bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial exposure expands a Ly6C+ subpopulation of long lived naive CD8 T cells with a rapid effector function via type I intereferons
Authors: Jergovic Mladen , Nikolich-Zugich Janko 
Published: January 2023

Abstract
Previously we have described human ‘memory T cells with a naïve phenotype’ which were increased in human subjects recovering from acute West Nile Virus infection (Pulko et al., Nature Immunology, 2016). These cells had a naïve phenotype but exhibited some signs of basal activation and displayed a rapid effector function upon polyclonal stimulation. These findings in humans prompted us to investigate effects of bystander infections on naïve CD8 T cells in mice, and here we have utilized viral (West Nile Virus) and bacterial (Listeria monocytogenes) models but most importantly we investigated naïve T cells under non specific pathogen free (SPF) conditions in B6 mice cohoused with pet shop mice hosting a variety of infections. We describe a novel population of naïve CD8 T cells characterized by expression of a single memory marker Ly6C with similar properties to human ‘memory T cells with a naïve phenotype’. Under basal conditions Ly6C is expressed on ~20% on naïve T cells and is transiently up regulated during acute infection but only on CD5hi cells with higher affinity for self peptide-MHC I complexes. Under conditions of ‘non SPF microbiome’ this population is expanded long term and enriched in the lymph nodes. We show that Ly6C+ naïve CD8s are enriched in the lymph nodes and receive improved homeostatic signals from lymph node stromal cells which lead to upregulation of survival factors such as BCL-2 and extend the lifespan of Ly6C+ cells. Our mechanistic studies have identified type I interferons as the only inflammatory signal required for the induction of this population. However this effect is partially indirect as type I interferon induced expression of Ly6C on CD8 T cells is prevented by MHC I blockade.
STAT1 restrains peripheral naive CD8+ T cell responsiveness to homeostatic cytokines by regulating mTORC1 signaling
Authors: Kye Yoon-Chul , Yun Cheol-Heui , Cho Jae-Ho 
Published: January 2023

Abstract
Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, South Korea In a steady-state, naïve CD8+ T cells are kept to be quiescent in response to homeostatic cues such as self-ligands and cytokines while preserving a robust responsiveness to foreign antigens. Although such a steady-state quiescence involves multiple regulators, an exact nature of the regulators and underlying mechanisms are still incompletely understood. Here we showed that the signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of type I and II interferon receptor signaling, plays a cell-intrinsic role in regulating naïve CD8+ T cell responsiveness to tonic homeostatic cytokines. Thus, mice lacking STAT1 led to abnormalities in the composition and number of naïve and effector/memory phenotype among CD8+ T cells. The observed alterations were not due to dysregulation in thymic development but rather resulted from enhanced proliferative capacity of peripheral mature STAT1-deficient naïve CD8+ T cells in a cell-autonomous manner. In vitro analyses revealed that two key cytokines, IL-7 and type I interferon, serve as a major driver to induce abnormal proliferation of STAT1-deficient but not wild-type CD8+ T cells depending on a pathway that is sensitive to rapamycin, indicating a role of mTORC1 signaling. Based on these findings, we suggest that, under steady-state, naïve CD8+ T cells that are continuously exposed to homeostatic cytokines actively restrain their responsiveness to the “Goldilocks” levels – that is, not too strong to induce activation/proliferation and not too weak to lose a survival ability – presumably via blocking mTORC1 pathway, therefore maintaining a functional state of quiescence before encountering a cognate foreign antigen.
Candida albicans secrete a small cysteine-rich protein Sel1 to trigger TLR2/4-dependent inflammatory response during invasive infection
Authors: Xiao Hui , Wang Wenjuan , Deng Zihou , Li Tiantian , Wu Hongyu , Chen Jiangye 
Published: January 2023

Abstract
Despite being a commensal for healthy individuals, Candida albicans can rapidly switch to pathogenic mode featured with hyphal development, altered cell wall composition and secreted virulence factors, thereby causing mucosal or disseminated candidiasis in immunocompromised patients. The host relies on a diversity of pattern-recognition receptors, particularly Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) to sense invading fungal pathogens and launch immune defense mechanisms. However, the complex interplay between fungus and host innate immune system remains incompletely understood. Here we report that Candida albicans upregulate the expression of a small secreted cysteine-rich protein Sel1 upon encountering limited nitrogen and abundant serum, two hallmarks of human bloodstream, leading to marked proinflammatory response. Notably, Sel1 was able to trigger the activation of signaling pathways NF-kB and MAP kinases, leading to the expression of a myriad of proinflammatory cytokines and chemokines in macrophages and dendritic cells. Comprehensive genetic and biochemical analyses revealed that both TLR2 and TLR4 are required for the recognition of Sel1, and TLR2/4-deficient macrophages were blunted in response to Sel1 stimulation. Further, SEL1-deficient mutant of C. albicans was less efficient in eliciting immune response in vivo, thus causing severer morbidity and mortality in bloodstream infection model. Together, our results reveal a previous unsuspected mechanism underlying TLRs-mediated immune recognition of C. albicans, hence open a new avenue to tackle candida infection and inflammation.
Neonatal granulocytic myeloid-derived suppressor cells possess phagocytic properties during bacterial infection
Authors: Seman Brittany G. , Vance Jordan K. , Witt Michelle R. , Robinson Cory M. 
Published: January 2023

Abstract
Neonates exhibit high susceptibility to bacterial sepsis due to immature immunity in transition from the fetal-maternal environment. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive and more abundant in neonates than at older ages, suggesting a possible role for these cells in susceptibility to infection. MDSCs have been well characterized for their suppression of T cell activity in neonates. Further, although they are related to other myeloid-derived professional phagocytes, their direct response to bacteria during infection has not been rigorously examined. We aimed to thoroughly determine the phagocytic capacity of human MDSCs during bacterial infection. Nearly half of neonatal sepsis deaths in the U.S. are caused by Escherichia coli. Using CD66+ MDSCs isolated from human umbilical cord blood, we compared the ability of MDSCs to phagocytose E. coli to CD14+ monocytes using three approaches: flow cytometry, fluorescence microscopy, and bacterial recovery assays. We found that MDSCs internalize bacteria within acidic compartments in a dose-dependent manner. However, the rate of phagocytosis and killing by MDSCs is significantly reduced compared to monocytes, suggesting that MDSCs are less efficient at microbial uptake and elimination. Overall, we show that granulocytic MDSCs possess the ability to clear bacteria, although with reduced efficiency relative to monocytes. Work is ongoing to further characterize these mechanisms and understand how MDSCs exposed to bacteria interact with other immune cells to control host response during infection. This understanding of MDSC activity during bacterial infection may direct the use of novel therapies to improve neonatal immunity and disease outcome.
TLR4 abrogates Th1 immune response against L. infantum infection through IRF1 and IFN-β-dependent mechanism preventing immunopathology
Authors: Sacramento Laís Amorim , Benevides Luciana , Maruyama Sandra , Tavares Lucas , Fukutani Kiyoshi , Cunha Fernando , Almeida Roque , Silva João , Carregaro Vanessa 
Published: January 2023

Abstract
Toll-like receptors (TLRs) are thought to be among the most ancient pathogen recognition systems, and these receptors directly interact with Leishmania species during the initial sensing of these parasites and mount the subsequent adaptive immune response. Herein, we aimed to evaluate the role of TLR4 during visceral leishmaniasis (VL) induced by Leishmania infantum. Initially, we observed that tlr4 messenger RNA (mRNA) expression was detected only the later stage of infection in target organs of VL, suggesting that TLR4 contributes significantly during the chronic phases of the disease. We have shown that Tlr4-deficient mice harbor fewer parasites in the spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, correlating with the increased activation of dendritic cells (DCs). Transcription analysis demonstrated that IRF1 and IFN-β are downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-genetically deficient mice harbored fewer parasites in the target organs than wild-type mice due to the increased Th1 response. The absence of TLR4 or IFNAR increases the serum transaminase level of infected mice. In addition, IFN-β acts directly on Th1 cells to limit IFN-γ production, without affecting the cell proliferation. Importantly, TLR4 and type I IFN (IFN-I) were positively modulated in asymptomatic subjects compared to VL patients. Thus, the TLR4-IRF1 pathway culminates in IFN-β production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development.
Neutrophils transiently harbor Mycobacterium tuberculosis and represent a metabolically permissive niche for bacterial growth
Authors: Huang Lu , Russell David 
Published: January 2023

Abstract
Neutrophils are rapidly recruited to sites of mycobacterial infection, where they phagocytose bacilli. At the early stage of infection, Mycobacterium tuberculosis is predominantly present in neutrophils, which are also frequently infected in human TB. However, neutrophils are less well studied than other components of the host response to Mtb and much of the available data are conflicting. To better understand the role of neutrophils in tuberculosis, we focused on the fate of Mtb in neutrophils. We demonstrated that Mtb-infected neutrophils are short-lived and actively engulfed by two ontologically distinct lung macrophages, alveolar and interstitial macrophages in vivo. RNA-seq data also confirms the expression of efferocytosis-related genes in both types of macrophages. Importantly, Mtb remains viable in lung macrophages after being transported from neutrophils, implying a critical step for Mtb spreading between host phagocytes. Furthermore, neutrophils upregulate CD64 and reveal a more activated phenotype. Exploitation of reporter Mtb strains, we observed comparable replication status of Mtb in both CD64+ and CD64− neutrophils, indicating that Mtb replication is independent of the neutrophil activation state. Mechanistically, although CD64+ neutrophils are more glycolytically active than CD64− neutrophils, CD64+ neutrophils highly express CD36, and internalize greater amounts of fatty acid, LDL and oxLDL, the preferred nutrients for Mtb growth. In conclusion, our data support the hypothesis that neutrophils function as a transient carrier that delivers Mtb to macrophages. The metabolic state in neutrophils is distinct from macrophages yet still represents a hospitable environment supporting bacterial growth.
Ephrin B receptor tyrosine kinase ligands modulate the germinal center reaction and control humoral immune responses to malaria
Authors: Olatunde Adesola C , Mimche Patrice N , Seely Spencer O , Stewart Taryn P , Lamb Tracey J 
Published: January 2023

Abstract
Malaria remains a global health priority causing half a million deaths annually. Protective antibody responses that can control the Plasmodium parasites that cause malaria are an essential component of naturally acquired immunity and develop after years of continuous exposure to Plasmodium parasites. The protective humoral response is short-lived and tends to wane in the absence of parasite re-infections. The cellular and molecular mechanisms that prevent the development of long-lived humoral immunity against malaria remain poorly understood. Recently, ephrin B1, a ligand for the Eph B receptor tyrosine kinase subfamily, was shown to be involved in T follicular helper (Tfh) cell recruitment, retention and contact-dependent interaction with germinal center (GC) B cells, key processes in the production of efficacious antibody responses. We hypothesize that EphB/EphrinB signaling pathway is required for the development of Plasmodium humoral responses. Using a non-lethal P. yoelii XNL infection model, we observed an upregulation in the expression of Ephrin B on both GC B cell and Tfh cells at the peak of the infection in wild type mice. Selective deficiency of Ephrin B1/B2 on B cells (CD19cre+ Ephrin B1/B2fl/fl mice) led to lethality in some mice infected with an otherwise non-lethal P. yoelii XNL infection. On the other hand mice that lack the expression of Ephrin B1/B2 on T cells (CD4cre+ Eprhin B1/B2fl/fl mice) were able to control P. yoelii XNL infection. Our data show a requirement for Ephrin B1/B2 signaling on B cells for an effective contact-dependent interaction with Tfh cells and for optimal antibody responses during Plasmodium infection.
Characterization of a potential host-directed therapy against TB in non-human primates
Authors: Winchell Caylin G , Maiello Pauline A. , Flynn JoAnne L 
Published: January 2023

Abstract
An estimated 558,000 cases of drug-resistant tuberculosis (TB) occurred in 2017, emphasizing a need for new treatment strategies. We assessed a host-directed therapy (HDT) for TB using two FDA-approved drugs. Linezolid (LZD) is a potent antibiotic for antibiotic-resistant Gram-positive infections and is an effective treatment for TB. However, lengthy antibiotic regiments (&gt;4 weeks) may lead to LZD-associated host toxicities, most commonly bone marrow (BM) suppression. LZD toxicities are mediated by IL-1, a pathway important for early immunity during Mtb infection that later contributes to pathological TB disease. We hypothesized LZD efficacy could be enhanced by addition of Anakinra, a recombinant IL-1R antagonist (rIL-1RA), by reducing BM toxicity and TB-associated inflammation. We tested this HDT in a non-human primate (NHP) model which emulates the spectrum of human TB, combined with PET/CT to monitor disease progression. NHPs with active TB were treated with LZD or LZD+rIL-1RA and tracked by PET/CT to monitor granuloma formation and inflammation. Analysis of BM erythroid progenitor cells determined little evidence of BM suppression associated with short-term high dose LZD. However, we observed sterilization of the majority of granulomas and a trend of enhanced bacterial clearance with rIL-1RA. Addition of rIL-1RA decreased granuloma inflammation (measured by PET/CT) compared to LZD alone, however few differences in immune cell populations were observed. Together, these data indicate LZD as a promising addition to treatment of drug resistant TB and the potential of HDTs in improving therapy.
Mechanisms controlling Cryptococcus Intracellular Parasitism
Authors: de Figueiredo Paul , Pandey Aseem , Ding Sheng-Li , Qin Qing-Ming , Gupta Rahul , Gomez Gabriel , Lin Furong , Feng Xuehuan , de Costa Luciana Fachini , Chaki Sankar P , Katepalli Madhu , Case Elizabeth , Van Schaik Erin , Sidiq Tabasum , Khalaf Omar , Arenas Angela , Kobayashi Koichi S , Samuel James E , Rivera Gonzalo , Alaniz Robert Christopher , Sze Sing-Hoi , Qian Xiaoning , Brown William J , Rice-Ficht Allison , Russell William , Ficht Thomas A 
Published: January 2023

Abstract
Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we describe insights that have emerged from a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis revealed diverse host proteins that were differentially phosphorylated following fungal infection, indicating global reprogramming of host kinase signaling during this process. Notably, phagocytosis of the pathogen activated the host autophagy initiation complex (AIC) as well as regulatory components that reside upstream of this complex. Cn-containing vacuoles (CnCVs) were found to be decorated with the cell surface marker CD44, which colocalized with components of the AIC complex. Taken together, these findings suggest that associations between CD44 and AIC proteins confer susceptibility to infection, thereby implicating novel host mechanisms in regulating fungal intracellular parasitism.
β-glucan priming enhances neutrophil Fcγ receptor-mediated antifungal activity during oral mucosal infection
Authors: Swidergall Marc , Solis Norma V , Wang Zeping , Phan Quynh T , Marshall Michaela E , Lionakis Michail S , Pearlman Eric , Filler Scott G 
Published: January 2023

Abstract
Neutrophils are key to control fungal proliferation in the oral cavity. Recently we identified that the ephrin type-A receptor 2 (EphA2) functions as an oral epithelial cell β-glucan receptor that triggers epithelial cell production of proinflammatory mediators in response to Candida albicans infection. Because EphA2 is also expressed by neutrophils, we investigated the role of EphA2 in neutrophil candidacidal activity during OPC. We found that when OPC was induced in EphA2−/− mice, there was delayed accumulation of phagocytes into the oral tissues and more severe disease relative to wild-type mice. Depletion of neutrophils in EphA2−/− mice did not further increase oral fungal burden, nor did adoptive transfer of EphA2−/− neutrophils into CD18−/− mice decrease oral fungal burden, indicating that EphA2 on neutrophils plays a central role in the host defense against OPC. Mice lacking the Fcγ receptor I (CD64) were also highly susceptible to OPC. In vitro studies showed that EphA2 signaling augments neutrophil Fcγ receptor-mediated antifungal activity. The interaction of serum-opsonized C. albicansyeast with neutrophil EphA2 activated the MEK-ERK signaling pathway, leading to NADPH subunit p47phox site specific phospho-priming. EphA2-induced priming of neutrophil p47phox increased intracellular ROS production and enhanced killing of opsonized C. albicans yeast. Thus, in neutrophils, EphA2 serves as a receptor for β-glucans that enhances Fcγ receptor-mediated antifungal activity and is crucial to control early fungal proliferation during OPC.
The role of NKT cells in systemic Methicillin-resistant Staphylococcus aureus (MRSA) infection
Authors: Genardi Samantha , Cao Liang , Visvabharathy Lavanya , Berdyshev Evgeny , Wang Chyung-Ru 
Published: January 2023

Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is an extracellular pathogen responsible for many deaths in the hospital setting each year. The role of conventional T cells in MRSA infection has been extensively studied, however the role of CD1d-restricted natural killer T (NKT) cells in MRSA infection is unknown. NKT cells are divided into 2 subsets, type I expressing an invariant TCR, and type II NKT cells, expressing diverse TCR. Mice lacking both NKT cell subsets showed increased bacterial burdens, inflammatory foci, and neutrophilic infiltrates in the kidneys and increased bacterial burdens in the liver at early times post infection. Both type I and type II NKT cells are activated after SA infection and produce IFN-g. We identified polar lipid species from the cell membrane of MRSA that induce CD1d-dependent IFN-g production by type II NKT cells. We also demonstrate that type I NKT cells, together with neutrophils, control bacterial burdens in infected macrophages. Therefore, NKT cells can become activated and produce protective cytokines in response to MRSA infection that enhances control of infection prior to conventional T cell activation.
Transcriptional profile of CD8+Vα7.2+CD161+ MAITs reveals distinct gene expression compared to CD8 memory T cells
Authors: Lindestam Arlehamn Cecilia S , Pomaznoy Mikhail , Burel Julie G , Kuan Rebecca , Seumois Gregory , Vijayanand Pandurangan , Lewinsohn David Michael , Sette Alessandro , Peters Bjoern 
Published: January 2023

Abstract
Here, we applied a cell population transcriptomics strategy to sorted human memory CD8 T cells to define novel immune signatures of latent tuberculosis infection (LTBI) and understand the phenotype of tuberculosis (TB)-specific T cells. We found a 41-gene signature that could discriminate between memory CD8 T cells from healthy LTBI subjects and noninfected controls. The gene signature was dominated by genes known to be associated with mucosal associated invariant T cells (MAITs) and reflected the lower frequency of MAITs observed in individuals with LTBI. There was no evidence for a conventional CD8 T cell specific signature between the two cohorts. We therefore investigated the MAITs in more detail in these cohorts. Phenotyping based on Vα7.2 and CD161 expression and MR1 tetramers revealed 2 distinct populations of CD8+Vα7.2+CD161+ T cells: MR1 tetramer-restricted and MR1 tetramer-unrestricted, both of which had a distinct gene expression profile compared to CD8 memory T cells. Transcriptomic analysis of LTBI vs. noninfected individuals did not reveal significant differences for MR1 tetramer-restricted cells. However, interestingly, gene expression of MR1 tetramer-unrestricted cells showed a very different profile with large inter-individual diversity and a TB-specific signature. This was further strengthened by a more diverse TCR-α and -β repertoire of MR1 tetramer-unrestricted cells as compared to MR1 tetramer-restricted. Thus, cell population transcriptomics revealed a dominant MAIT signature in CD8 memory T cells that upon detailed investigation provided novel insights into the phenotype of different MAIT populations implicated in tuberculosis.
NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronic Toxoplasma gondii infection
Authors: Gigley Jason P. , Ivanova Daria L , Denton Stephen L 
Published: January 2023

Abstract
Previous studies demonstrate CD8 T cell immune exhaustion is a major factor in promoting chronic Toxoplasma gondii (T. gondii) infection. How other immune cells are impacted by chronic T. gondii infection to promote CD8 T cell exhaustion and chronic parasite infection are not known. We investigated natural killer cells (NK cells) and how they contribute to chronic Toxoplasmosis. We find NK cells are not exhausted because NK cell numbers do not decrease during late stage infection and do not up regulate PD-1 or LAG3. NK cells in chronic parasite infection have reduced IFNγ, do not produce IL-10 or increase their expression of PD-L1, however, they expressed elevated CD107a. We also find NK cells become more highly mature (KLRG1+) during chronic T. gondii infection. We conclude that they do not become exhausted as do CD8 T cells, but alter their function during chronic T. gondii infection. Importantly, we demonstrate NK cell depletion with anti-NK1.1 is therapeutic and rescues mice from death normally caused by CD8 T cell exhaustion and parasite reactivation. This treatment reduced CD8 T cell apoptosis, increased parasite specific polyfunctional CD8 T cell responses and prevented parasite reactivation. NKp46+ NK cells were enriched for expression of CD94 and NKG2A. NKp46 ligand and Qa-1b expression were altered to promote enrichment of this specific NK cell population. Blockade with anti-NKp46 also rescued the mice from death associated with exhausted CD8 T cells and parasite reactivation. We hypothesize NK cells via NKp46 significantly contribute to promoting chronic T. gondii infection. Understanding how NK cells develop this response will improve therapies for individuals at risk for reactivation of chronic infections.