.

Results
CD19+ B lymphocytes present a constitutive activation of NLRP3 inflammasome. But, differently from myeloid cells, LPS and β-glucan induced a higher NLRP3+ASC+ “specks” formation, caspase-1 activation and IL-1β production in B lymphocytes from HIV-infected patients compared to HD, as well as CpG induced a higher IgM production in a NLRP3-dependent way. Differently from CD19+ B lymphocytes, CD4+ T lymphocytes from HIV-infected patients present a NLRP3-independent activation of caspase-1 and IL-1β production, which was amplified by αCD3-αCD28 stimulation.

Conclusions
Our findings suggest that inflammasome is more activated in lymphocytes from HIV-infected patients in a cell and receptor specific manner, which could contribute to disease outcome during chronic infection.
Autocrine prostaglandin feedback determines the kinetics of bacterial type I interferon induction by restricting endosomal TLR4/TRIF complex assembly
Authors: Perkins Darren , Richard Katharina , Hansen anne-marie , Koller Beverly , Vogel Stefanie 
Published: January 2023

Abstract
TLR4 is unique in its capacity to initiate two qualitatively distinct transcriptional programs from two cellular locations. Cell surface TLR4/MyD88 complexes drive pro-inflammatory cytokine transcription through NF-κB, while endosomal TLR4/TRIF complexes activate IRF3 and a type I interferon response. Feedback circuits to limit signals from both locations are necessary to balance the inflammatory response to Gram negative bacteria, yet how endosomal TLR4/TRIF signals are terminated has remained an open question. We find that activation of TLR4 triggers rapid prostaglandin PGE2 production, necessary to limit the kinetics of endosomal TRIF, but not MyD88, signaling. Mechanistically, autocrine PGE2 activates the specific EP4 receptor to inhibit small GTPase mediated TLR4 trafficking to endosomes and to accelerate autophagic degradation of active TLR4/TRIF complexes. Inhibition of EP4 receptor function does not impair cell surface MyD88 signals, but leads to hyper TRIF dependent type I interferon production in response to bacterial LPS or to macrophage infection by live Gram negative pathogens.
NOD2 suppresses chronic intestinal inflammation through dampening TLR4 signaling
Authors: Khan Shahanshah , Zaki Hasan 
Published: January 2023

Abstract
The cytosolic NOD-like receptor (NLR) family protein NOD2 activates NF-kB and MAPK pathways in response to MDP. 15–20% of inflammatory bowel disease (IBD) patients carry mutations in NOD2. However, the mechanism of NOD2-mediated suppression of colitis is poorly understood. We recently showed that Nod2−/− mice are highly susceptible to chemical-induced acute colitis. Further, we observed that NOD2 suppresses NF-kB and MAPK pathways in LPS stimulated macrophages. However, it is not known whether such as a crosstalk between NOD2 and TLR4, sensor for LPS, occurs during chronic inflammation. We, therefore, primed wild-type and Nod2−/− macrophages with LPS or other TLR ligands overnight and then re-stimulated with LPS. Interestingly, we observed increased activation of NF-kB and MAPK pathways as well as higher expression of inflammatory molecules in primed Nod2−/− macrophages compared to wild-type. Increased inflammatory response in Nod2−/− macrophages was accompanied by reduced expression of IRF4, a negative regulator of NF-kB and MAPK pathways. To observe in vivo relevance of NOD2-mediated suppression of inflammatory responses, we crossed Nod2−/− mice with Il10−/− mice and induce colitis in them with piroxicam fortified diet. Mice double deficient in Nod2 and Il10 showed increased body weight loss and histopathological changes compared to Il10−/− mice. Higher colitis susceptibility of Nod2−/−Il10−/− mice was associated with increased activation of NF-kB and MAPK pathways and reduced expression of IRF4. These data, therefore, suggest that NOD2-mediated protection against colitis involves suppression of TLR4 downstream inflammatory signaling pathways via induction of IRF4.
Mitochondrial Calcium Signaling Facilitates Bacterial Survival by Restraining LC3-associated Phagocytosis
Authors: Wen Haitao , Li Tianliang , Li Xinghui , Lei Yu , Green Douglas R 
Published: January 2023

Abstract
Mitochondria in eukaryotic cells are believed to have originated from proteobacteria through endosymbiosis 2.5 billion years ago. Accumulating evidence suggests essential roles of mitochondria in host defense response against invading pathogens. Whether intracellular bacteria can hijack mitochondria to promote their survival remains elusive. Here, we demonstrate a previously unappreciated pro-survival strategy employed by intracellular bacteria Listeria monocytogenesthat involves the suppression of LC3-associated phagocytosis (LAP) by mitochondrial Ca2+ signaling. Invasion of macrophages by L. monocytogenes caused a robust mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU), leading to elevated acetyl-coenzyme A (acetyl-CoA) production via the pyruvate dehydrogenase (PDH). Acetylation of LAP effector Rubicon with the use of acetyl-CoA antagonized LAP formation. Genetic ablation of Mcuimproved bacterial killing due to elevated LAP formation. Our study indicates that modulation of mitochondrial Ca2+ signaling is a beneficial strategy for bacterial survival and highlights the importance of mitochondrial metabolism in host-microbial interaction.
Mechanistic investigations of Granzyme A-mediated TB protective effects
Authors: Rasi Valerio , Xia Mei , Wood David , Eickhoff Christopher , Hoft Daniel F 
Published: January 2023

Abstract
One fourth of the world population is infected with Mycobacterium tuberculosis (Mtb). Currently, BCG strains are the only vaccines available to protect against tuberculosis (TB). Our lab has identified γδ T cells that secrete Granzyme A (GzmA) with TB protective effects. GzmA when released by TB-specific γδ T cells has been shown to inhibit the intracellular replication of the pathogen. To elucidate the mechanism(s) involved in this inhibition, the lab has purified human GzmA. We have proven that Granzyme A’s intact active site is necessary to inhibit the intracellular replication of mycobacteria. The substitution of serine to alanine in the active site rendered the protein unable to control the mycobacterial infection as measured by mycobacterial growth inhibition assays, and the measurement of the pro-inflammatory marker TNF. Conversely, the effects of highly pure and active GzmA on mycobacterial replication inside human macrophages have been investigated using systems biology. A 2D-DIGE proteomic approach using adherent human monocytes has been performed to identify the pathways stimulated by GzmA involved in control of mycobacterial replication. Our analysis indicates that ER-stress responses (HSPA5, HSP90B1, P4HB, PDIA3) and purinergic channel receptor activation (ATP5B/C1/D/H/O) may be important for GzmA-mediated intracellular mycobacterial inhibition. Modulation of key proteins in these pathways are currently being targeted by pharmaceutical intervention and gene alteration to test the effects on GzmA-mediated inhibitory effects. Confirmation that these pathways are involved in pathogen clearance will lead to the development of novel host-directed therapies for control of Mtb infection.
A naturally-occurring mutation in IL-17F reveals a protective role for the IL-17AF heterodimer in oropharyngeal candidiasis (OPC)
Authors: Zhou Chunsheng , Aggor Felix E.Y. , Monin Leticia A , Gordon Rachael A , Edwards Tara N , Kaplan Daniel H , Shlomchik Mark J , Gingras Sebastien , Gaffen Sarah L 
Published: January 2023

Abstract
IL-17A is the original member of the IL-17 family of cytokines. Among the IL-17 family, IL-17F shares the most homology with IL-17A at the amino acid level. IL-17A and IL-17F exist as homodimers and also form a heterodimer (IL-17AF). All of these cytokine dimers signal through the same IL-17RA:IL-17RC receptor complex, but the ligands exhibit different signaling strengths (IL-17A &gt; IL-17AF &gt; IL-17F). We previously showed that IL-17 signaling is critical for immunity against oropharyngeal candidiasis (OPC), an opportunistic infection of the oral mucosa caused by the commensal fungus C. albicans. Mice lacking IL-17RA, IL-17RC, or the adaptor ACT1 all have higher oral fungal burdens than wild type (WT) following oral infection with C. albicans. IL-17A deficient mice are also mildly susceptible to C. albicans oral infection, but blockade of IL-17F does not cause disease susceptibility. Furthermore, double blockade of IL-17A and IL-17F during OPC reveals a cooperative antifungal activity of IL-17A and IL-17F. However, the role of the IL-17AF heterodimer still remains poorly understood. Here, we took advantage of a dominant-negative mutation (IL-17F.S65L) that was previously identified in chronic mucocutaneous candidiasis disease (CMCD) patients. This mutation blocks the signals of IL-17F and IL-17AF but not IL-17A. Using CRISPR/Cas9 technology, we created mice with the analogous IL-17F S65L mutation. These IL-17FS65L/S65L mice showed a similar degree of susceptibility as IL-17A−/− mice though less than IL-17RA−/− mice upon C. albicans oral infection. This result suggests that IL-17AF contributes to protection against OPC.
Serine phosphorylation of CREB-binding protein (CBP) is critical to intestinal homeostasis but not CD4 T cell differentiation
Authors: Miaw Shi-Chuen , Lin Yi-Ting , Hsu Yu-Hua , Liu Chi , Shun Chia-Tung , Chen Ching-Chow 
Published: January 2023

Abstract
CREB-binding protein (CBP) is a transcriptional coactivator involved in the regulation of DNA accessibility to transcription factors. Phosphorylation of human CBP by IKKα at Ser1382/1386 plays a critical role in the regulation of cell fate by suppressing p53-mediated gene expression. Therefore, we evaluated whether impaired serine phosphorylation of CBP is involved in the pathogenesis of disease. We generated mutated serine 1383/1387 to alanine knock-in mice (AA mice) to study whether they exhibit any phenotype alteration. AA mice showed an IBD-like phenotype with softer, looser and hemoccult stools and shorter colon length compared to the wild type mice. Increased p53 accompanied with apoptosis in colonic tissues of AA mice was demonstrated by IHC and TUNEL staining. In addition, male AA mice were more vulnerable to DSS-induced colitis with severe crypt loss and epithelial disruption. Elevated immune cells in mesenteric lymph nodes are more prominent in AA mice with infiltration of neutrophil and macrophage. However, the differentiation of CD4+ T cells was not affected with Cbp mutation (AA) ex vivo. Taken together, deficiency of NF-kB signaling in AA mice did not affect immune cells but modulated apoptosis of IECs. Our findings suggested that serine phosphorylation of CBP by IKKα might be a critical regulator to maintain intestinal homeostasis.
Transcriptomic approaches elucidate novel aspects of the host immune response to candidemia
Authors: Steinbrink Julie Marie , Myers Rachel , Johnson Melissa D. , Alexander Barbara D. , McClain Micah T. 
Published: January 2023

Abstract

Objective
Examination of the human transcriptome in circulating leukocytes during invasive candidiasis can provide an innovative approach to defining immunologic mechanisms driving the host response to this deadly infection.

Methods
RNA sequencing was performed on peripheral blood samples from 50 hospitalized patients with blood culture positive invasive candidiasis, along with 30 control subjects. Generalized linear hypothesis testing and weighted gene co-expression network analysis (WGCNA) were used to define biological networks contributing to the host response to Candida infection.

Results
1,748 genes were differentially upregulated and 2,149 genes downregulated in the presence of candidemia compared to matched controls. These genes reflected many canonical antifungal immune response pathways including phagocytosis, neutrophil activation, type I interferon responses, and T cell signaling. However, the data also demonstrated activation of some less well described antifungal immune mechanisms, including B cell activation, upregulation of humoral immune response pathways, and a profound alteration in the host regulation of heme synthesis and iron metabolism. While iron is known to be critical for fungal pathogens such as Candida in vitro, this analysis offers evidence that the human host manipulates this system as a part of the overall response to fungal infection.

Conclusion
Analysis of the transcriptome in circulating white blood cells of infected human subjects offers unique and novel insight into the complex immunologic response to invasive candidiasis.
Vaccine elicited ASGM1+ CD8+ T cells are essential for protective immunity against Toxoplasma gondii infection
Authors: Gigley Jason P. , Ivanova Daria L , Denton Stephen 
Published: January 2023

Abstract
The importance of enriched asialylated sphingolipid GM1 (ASGM1) in CD8+ T cell dependent protective immunity against T. gondii infection is unknown. Using a vaccine challenge model of T. gondii infection, we observed treatment of animals with anti-ASGM1 resulted in 100% death and greater parasite burden at the site of infection. Upon further dissection of this phenotype, we found that anti-ASGM1 treatment depleted not only NK cells but also T cells in vaccinated mice. While both CD8+ and CD4+ T cells were affected, CD8+ T cells were more susceptible to the anti-ASGM1 treatment. ASGM1 on the surface of the T cells was expressed on a higher percentage of CD8+ T cells than CD4+ T cells. ASGM1 was highly enriched on the surface of memory CD8+ T cells (Tem and Tcm). However, Tem were more susceptible to anti-ASGM1 treatment. Anti-ASGM1 treatment during rechallenge resulted in greater depletion of activated CD8+ IFNγ+, Granzyme B+, Tem and Tef than Tcm cells. In addition, anti-ASGM1 depleted IFNγ+ CD4+ T cells. Recombinant IFNγ supplementation prolonged the survival of anti-ASGM1 treated mice, demonstrating that this antibody eliminated the protective T. gondii specific IFNγ-producing T cells important for control of the parasite. This study demonstrates that ASGM1 is enriched on effector T cells during T. gondii infection and the potential importance of changes in sialylation in lipid rafts for T cell activation during T. gondii infection.
Immunity to Invasive Infection by Intestinal Commensal Microbes
Authors: Shao Tzu-Yu , Ang W.X. Gladys , Huang Felicia Scaggs , Haslam David , Way Sing Sing 
Published: January 2023

Abstract
Commensal microbes that colonize the intestine are an important cause of invasive infection. However, how colonization of individuals impacts their susceptibility to invasive infection remains undefined. This knowledge gap reflects technical roadblocks in models of long-term commensal colonization by microbes that can also cause invasive infection, and conceptual appreciation for systemic antigen-specific immune modulation primed by commensals. To address this knowledge gap, a model of intestinal colonization with the human commensal and pathogenic fungi, Candida albicans was developed. We show C. albicans intestinal colonization protects against subsequent invasive C. albicans infection. These benefits require tonic stimulation since protection is eliminated in mice eradicated of commensal fungi. Protection against invasive infection parallels the systemic expansion of C. albicans-specific RORγt+ Th17 cells and enhanced IL-17 responsiveness by circulating neutrophils. Reciprocally, the protective benefits of intestinal colonization are overturned by depletion of CD4+ T cells or Ly6G+ neutrophils, or IL-17 neutralization. These results highlight a new facet in the symbiotic relationship between host and microbe in mucosal tissues
Streptococcus pneumoniae coinfection dictates susceptibility to oral Listeria monocytogenes through suppressive Natural Killer (NK) cell activity
Authors: Bortell Nikki , Lenz Laurel L 
Published: January 2023

Abstract
Coinfection with viral and bacterial pathogens is a major health concern and results in significant morbidity and mortality. Recent research has aimed to understand the complex interplay between multiple pathogens and the immune response during viral:bacterial coinfections. However, studies using bacterial-bacterial coinfections are lacking. Streptococcus pneumoniae (Spn) and Listeria monocytogenes (Lm) are both bacterial pathogens that are capable of causing severe infections in young, elderly, and immunocompromised populations. Here we show that coinfection with intratracheal (IT) Spn increases susceptibility of typically resistant mice to oral Lm infection. On day 3 post infection (p.i.), the presence of Spn increased oral Lm burdens in the spleen, liver, and lungs of coinfected C57/BL6 mice. In addition, while the anti-inflammatory cytokine Interleukin-10 (IL-10) is limited during oral Lm infection, Spn infection induced the production of IL-10 from Natural Killer (NK) cells, and that this correlated with an increase in Lm burdens during coinfection. To assess the importance of NK cell IL-10 in the absence of an ongoing infection, mice were inoculated with a recombinant Lm polypeptide, designated L1S, which stimulates NK cell IL-10 production. In the presence of L1S, the induction of NK cell IL-10 similarly increased systemic burdens of oral Lm. Lastly, BMMs stimulated with rIL-10 and infected with Lm have increased bacterial burdens when compared to untreated but infected controls. Overall, our data show that coinfection impairs host protection through the induction of NK cell production of IL-10 and dictates susceptibility to oral Lm infection.
Male microbiota-associated metabolites restore macrophage apoptotic cell clearance function in female lupus-prone mice
Authors: Harder James W , Ma Jing , Alard Pascale , Zhang Xiang , Yuan Fang , Kosiewicz Michele M 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) has been linked to microbiota dysbiosis. We have previously shown that lupus-prone female and non-lupus-prone male BWF1 mice have significantly different gut microbiota compositions and metabolomic profiles. Transferring microbiota from male into female BWF1 mice suppresses disease. This protective phenotype is androgen dependent, as microbiota from castrated male BWF1 mice (i.e., lupus-prone) fails to protect against disease. This protection could be mediated via differential metabolite production. Metabolomic analyses of female, and castrated and intact male BWF1 feces identified &gt;100 differentially produced metabolites including phytol and phytanic acid, byproducts of chlorophyll degradation that can act as RXR agonists. These metabolites were produced at higher levels in non-lupus-prone male mice than in lupus-prone female and castrated male mice. Their presence in male BWF1 mice correlated with higher levels of a bacterial family, Lachnospiraceae, which contains species that express chlorophyll-degrading enzymes. Feeding phytanic acid to female mice delayed kidney disease onset. This male microbiota metabolite may confer protection, in part, by improving splenic macrophage phagocytosis of apoptotic cells. Macrophage clearance of apoptotic debris (efferocytosis) is defective in SLE patients, and this is thought to drive disease progression. We found lupus-prone female and castrated male BWF1 mice also have defective macrophage efferocytosis and this defect could be corrected in vitro by phytanic acid treatment. Taken together, our data indicate that BWF1 male microbiota produce metabolites that enhance macrophage efferocytosis and protect against disease.