bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal EGF limits bacterial translocation in the offspring: a model of enterally acquired Late Onset Sepsis
Authors: Knoop Kathryn A , Coughlin Paige , Floyd Alexandria , Hall-Moore Carla , Ndao Malick , Warner Barbara , Tarr Phillip , Newberry Rodney 
Published: January 2023

Abstract
Late-onset neonatal sepsis (LOS), an important cause of morbidity and mortality in prematurely born infants, results from a bloodstream infection by bacteria of gut origin. It remains unclear how such bacteria translocate from the intestine, though it has been repeatedly observed that breastfed infants, particularly those fed mother’s own milk (MOM), have reduced risk of LOS compared to formula fed infants. Epidermal growth factor (EGF) promotes intestinal barrier function in infants and is present at high concentrations in breast milk post-partum and decreases throughout lactation. We found reduced concentrations of EGF in the stool of premature formula-fed infants compared to MOM-fed infants, and observed a similar decrease in EGF concentrations of stool of neonatal mice asynchronously cross-fostered (ACF) to dams that had delivered two weeks prior. LOS bloodstream isolates of E. coli colonized the tracts of all pups but translocated and disseminated systemically only in ACF mice resulting in bacteremia and rapid death. Oral gavage of recombinant EGF reduced bacteria translocation and prevented the development of systemic disease in ACF mice. Thus, disruption of maternally delivered EGF in ACF mice results in translocation of pathogens from the gut, and a sepsis-like disease. In conclusion we have identified a mechanism whereby gut-residing pathogens gain systemic access and have developed a novel animal model replicating this mechanism to explore the protective effect of breastmilk and EGF in LOS.
PTP1B negatively regulates Pseudomonas aeruginosa killing by neutrophil through TLR4-STAT1-iNOS signaling
Authors: Yue Lei , Yan Min , Li Hua , Yang Ting , Lin Tong-Jun , Xie Zhongping 
Published: January 2023

Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals and chronic obstructive pulmonary diseases (COPD) patients. Mechanisms involved in immune responses to P. aeruginosa infection and bacterial clearance remain incompletely defined. Here we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa killing by neutrophil. PTP1B-deficient neutrophil display greatly enhanced bacterial killing capability and TLR4 transcription following P. aeruginosa infection. The negative regulation of PTP1B on the production of nitric oxide by neutrophil is blocked by TLR4 antagonist. Furthermore, the STAT1 activation in neutrophils following P. aeruginosa infection occurs in the downstream of TLR4, and PTP1B deficiency leads to enhanced TLR4 dependent STAT1 activation and iNOS expression by neutrophil. Interestingly, PTP1B deficiency mainly up-regulates the production of pro-inflammatory cytokines by neutrophil, including IL-6, IL-1β and TNFα, but only IL-6 is blocked by TLR4 antagonist. Further studies reveal that PTP1B and STAT1 are physically associated. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-STAT1 interaction. This novel PTP1B-STAT1-iNOS pathway may have broader implications in Toll-like receptor mediated innate immunity.
Expression of human TLR4/MD-2 directs an early innate immune response associated with modest increase in bacterial burden during Coxiella burnetii infection
Authors: Hedges Jodi F , Robison Amanda , Snyder Deann Teresa , Hajjar Adeline M. , Jutila Mark A 
Published: January 2023

Abstract
Human and mouse TLR4 molecules respond differently to hypo-acylated LPS. The LPS of Coxiella burnetii is hypo-acylated, heavily glycosylated and known to cause a minimal response by human cells. We hypothesized that mice expressing hTLR4 molecules would be more susceptible to C. burnetii infection. Our results suggested that transgenic mice expressing hTLR4 and the human MD-2 adaptor protein (hTLR4/MD-2) generally respond similarly to wild type mice, contrary to our hypothesis. Small differences in bacterial burdens in spleens and/or lungs of infected mice were noted and lung pathology was increased in hTLR4/MD2 compared to wild type mice. Surprisingly, bone marrow chimera experiments indicated that hTLR4/MD-2 expression on non-hematopoietic cells, rather than the target cells for C. burnetii infection, accounted for increased bacterial burden. Very early during infection, cytokines involved in myeloid cell recruitment were detected in the plasma of hTLR4/MD2 mice, but not in wild type mice. This restricted cytokine response was accompanied by early neutrophil recruitment to the lung in hTLR4/MD2 mice. These data suggest that hTLR4/MD-2 may alter early responses to C. burnetii infection. Our results suggest that during C. burnetii infection, the species of origin for TLR4 may be less important than with other pathogens with hypoacylated LPS.
Innate immune role for the Macrophage Galactose Lectin (MGL) pathway in pulmonary tuberculosis
Authors: Naqvi Kubra Fatima , Saito Tais B , Huante Matthew B , Gelman Benjamin B , Endsley Janice J 
Published: January 2023

Abstract
Pulmonary tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), remains a significant public health threat and accounts for 1.3 million deaths each year. Innate immune responses to Mtb through pathogen recognition receptor signaling are capable of producing protective immune responses and controlling infection. To date, however, an anti-mycobacterial role for the C-type lectin receptor Macrophage Galactose Lectin (MGL), present on the surface of alternatively activated macrophages and dendritic cells, has not been described. MGL has been shown to be an important anti-inflammatory immune receptor during Klebsiella pneumoniae pneumonic sepsis, suggesting its involvement during lung infections; although the role of MGL during TB has not been studied. In preliminary studies, we identified HIV-mediated disruption of MGL gene expression in the lungs of humanized mice co-infected with HIV and Mtb by using a custom macrophage transcriptome array. To further investigate a role for how loss of MGL activation would affect innate immunity to Mtb, we compared disease following pulmonary challenge of MGL−\− and WT mice with Mtb H37Rv. Compared to WT mice, we observed greater mycobacterial burden in the lungs of MGL−\− mice. We additionally observed differences in pulmonary pathology including the accumulation of foamy macrophages and altered patterns of leukocyte organization in granulomas. These data suggest that MGL signaling may regulate myeloid cell antimicrobial activity and inflammatory outcomes at sites of Mtb infection in the lung.
Egr-1 deficiency protects host against Pseudomonas aeruginosa lung infection
Authors: Pang Zheng , Raudonis Renee , Cheng Zhenyu 
Published: January 2023

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that is the major cause of nosocomial infections in cystic fibrosis patients and immunocompromised individuals. The molecular mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Early Growth Response 1 (Egr-1) is a zinc-finger transcription factor that binds to the GC-rich DNA consensus sequences in the promotor of target genes, important for cell growth, differentiation and survive. Aberrant expression of Egr-1 has been implicated in many inflammatory diseases. In this study, we demonstrate that Egr-1 deficiency protects host against P. aeruginosa infection in a mouse model of acute bacterial pneumonia. Egr-1 expression was rapidly and transiently induced both in vitro and in vivo upon P. aeruginosa infection. Egr-1-deficient mice displayed decreased disease score, reduced systemic levels of proinflammatory cytokines and impaired NF-κB and NFAT activation compared to wild-type mice. Interestingly, Egr-1 deficiency leads to enhanced bacterial clearance and increased nitric oxide production in lung whereas it has no impact on neutrophil recruitment. Further studies revealed that Egr-1-deficient neutrophils displayed elevated bacterial killing ability. Altogether, these findings suggest that Egr-1 promotes inflammatory responses by enhancing NF-κB and NFAT activation and plays a detrimental role in host defense against P. aeruginosa lung infection by negatively regulating nitric oxide production for bacterial clearance.
Suppression of human STAT2 by ZIKV NS5
Authors: Hai Rong , Wang Boxiao , Thurmond Stephanie , Song Jikui 
Published: January 2023

Abstract
The infection of ZIKA virus (ZIKV), a mosquito-transmitted flavivirus, has been shown to cause congenital disease in the context of infection during pregnancy in its 2015 outbreak. To establish the infection, ZIKV must suppress host interferon (IFN) response. Previous studies have shown that ZIKV utilizes its non-structural NS5 protein to trigger the human STAT2, a critical mediator to boost host interferon (IFN) response, for the proteasome-dependent degradation. However, the underlying mechanisms of viral NS5 and hSTAT2 remain elusive largely due to the lack of atom level conformational information. Here, we report the structure of hSTAT2 in complex with ZIKV NS5. hSTAT2, with the SH2 domain occluded by the C-terminal tyrosine-phosphorylation (pY)-tail segment, inserts the coiled-coil domain into the cleft between the methyltransferase and RdRP domains of NS5 in a manner that would occlude the association of hSTAT2 with cellular regulatory protein IRF9. Disruption of the ZIKV NS5 – hSTAT2 association in cells compromises the NS5-mediated hSTAT2 degradation and IFN responses. This study provides a basis for understanding the functional antagonism between viral antagonists and STAT2.
Dual oxidase1 ameliorates survival, viral clearance and pulmonary pathology during influenza infection
Authors: Sarr Demba , Gingerich Aaron , Colon Maria , Nagy Tamas , Tripp Ralph A , Rada Balazs 
Published: January 2023

Abstract
Influenza virus infections cause severe morbidity and mortality, especially in high-risk patient populations. Bronchoepithelial cells orchestrate an oxidative antimicrobial system present in the airway liquid consisting of lactoperoxidase, the thiocyanate ion, and hydrogen peroxide. Dual Oxidase 1 (Duox1), an enzyme highly expressed in these cells, is the source of hydrogen peroxide. While in vitro studies suggest an anti-influenza, and a general antimicrobial role of Duox1, its antiviral role in vivo has not been addressed so far. We hypothesized that Duox1 has a protective effect in vivo against influenza. To test this hypothesis, we infected wild-type C57BL/6 and Duox1-deficient mice intranasally with the mouse-adapted A/Puerto Rico/8/1934 H1N1 (PR8) influenza virus strain. To evaluate the clinical and immunological significance of Duox1 in influenza infection, multicolor flow cytometry, multiplex ELISA, viral titration, histology and immunostaining techniques were used. Our results indicate that Duox1-deficient mice have increased mortality following influenza infection. Weight loss of Duox1-deficient mice post-infection was also significantly higher than in Duox1-expressing animals. Duox1 also limited influenza virus replication in the lung. Characterization of infiltrated leukocyte subsets following influenza infection revealed impaired natural killer cell recruitment in Duox1-deficient animals while other lymphoid or myeloid leukocyte subsets were not affected In summary, our results provide the first evidence for the in vivo antiviral role of Duox1, and also implicate that targeting the Duox1-based system has the potential to provide novel treatment or prophylactic strategies against influenza.
Dysregulation of innate interferon signaling by Epstein-Barr virus tegument protein BGLF2
Authors: SONIA  , Yuen Kit-San , Chaudhary Vidyanath , Botelho Michael George , Jin Dong-Yan 
Published: January 2023

Abstract
Epstein-Barr virus (EBV) successfully infects more than 90% of adults, causing lymphoid or epithelial malignancies such as lymphomas, nasopharyngeal and gastric carcinomas only in a small subset of infected people. EBV can switch between latency and lytic replication in B lymphocytes and epithelial cells. To maintain its life cycle, EBV has to develop mechanisms to evade host innate immune responses. In this study we identified EBV tegument protein BGLF2 as another viral modulator of JAK-STAT-dependent innate immune responses. BGLF2 interacted with STAT2 and promoted its degradation by enhancing K48-linked ubiquitination. BGLF2 also inhibited phosphorylation of JAK1 and STAT1, probably by recruiting a tyrosine phosphatase to these targets. As a result, BGLF2 suppressed ISRE-dependent transcription of interferon (IFN)-stimulated genes (ISGs) induced by type I IFNs. In addition, BGLF2 also exerted an inhibitory effect on type II and type III IFN signaling. Pre-treatment of host cells with IFN-β desensitized them for EBV primary infection and reactivation. Expression of BGLF2 in IFN-β-pre-treated cells reversed IFN-β-mediated inhibition and restored EBV infectivity. Thus, BGLF2 might subserve an IFN-antagonizing function in EBV lytic infection. Our findings reveal a novel EBV modulator of innate IFN response. Supported by HMRF 17160822, RGC C7027-16G and AoE/M-06/08.
Transient Receptor Potential Vanilloid 4 (TRPV4) Regulates the Host Defense Response to Bacterial Pneumonia Through a MAPK Molecular Switch
Authors: Scheraga Rachel Greenberg , Abraham Susamma , Grove Lisa , Southern Brian D , Crish James , Hamilton Thomas A , McDonald Christine , Olman Mitchell 
Published: January 2023

Abstract
We have shown that macrophage activation in response to lipopolysaccharide (LPS) is sensitive to the biophysical properties of the matrix through the mechanosensitive channel, transient receptor potential vanilloid 4 (TRPV4). However, the signals that drive macrophage activation are not fully known. Studies suggest that LPS-induced macrophage activation is controlled in part by the MAPK pathway (i.e. p38, ERK, JNK). Thus, we investigated if TRPV4 mediates the macrophage response to LPS through MAPKs. In TRPV4 deleted BMDMs, p38 activation was decreased (69%) while JNK activation was increased (2-fold), and ERK was unchanged after LPS, in a matrix stiffness-dependent manner. Further studies reveal that activation of p38 enhances LPS-induced macrophage phagocytosis (2-fold), but blocks IL-1β secretion (2-fold); while JNK enhances secretion of IL-6, IL-8, and MIP-2 (2 fold). Hence, the TRPV4 and LPS signals synergizes to activate p38 which increases phagocytosis and limits IL-1β secretion while downregulating JNK activation to limit other pro-inflammatory cytokines. In order to evaluate the role of TRPV4 in chronic pneumonia/lung injury, WT and TRPV4 KO mice were intratracheally administered agarose-embedded P. aeruginosa. Loss of TRPV4 led to decreased phagocytosis/bacterial clearance (6-fold), increased lung inflammation as measured by inflammatory cell infiltration (80±3%), vascular permeability (63±6%), and pro-inflammatory cytokine secretion (IL-1β &gt; by 71±4%). Thus, in the setting of lung infection TRPV4 functions to induce a molecular switch towards p38 which mediates bacterial clearance and downregulates pro-inflammatory cytokine secretion, to reduce infection-associated lung inflammation.
BATF-interacting proteins dictate specificity in Th subset activity
Authors: Fu Yongyao , koh Byunghee , Ulrich Benjamin J. , Kharwadkar Rakshin , Kaplan Mark H. 
Published: January 2023

Abstract
The basic leucine zipper transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells. The mechanism for this restricted activity is unclear. In this report we define BATF binding partners that contribute to Th subset-specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. We observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest but significant increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, co-transduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cell. Taken together, our results reveal that JunB, c-Jun and Bach2 cooperate with BATF to contribute to the specificity of BATF-dependent cytokine induction in Th subsets.
Cold . . . is not so cold: CD4+ T cells are active but suppressed in colorectal cancer
Authors: Jessup J. Milburn 
Published: January 2023

Abstract

Introduction
Checkpoint inhibitors blocking the PD-1/PD-L1 axis or CTLA4 are standard of care for lung and kidney cancer and melanoma. However, colorectal carcinoma (CRC), the second most lethal cancer in the US, has only a 7% response rate to checkpoint inhibitors because more than 60% of CRC lack tumor infiltrating lymphocytes, PD-L1 expression, or have low mutational burden. We postulated that cellular immune responses to autologous tumor antigens in patients with CRC are present but suppressed.

Methods
Patients with stage I – III CRC were studied as part of a vaccine program to determine cellular immunity to their autologous tumor. Single cell suspensions of tumor and normal mucosa were made and cryopreserved from each patient. All patients had IgG or IgA antibodies that reacted with autologous tumor by indirect immunofluorescence. Peripheral blood mononuclear cells (PBMC) were isolated and CD4+ and CD8+ T cell subsets were cultured with Mitomycin C-treated autologous Tumor or mucosal cells. Proliferation was measured after 3 days by 3H-thymidine post-labeling.

Results
4 of 5 unvaccinated patients had CD4+ T cell subset proliferation whereas PBMC or CD8+ T cell subsets did not. When CD8+ T cells were added back to CD4+ T cells, proliferation was inhibited. Patients vaccinated with BCG and autologous tumor cells displayed specific cellular-immune responses for up to 9 months.

Conclusion
CRC patients with T-dependent IgG or IgA autoantibodies frequently contain a CD4+ T cell subset that may be boosted to support systemic immunity or, possibly, checkpoint inhibitor therapy.
Peroxynitrite affects MHC I peptide repertoire presented on tumor cells and impedes the efficacy of antitumor cytotoxic T-lymphocytes
Authors: Tcyganov Evgenii , Gabrilovich Dmitry I 
Published: January 2023

Abstract
Despite the advancements in enhancing antigen-specific T cell responses in cancer their clinical benefit remains limited. Recent studies demonstrated that tumor microenvironment factors are able to dampen in vivo anti-tumor T cell response. Previously, we found that myeloid cells produce large amounts of peroxynitrite (PNT) in the tumor. The pretreatment with PNT blocked binding of exogeneous peptides by tumor MHC I and decreased tumor killing by cytotoxic T lymphocytes (CTL). We hypothesized that PNT affects tumor MHC I peptide repertoire, resulting in inability of CTL to recognize and eliminate tumor cells. To test this hypothesis, we treated tumor cells with PNT and analyzed MHC I peptides by LC-MS/MS. We found that PNT dramatically affected the repertoire of tumor MHC I peptides. We identified two groups of peptides: “stable” peptides that were retained on MHC class I after PNT treatment and “non-stable” peptides that were significantly reduced after treatment. The characterization of peptides had revealed similar binding capacity for both “stable” and “non-stable” peptides. However, the dissociation rate of “non-stable” peptides from peptide-MHC I complexes was significantly higher. We found that PNT treatment impaired proteasomal activity in tumor cells. This may skew MHC I repertoire towards more “stable” peptides. To examine biological relevance of PNT, we generated CTLs specific to representative “stable” and “non-stable” peptides. We confirmed that PNT pretreatment of tumor cells decreased the killing efficacy of CTLs specific to “non-stable”, but not to “stable” peptides.
Overall, our findings demonstrate a novel PNT-mediated mechanism of tumor cell resistance to CTLs that could be targeted for cancer immunotherapy.
Suboptimal ER stress Induced Autophagy Potentiates Anti-tumor T Cell Response
Authors: Chakraborty Paramita , Chatterjee Shilpak , Tran Danh , Nadig Satish , Atkinson Carl , Mehrotra Shikhar 
Published: January 2023

Abstract
Endoplasmic reticulum (ER) stress induced by external or internal stimuli, activates a number of well-orchestrated cellular signaling processes aiming either to promote cell apoptosis or to restore cellular function and resolve the stress. In tumor microenvironment, induction of ER stress is known to dampen the antitumor activity of T cells by reducing their mitochondrial function. However, if magnitude of ER stress governs the T cell fate and function is unknown. Using melanoma antigen gp100 reactive T cells, we found that low level of ER stress enhances T cell stemness and promotes mitochondrial biogenesis, whereas high level of ER stress triggers T cell death. Moreover, upon adoptive transfer, T cells treated with low dose ER stress inducer are able to form long-lived memory in vivo, express reduced level of co-inhibitory molecule, and demonstrate superior anti-tumor immunity by increasing overall survival of B16 melanoma bearing mouse. Mechanistically, we discovered that, upon ER insult at suboptimal level, a protective autophagy pathway is induced to promote cell survival and maintain stemness through the protein kinase R-like endoplasmic reticulum kinase (PERK)/ activating transcription factor-4 (ATF4)-dependent manner. Conversely, knockdown of PERK abrogates autophagy activation, hampers mitochondrial biogenesis in response to suboptimal ER stress, which in-turn compromises the antitumor function of melanoma antigen specific T cells. Overall, these preclinical data highlights that, low level of ER stress is important for healthy cellular function and therapeutically, ER stress pathways can be manipulated in T cells in order to regulate their antitumor potential.