bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic stress-induced lymphocyte reduction in a nitric oxide dependent manner
Authors: Yin Deling , Yao Bifeng , Caudle Yi 
Published: January 2023

Abstract
Psychological and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Recent evidence demonstrated that nitric oxide (NO) modulates cell-mediated immune responses. Inducible nitric oxide synthase (iNOS) plays a major role in immune regulation. To investigate the role of NO in the chronic stress-induced lymphocyte depletion, we utilized a selective inhibitor of iNOS activity, NG-monomethyl-L-arginine (L-NMMA), which has been widely used, including from our laboratory and others, to evaluate the role of NO in immune responses both in vitro and in vivo. Here we demonstrate that administration of L-NMMA prevents chronic stress-induced lymphocyte reduction. Moreover, inhibition of iNOS prevents the alterations of cleaved-caspase-1 and p-JNK following chronic stress. These results reveal that chronic stress-induced lymphocyte reduction in a NO dependent manner.
Sphingosine-1-phosphate lyase inhibition exacerbates DSS-induced colitis via promoting the disruption of epithelial barrier
Authors: Lundborg Luke R , Guzman Mauricio , Tyler Christopher J , Yeasmin Shaila , Rivera-Nieves Jesus 
Published: January 2023

Abstract
S1P is a bioactive sphingolipid that participates as a critical regulator of many physiological processes, mainly in lymphocyte egress from lymphoid tissue, mediated by S1P gradients through the activity of S1P lyase (SPL). Inhibition of both S1P-specific receptors and Lyase activity has been shown to improve inflammatory conditions during Crohn’s-like ileitis. In contrast to this, initial observations show acute DSS-induced colitis was aggravated by SPL inhibition. Here we investigate whether the inhibition of Lyase in the intestinal epithelium is the cause of the exacerbation of colitis.
To induce global or epithelial cell specific SPL deletion, Gt(rosa)-cre or Villin-cre Sgpl1 transgenic mice were administered with tamoxifen (80 mg/kg) by oral gavage for 5 consecutive days. Then, mice were treated with DSS (2.5%) in drinking water for 7 days. Clinical features and histological scores were recorded. Permeability assays were performed to evaluate integrity of the intestinal epithelium with fluorescein isothiocyanate (FITC)-dextran 4 kDa.
Significant differences in the histopathological features (inflammation and injury) in colon were observed between Gt(rosa)Cre+/−/SPL−/− or VillinCre+/−/SPL−/− mice compared to their respective controls (without tamoxifen treatment) (n&gt;10, p&lt;0.001). In addition, these animals presented higher levels of epithelial permeability since the concentration of serum (FITC)-dextran was higher than their respective controls (n&gt;10, p&lt;0.001).
In conclusion, in the acute model of DSS-induced colitis the presence of S1P in the intestinal epithelium exacerbates inflammatory conditions, demonstrating that there could be differences in the mechanisms with chronic models of IBD.
Evolutionary conserved sequence patterns that determine functional specialization of metazoan TIR domains
Authors: Toshchakov Vladimir Y , Neuwald Andrew F 
Published: January 2023

Abstract
Toll-Interleukin-1R Resistance (TIR) domains represent a type of protein fold ubiquitously present in all forms of cellular life. The TIR domains are present in functionally and architecturally diverse proteins. A large subgroup of metazoan TIRs is involved in signaling that initiate and regulate the immune response elicited by infection or damaged self. This study applies Bayesian partitioning with pattern selection (BPPS) to classify the TIR domains based on sequence patterns that best distinguish individual groups. The algorithm was applied to &gt;26000 phylogenetically diverse TIR domain sequences selected for non-redundancy from publicly available protein sequence banks. The analysis has revealed 10 metazoan groups, nine of which comprise either orthologous proteins or a protein family. Available structural data suggest that the identified groups may be uniquely characterized by regional backbone fold variants, which can be associated with a corresponding group-specific sequence motif. In addition to these fold-defining motifs, the BPPS also identified groups of surface-exposed residues conserved in TIRAP and MyD88 orthologs, which correspond to predicted sites that mediate the signal-dependent TIR oligomerization. This analysis also has clarified the functional significance of locally conserved sequence motifs, named Box 2 and Box 3, as each of these motifs is a part of a larger block of conserved, intramolecularly interacting residues. Finally, this study has identified the sequence patterns that differentiate TIRs of different classes, such TIRs of TLRs, from TIRs of the IL-1R family, or their adapter proteins, and highlights the differences between metazoan, plant, and bacterial TIRs.
Deficiency of the methylcytosine dioxygenase Tet2 enhances CD4 T cell memory generation
Authors: Baessler Andrew Stephen , Novis Camille Leite , Sircy Linda , Thiede Kendall , Newman Jordan , Hale J Scott 
Published: January 2023

Abstract
In response to viral infection, antigen-specific CD4 T cells differentiate into Th1 and T follicular helper (Tfh) cell subsets that acquire distinct DNA demethylation changes which act to enforce their lineage commitment and functions. Following viral clearance, the populations of Th1 and Tfh cells contract and form distinct memory populations that maintain their specific methylation programming. Previously, we found that deficiency of Tet2, an oxygenase that mediates CpG demethylation, skews the balance of Th1 and Tfh cells at 7 days post infection leading to the formation of significantly more germinal center (GC) Tfh cells. Here we examined whether Tet2 impacts CD4 T cell memory formation and the recall of lineage specific functions upon re-challenge. At days 15, 30, and 45 post infection with lymphocytic choriomeningitis virus (LCMV) there was a greater frequency of Tet2 deficient cells positive for memory markers in the blood when compared to WT cells. To assess the recall ability of Tet2 deficient memory CD4 T cells, Tet2KO and WT memory cells were purified from spleens of recipient mice at 90 days post-infection and equivalent numbers of WT and Tet2KO cells were then re-transferred into naive C57BL6/J recipient mice followed by LCMV infection. At 7 days post re-challenge, we observed a greater secondary expansion of Tet2KO cells compared to WT. Tet2KO memory cells also retained the ability to generate higher frequencies of GC Tfh cells in response to re-challenge. Ongoing work will identify whether Tet2 deficient memory Tfh cells can provide enhanced help for B cells during secondary infection and improve the antibody response. Taken together, these data suggest that Tet2 can act to restrict memory differentiation in CD4 T cells.
FcγRIIb signaling by germinal B cells following Borrelia burgdorferi infection
Authors: Tran Vuvi G. , Olsen Kimberly , Baumgarth Nicole 
Published: January 2023

Abstract
Tick-borne infection with Borrelia burgdorferi (Bb) causes Lyme disease in humans and persistent infection of mice, its natural reservoir host. IgG responses critically control Bb tissue burden but do not clear the infection. We previously showed induction of germinal centers (GC) in mice after Bb infection followed by their rapid collapse within 30 days, despite ongoing infection. This was consistent with the lack of long-lived and high-affinity antibody responses in these mice. Our recent experiments showed that serum IgG from Bb-infected mice bound more strongly to the inhibitory FcγRIIb on B cells, as well as recombinant FcγRIIb than those from uninfected mice, as assessed by flow cytometry and ELISA, respectively. The data prompted us to investigate whether the interaction between Bb infection-induced IgG and FcγRIIb results in the suppression of GC. Indeed, Bb-infected mice lacking FcγRIIb signaling (FcγRIIb−/−) maintained GC B cells and CD4 TFH for at least 90 days after infection, and GC B cells showed reduced apoptosis, as assessed by staining for Annexin V. Furthermore, transfer of serum from Bb-infected wild type but not AID−/−sIgM−/− mice lacking IgG, IgM and from non-infected wild type mice, into 14-day Bb-infected wild type mice resulted in reduced GC at day 21. However, despite GC maintenance and the resulting increases in Bb-specific, T cell-dependent IgG responses, enhanced antibody affinity maturation was not observed and Bb tissue burdens of FcγRIIb−/− and control mice were comparable. The data show the importance for FcγRIIb in the regulation of GC during Bb infection, while additional mechanisms currently under investigation seem to underlie their functional deficits, enabling the establishment of Bb persistence.
Experimental evolution identifies an IL-1α dependent host response against Aspergillus fumigatus regulated by the fungal SakA-HOG1 pathway
Authors: Mitchell Marina E Kirkland , Caffrey-Carr Alayna , Stannard McKenzie , Kowalski Caitlin H , Mould Dallas L , Temple Rachel , Cramer Robert A , Obar Joshua J 
Published: January 2023

Abstract
Fungal infections are emerging global health threats, costing the United States $7.2 billion annually in health care costs, with Aspergillus fumigatus accounting for $1.2 billion of those costs, the highest for a single fungal species and tied with Candida spp. infections. A. fumigatus has an inexcusably high mortality rate of 40–90%, disproportionately affecting those with compromised immune systems or impaired pulmonary clearance disorders such as CF and COPD. It is critical that the mechanisms behind A. fumigatus pathogenesis is elucidated. In this study, we explore A. fumigatus divergent pathologies amongst multiple strains which induce distinctly different host immune responses based on germination rate. In vivo and in vitro germination of fungal conidia segregate into two distinct groups of “fast” germinators, which elicit an IL-1α dependent host response, and “slow” germinators, which invoke a type I and III interferon dominant response. Here we use experimental evolution to find that the SakA-HOG1 stress response pathway regulates fungal growth in the lung, and serves as a switch for the induction of IL-1α dominant defense. This study demonstrates a need for revision of clinical protocols for treatment of A. fumigatus based on the strain and type of inflammation on-going in patients with A. fumigatus infections as health care standards move toward individualized patient care and antifungal stewardship.
B-Cell Responses in the Lung during Acute Pneumocystis Infection
Authors: Noell Kristin M , Kolls Jay K 
Published: January 2023

Abstract
Pneumocystis jiroveci is an opportunistic fungal organism that causes Pneumocystis pneumonia (PCP) in humans with HIV-AIDS or other immunocompromised individuals. Pneumocystis can replicate in the alveoli where it disrupts gas exchange and promotes inflammation in the lung. Although Pneumocystis association is with T cell immunodeficiency, recent evidence shows that B cells play a key role as APCs in the lung to prime fungal T cell responses. We hypothesized that B cells are recruited and undergo tissue specific CSR during PCP infection and that these cells are critical to the priming of PCP specific T cells. To test this hypothesis we inoculated 4 to 6wk old male and female C57Bl/6 mice with Pneumocystis murina by oral pharyngeal aspiration. Flow cytometry analysis revealed that IgG+ and IgA+ B cells were at higher abundance in infected lung tissue at days 14 and 24. Single cell BCR-sequencing revealed an increase in class switched B cell clonotypes (both IgG and IgA) at day 14 compared to spleen. Our lab has previously shown that germ encoded IgM has specificity to PC antigens. To understand the role of germline encoded IgM and class-switched antibody responses, 4 to 6 wk old Aicda, Ighm −/− or C57Bl/6 mice were inoculated with P. murina for 14 days. We found at day 14 that fungal burden loads were slightly higher in the Aicda,Ighm −/− mice than C57Bl/6 mice, but H&E staining showed that Aicda,Ighm −/− mice possessed high levels of immunopathology. Bulk RNA sequencing revealed a lack of Type II immune responses, which have been shown to control Pneumocystis lung burden. Our data suggests that both germline encoded IgM and class switched antibody responses are critical in controlling pneumocystis infection.
Leishmania donovani modulates host macrophage mitochondrial metabolism, integrity, and function
Authors: Ospina Hamlet Acevedo , Descoteaux Albert 
Published: January 2023

Abstract
To colonize macrophages, Leishmania promastigotes employ virulence factors, including lipophosphoglycan (LPG), to impair host cell processes. Whereas previous studies revealed that Leishmania alters signaling axes that regulate mitochondrial function, scarce attention has been paid to the characterization of host cell mitochondrial metabolism during Leishmania infection and to the effectors involved therein. In this study, we addressed the hypothesis that L. donovani modulates host cell mitochondrial metabolism and function in an LPG-dependent manner. To this end, we infected bone-marrow-derived macrophages with metacyclic promastigotes and we assessed the expression kinetics of host cell nuclear and mitochondrial genes that control mitochondrial biogenesis, and we measured host mitochondrial metabolic fluxes. We found that host cell nuclear and mitochondrial genes that control mitochondrial biogenesis are upregulated in an LPG-dependent manner. We also observed that IRG-1, the enzyme that synthesizes itaconate, is highly induced during infection in an LPG-dependent manner and this response was independent of endosomal TLRs. We next found that L. donovani induces a doubling in the mtDNA/nDNA ratio in an endosomal TLRs and IFNAR-dependent manner, suggesting that L. donovani promotes host mitochondrial biogenesis in an inflammatory context. Metabolic flux analyzes showed that the OCR/ECAR ratio is modulated multiple times during infection, independently of β-oxidation, suggesing that L. donovani promastigotes induce the Warburg effect to promote energetic metabolic changes. Collectively, our data indicate that L. donovani alters host cell mitochondrial dynamics during the colonization process.
Defining the role of CD8 T cell subsets in tuberculosis in non-human primates
Authors: Winchell Caylin G , Maiello Pauline , Nyquist Sarah , Shalek Alex , Lin Philana , Flynn JoAnne L 
Published: January 2023

Abstract
Tuberculosis (TB) is the number one cause of death by a single infectious agent with no protective vaccine available. Challenges in vaccine development are partially attributed to a deficiency in knowledge regarding specific immune cells’ contribution to protection. CD8 T cells comprise ~30–40% of T cells in the lung granuloma, an organized collection of immune cells that is a hallmark of Mycobacterium tuberculosis (Mtb) infection. However, few studies have explored the diversity, function and contribution to protection of CD8 subsets during TB. We investigated the roles of conventional CD8αβ T cells and unconventional CD8αα T cells during early Mtb infection. Cynomolgus macaques were CD8-depleted using anti-CD8α or anti-CD8β antibodies prior to and during Mtb infection and necropsied at 6 weeks post-infection. CD8α depleted NHPs (CD8αα and CD8αβ depletion) had higher bacterial burdens, worse pathology and overall poorer disease outcome compared to IgG controls, while CD8β depleted (CD8αβ only depletion) displayed an intermediate phenotype. This provides the first evidence for an important early role for non-conventional CD8 T cells in TB. Using spectral flow cytometry we identified multiple CD8 subsets and assessed their functions in granulomas for the first time in NHPs. After CD8α depletion, the repertoire of CD8 subsets dramatically changed in granulomas. This was associated with functional alterations in other immune cell populations which we validated and expanded upon using single-cell RNA sequencing. These studies provide a functional immune landscape of early events in Mtb granulomas as well as the effects of CD8 depletion, shedding light on the protective potential of CD8 T cell subsets during primary Mtb infection.
Vancomycin intermediate strains of Staphylococcus aureus have dampened induction of type I interferon production
Authors: Peignier Adeline Carole Marine , Parker Dane 
Published: January 2023

Abstract
Studies by our group have shown that interferon (IFN) signaling contributes to pathogenesis of Staphylococcus aureus pneumonia and that different strains of S. aureus can activate type I IFN signaling via distinct receptors, such as TLR9 and NOD2, at various amplitudes. In this study we investigated the capacity of a wide range of S. aureus strains to induce both type I & III IFN. We screened 78 S. aureus strains from various clinical scenarios for their ability to induce IFN-β and IFN-λ in bone marrow-derived dendritic cells (BMDC) and found that both cytokines are differentially induced by various S. aureus strains independently of their isolation sites or methicillin resistance profiles. These induction patterns persisted over time and type I & III IFN differentially correlated with tumor necrosis factor α (TNF-α) production. Furthermore, vancomycin intermediate S. aureus (VISA) strains induced up to 45-fold less (P&lt;0.001) IFN-β than the current epidemic methicillin-resistant S. aureus strain USA300 and displayed increased in vitro survival (up to 9-fold) after 4-hour exposure to BMDC. Further investigation of one VISA strain, HIP07930, showed decreased autolysis and increased resistance to lysostaphin compared to USA300, consistent with its reduction in IFN β induction. Interestingly, this strain also displayed decreased in vivo virulence compared to USA300 in a murine acute pneumonia model of infection (4.9-fold and 54.5-fold decrease in colony forming units in bronchoalveolar lavage fluid and lung homogenates, respectively, 24 hours post infection). Overall, this study demonstrates the heterogeneity of IFN induction by S. aureus and uncovered a unique property of VISA strains in their inability to induce type I IFN production.
Oral Probiotic Lactobacillus kefiri prevents Lipopolysaccharide-induced preterm birth, reduces inflammation and modulates the vaginal microbiota inpregnant mice
Authors: VENTIMIGLIA MARIA SILVIA , ALBAN MARLON IRWIN POZO , Valeff Natalin Jimena , Schander JULIETA , Quadrana Florencia , DE LOS ANGELES SERRADELL MARIA , Jensen Federico 
Published: January 2023

Abstract
Prevention and treatment of preterm birth (PTB) are an unresolved global challenge in obstetric care. Human PTB is defined as delivery prior to 37 weeks of gestation. It is known that inflammation is a contributing factor where an inflammatory cascade within the gestational tissues followed by a massive influx of leukocytes takes place. The efficacy of actual interventions are largely unsatisfactory. We have shown that treatment with probiotic Lactobacillus Kefiri (Lk) completely prevented PTB (100%) in a lipopolysaccharide (LPS)-induced PTB mice model. Given this, we sought to elucidate the mechanisms behind PB-Lk protective role in PTB induction.
C57BL/6 females were oral treated every 48h during a week with Lk or vehicle before being mated with BALB/c males and during pregnancy. Females were challenged with LPS on gd 16 (~3 days before expected term). Samples from gestational tissues were harvest 18 h after LPS. Leukocytes influx was evaluated by flow cytometry. Metalloproteinase-9 activity was measured by zymography. In addition, histological examination by light microscopy was performed. The impact on vaginal microbiota was evaluated by a qualitative analysis (PCR-DGGE).
Treatment with Lk, significantly lowered leucocytes influx induced by LPS as well as MMP-9 activity. Histological studies confirmed these findings. In placenta, Lk treatment ameliorated changes in micro and macrocirculation and DGGE profiles allowed differentiation of groups in two clusters, suggesting that Lk induced changes in the vaginal community composition. Our results demonstrate that Lk administration may have the potential to serve as a prophylactic therapy for inflammation-associated conditions during pregnancy, including PTB.
Gut microbial metabolites as therapeutics to treat of alcoholic liver disease
Authors: Jala Venkatakrishna R , Singh Rajbir , Chandrashekharappa Sandeep , Joshi-Barve Swathi , McClain Craig , Bodduluri Bodduluri , Vemula Praveen Kumar 
Published: January 2023

Abstract
Alcoholic liver disease (ALD) is resultant of excessive consumption of alcohol. ALD is the world’s third largest risk factor for diseases and disabilities and accounting for 5.9% of all deaths worldwide. ALD patients exhibit increased gut permeability, gut microbial dysbiosis, endotoxemia and hepatic steatosis. Recent studies, unequivocally demonstrated the importance of gut microbiota and their metabolites in regulating host pathophysiology. Urolithin A (UroA) is a gut microbial metabolite derived from dietary ellagic acid and ellagitannins containing foods. Previously, we showed that UroA act as an AhR agonist and activate AhR-Nrf2 pathways to induce tight junction proteins and enhance gut barrier function. In the current study, we tested the hypothesis that correcting gut barrier dysfunction, blocking inflammation and reducing hepatic steatosis simultaneously by UroA would provide better therapeutic options to treat ALD. Our studies suggested that UroA significantly induced expression of tight junction (TJ) proteins (Occludin, Cldn4 and ZO1) in AhR-Nrf2 dependent manner and protected from alcohol-induced downregulation of TJ proteins and reduced gut barrier leakage. Further, UroA attenuated ALD pathogenesis in both acute and chronic experimental mouse models by reducing alcohol induced barrier permeability, systemic endotoxin levels and inflammatory mediators. In these models, UroA treatment also significantly reduced alcohol induced liver ALT/AST levels, inflammatory mediators (TNF-α, IL-6, IL-1β) and triglyceride levels as well as prevented liver damage. In summary, these studies highlight that the mechanisms of microbial metabolite, UroA and its multi-pronged beneficial effects in attenuating ALD.