bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local host level of cytokines and gene expression are associated with successful healing of combat-related extremity wounds with persistent critical colonization
Authors: Lisboa Felipe A. , Bradley Matthew J. , Forsberg Jonathan A. , Potter Benjamin K , Muñoz Beau J. , Hueman Matthew T. , Elster Eric A. 
Published: January 2023

Abstract
Persistent critical colonization (CC) may lead to wound healing failure (WF) despite antibiotic treatment. We investigated the local host gene expression and cytokine response of critically colonized wounds to identify early signs of WF.
Seventy-three patients with combat-related extremity wounds requiring serial operative debridements were assessed to determine whether there was an association between CC and WF. A total of 116wounds were identified. A subset of 44% (51/116) of these wounds developed CC (considered as growth of 105 bacterial CFU/g of tissue or μL of wound effluent). Samples were collected at each debridement and tested for 32 cytokines and 192 genes associated with wound healing. A two-tailed alpha &lt; 0.05 was considered statistically significant.
Wounds closed with CC had increased odds of failing to heal OR=3.3 (1.225 to 8.9). A. baumannii was the most commonly isolated species. A subset of 12 out of 51 (24%) wounds which developed CC, failed. Of those, 10 had CC present on day of wound closure. However, 10 additional wounds with CC present at time of closure healed successfully after a similar number of debridements. Comparing these wounds, WF was associated with a decrease in the level of EGF (p&lt;0.05) and lower gene expression of IFNB1 (p=0.01), FGF-8 (p=0.01) and HMGB1 (p=0.01). Successful healing was associated with an increase in the level of VEGF (p&lt;0.01).
Resolution of persistent CC before closure may prevent failure. Local host gene expression and cytokine response may provide additional insight for successful closure. Further studies investigating microbiology data and possible antibiotic resistant genes are needed.
IL-22-deficiency mediates resolution of colitis in Il10
−/− mice
Authors: Gunasekera Dilini C , Ramakrishnan Amritha , Ma Jinxia , Uprety Priyanka , Vacharathit Vimvara , Sheh Alexander , Whary Mark T. , Fox James G. , Bream Jay H. 
Published: January 2023

Abstract
The cytokines IL-10 and IL-22 play important, but presumably distinct roles in promoting intestinal homeostasis. Although the anti-inflammatory actions of IL-10 in the gut are well established, the role(s) of IL-22 remain unclear. Il10−/− mice develop chronic colitis characterized by rectal prolapse, colonic thickening and inflammatory infiltrates, including abundant Th17 cells. We have also observed a modest, but consistent elevation in IL-22 (mRNA and IL-22+CD4 T cells) in colons of Il10−/− mice. This is accompanied by an increased expression of IL-22-target bactericidal genes such as Reg3g, s100a8, and s100a9 and reduced intestinal microbial diversity in Il10−/− mice. To define a potential role for IL-22 in spontaneous colitis, we generated Il10−/− Il22−/− mice by backcrossing. Unexpectedly, concurrent IL-22 deficiency prevented colitis in Il10−/− mice, normalizing histopathology inflammatory scores and restoring microbial diversity to WT levels in Il10−/− Il22−/− mice, despite endemic Helicobacter spp. infection, an established risk factor for colitis in Il10−/− mice. Interestingly, prevention of disease was not accompanied by a reduction in Th17 cells. Importantly, introduction of recombinant IL-22 into the GI tracts of both Il10−/− Il22−/− and WT mice resulted in colonic shortening and thickening after only 2 weeks of treatment, suggesting that IL-22 is at least partially responsible for the immunopathology observed in Il10−/− mice. Thus, although beneficial during certain bacterial infections and in response to acute tissue damage, our data suggest that left unchecked, IL-22 expression can contribute to chronic colitis and appears to be negatively regulated by IL-10.
Association of baseline cytokine levels with anti-tumour necrosis factor treatment response in rheumatoid arthritis
Authors: Gibson David S , McGeough Cathy M , Slevin Mary M , Wright Gary , Gardiner Philip , Murray Helena A , Latten Mark J , Crockard Martin A , Lamont John V , Bjourson Anthony J 
Published: January 2023

Abstract

Background
Clinical trials of anti-tumour necrosis factor alpha (TNF) have shown efficacy in 60–70% of rheumatoid arthritis patients (RA). Predicting response to anti-TNF drugs at baseline remains an elusive goal in RA management. The purpose of this study was to determine if baseline levels of circulating cytokines, soluble receptors, adhesion molecules and metabolic factors differentiate future responders.

Methods
RA patients (n=29) with active disease were recruited, who had failed on disease modifying drugs and were recommended for anti-TNF treatment. Peripheral blood samples were collected at baseline. Responders were identified by a ≥1.2 reduction in disease activity score (DAS28-ESR) at 6 months. Five protein arrays quantified 33 proteins in pre-treatment plasma (Cytokine I, III and IV; Metabolic I; Adhesion molecule; Randox Laboratories Ltd., UK). Data was analysed by Pearson ranked correlation and logistic regression to clinical measures of disease activity at baseline and six months anti-TNF treatment.

Results
Elevated levels of interleukin 8 (p=0.043), monocyte chemoattractant protein (p=0.027), granulocyte-macrophage colony-stimulating factor (p=0.020) and soluble interleukin 2α receptor (p=0.01) were associated with high TJC at baseline. No significant relationship with the protein array panels was recorded relative to baseline DAS28-ESR. Significant inverse correlations were observed between absolute change in DAS28-ESR after 6 months of anti-TNF therapy and baseline levels of interleukin 6 (p=0.026) and resistin (p=0.044).

Conclusions
These findings suggest that baseline levels of specific circulating proteins may help to differentiate RA patient responders to anti-TNF therapies.
Catalase expression mediates redox regulation of autophagy and promiscuous gene expression in thymic stromal cells.
Authors: Hester Allison K , Semwal Manpreet Kaur , Xiao Yangming , Cepeda Sergio , Venables Thomas , Griffith Ann V 
Published: January 2023

Abstract
T lymphocytes develop in the thymus, where mutually inductive signaling between lymphoid progenitors and thymic stromal cells (TSCs) directs progenitors along a well-characterized differentiation program. However, the biology of stromal cells comprising the lymphopoietic thymic microenvironment remains relatively under-characterized because stromal cells are rare and difficult to isolate. Using a deconvolution technique to study gene expression essentially in situ, we previously identified a deficiency in the peroxide quenching enzyme catalase (CAT) in thymic stromal cells, and found that CAT deficiency results in high reactive oxygen species (ROS) levels in this population, eventually leading to thymic atrophy in aged mice. Here, we find that when catalase deficiency is complemented by overexpression targeted to mitochondria in transgenic mice (mCAT Tg), both ROS levels and stromal function decline in young mice relative to non-transgenic littermates. TSC transcriptome analysis reveals decreased expression of tissue-restricted antigen (TRA) and autophagy pathway genes in Cat Tg mice. Analysis of autophagy flux reporter mice ubiquitously expressing the RFP-EGFPLC3 fusion transgene also indicates diminished autophagic flux in mCAT Tg mice, particularly in TSCs. Stromal TRA expression and autophagic flux are required for self-antigen presentation, and therefore promote negative selection of potentially auto-reactive T cells. We propose that oxidative stress generated by low catalase levels in stromal cells promotes these key physiological functions in the young, steady state thymus; in contrast however, the resulting accumulated oxidative damage ultimately impairs function in the aged thymus.
Requirement for PBX1 in developmental programming of natural killer cells
Authors: Yonggang Zhou , Binqing Fu , Xiuxiu Xu , Xianhong Tong , Rui Sun , Zhigang Tian , Haiming Wei 
Published: January 2023

Abstract
Maintenance of the optimally functional natural killer (NK) cells pool is essential for the host immune surveillance. Some intracellular growth-promoting factors (GPFs) have been reported as a vital new molecular component for maintenance homeostatic expansion of NK cells, but transcriptional regulation mechanism of Gpfs genes in NK cells is unclear. To better understand the underlying mechanism for NK cells be regulated to express GPFs as a secreted or intracellular isoform, we investigated the potential role of transcription factor PBX1 within the NK cell compartment by using Pbx1 gene-targeted mice.
In terms of NK cell late development and homeostatic proliferation, here we report that PBX1 is the key transcriptional factor that underpins both of these events. The transcriptional factor PBX1 and GPFs are expressed in NK cell precursors and immature NK cells. After Pbx1 is knocked down on NK cells, NK cells shown a serious decline in the ability of expressing these GPFs. PBX1 regulates the transcription of GPFs genes in NK cells via direct binding. In the NK cell development, knocked down or excision of Pbx1 in mice harbor reduction of NK cells and the Pbx1-deficient developmental phenotype is NK cell intrinsic. In the NK cell homeostasis, PBX1 is necessary to support NK cell homeostasis in BM or spleen niche. The Pbx1-deficient mice is accompanied by impaired transition of NK cells from immature to mature, and diminished ability to differentiate into memory-like NK cells due to the impairment of GPFs.
Our study indicates that PBX1 represent a novel regulatory element for supporting the homeostatic developmental program of NK cells, and provides the basis for improved approaches to immunotherapy for virus clearance and tumor surveillance.
Alterations in the thymic selection threshold skew the self-reactivity of the T cell receptor repertoire in neonates
Authors: Dong Mengqi , Artusa Patricio , Kelly Stephanie A. , Fournier Marilaine , Baldwin Troy A. , Mandl Judith N. , Melichar Heather J. 
Published: January 2023

Abstract
Neonatal and adult T cells differ in their effector functions. Although it is known that cell-intrinsic differences in mature T cells contribute to this phenomenon, the factors involved remain unclear. Given emerging evidence that the binding strength of the TCR for self-peptide presented by MHC (self-pMHC) impacts T cell function, we sought to determine if altered thymic selection thresholds influence the self-reactivity of the TCR repertoire during ontogeny. We found that conventional and regulatory T cell subsets in the thymus of neonates and young mice expressed higher levels of cell-surface CD5, a surrogate marker for TCR avidity for self-pMHC, as compared to their adult counterparts and that this difference in self-reactivity was independent of their distinct TCR repertoire. The increased binding strength of the TCR repertoire for self-pMHC in neonates was not solely due to reported defects in clonal deletion. Rather, our data suggest that thymic selection is altered in young mice such that thymocytes bearing TCRs with low affinity for self-peptide are not efficiently selected into the neonatal repertoire and stronger TCR signals accompany both positive and agonist selection. Importantly, the differences in CD5 levels reflect physiologically relevant differences based on the preferential expansion of T cells from young mice to fill a lymphopenic environment. Therefore, differences in the thymic selection threshold in young versus adult mice skews the TCR repertoire, and the relatively higher self-reactivity of the T cell pool may contribute to the distinct immune responses observed in neonates.
Immunostimulation during primary neonatal RSV infection alters memory response.
Authors: Eichinger Katherine Marie , Kosanovich Jessica L , Manni Michelle L , Alcorn John F , Empey Kerry M 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is recognized as a leading cause of acute viral illness in neonates worldwide. However, those with balanced Th1/Th2 responses, as a result of higher IFNγ concentrations, have milder disease and better clinical outcomes. The present study examined the effect of IFNγ administration during primary, neonatal RSV infection on innate and T cell responses during primary and secondary RSV exposure.
During primary infection, neonates treated with IFNγ had increased alveolar macrophage (AM) expression of CD80, MHCII, and scavenger receptor A. Subsequent CD8 T cell recruitment and activation was reduced in this group compared to RSV controls, however the RSV-specific CD8 T cell response was enhanced. Upon secondary infection, neutrophil and monocyte recruitment was boosted and expression of CD86 and MHCII was significantly increased on AMs with a correlative decline in CD73 expression compared to primary infection controls. In mice previously infected with RSV, T cell recruitment and activation was significantly increased. However, only those mice that were treated with IFNγ during primary infection showed improved CD8 T cell specificity following secondary RSV exposure. Viral lung titers were also significantly reduced in groups previously exposed to RSV but only IFNγ treatment during primary infection demonstrated significant improvements in airway resistance following methacholine challenge.
These results suggest that immunostimulation with IFNγ during primary neonatal RSV is associated with increased innate cell activation and improved CD8 T cell specificity. These cellular changes are associated with enhanced viral clearance and improved airway function.
A staphylococcal superantigen unexpectedly augments the response magnitude of cognate anti-influenza CD8+ T cells in mice and humans.
Authors: Meilleur Courtney Erin , Memarnejadian Arash , McCormick John , Haeryfar S.M. Mansour 
Published: January 2023

Abstract
Staphylococcal enterotoxin B (SEB) is a bacterial superantigen (SAg) that induces proliferation and inflammatory cytokine secretion by up to 30% of T cells present in one’s repertoire. Eventually, the exposed T cells are thought to undergo activation-induced cell death or anergy, thus creating physical and/or functional holes in the repertoire. Using a mouse model of influenza A virus (IAV) vaccination, we found that primary IAV-specific CD8+ T cell (TCD8+) responses were enhanced, rather than diminished, in SEB-exposed animals. This effect was manifest for both local and systemic responses and validated when several different strains of IAV were utilized. Strikingly, the observed enhancement was easily detectable even one month post-SEB exposure, which was much later than the peak of the anti-IAV response. Importantly, IAV-specific TCD8+ in SEB-primed animals were not only capable of synthesizing interferon (IFN)-γ but also of lysing target cells pulsed with IAV-derived peptides in vivo. Finally, in vitro cultures of human peripheral blood mononuclear cells with SEB revealed that memory TCD8+, which recognize IAV but not Epstein-Barr virus or cytomegalovirus, were specifically expanded by this SAg and persisted long after deletion should have theoretically occurred. Taken together, our findings define a novel phenomenon in the context of TCD8+ responses to SAgs, which has important implications for vaccination against flu in critical care patients afflicted by staphylococcal infections and/or SAg-mediated illnesses.
Respiratory viral co-infections manipulate host immune responses to reduce disease severity.
Authors: Gonzalez Andres , Clary John , Rodriguez Anna , Miura Tanya 
Published: January 2023

Abstract
Patients with respiratory infections are frequently co-infected by more than one virus, but it is unknown how co-infection alters immune responses and disease outcomes compared to infection by the individual viruses. Our lab recently found that infection of mice with a mild rhinovirus pathogen (RV1B) two days before a more virulent virus (influenza A virus, PR8, or pneumonia virus of mice, PVM) reduced disease severity. In this study, we expanded these observations to determine how the timing of RV1B co-infection affects protection. Mice were inoculated with RV1B simultaneously with or two days after inoculation with PR8 or PVM. RV1B inoculated simultaneously with PR8 or PVM reduced disease whereas RV1B inoculated two days after PR8 and PVM increased the severity of PR8 and PVM. Next, mice were inoculated with RV1B two days before PR8 and then euthanized on days 4, 7 and 10 to quantify viral loads in the lungs. By day 7, co-infected mice had cleared PR8 while mice inoculated with PR8 alone had detectable virus. To identify immune cell populations that correspond with disease protection, groups of mice were inoculated with RV1B or mock two days before PR8 or PVM and flow cytometry analysis was performed on whole lungs on days 0, 2, 4, and 6 after the second virus. Co-infection by RV1B generated a stronger early innate response that contracted sooner than infection by PR8 or PVM alone. RV1B and PVM co-infection also had a stronger CD4 and CD8 T cell response later in infection. These data provide evidence that protection conferred by co-infection may be attributed to an earlier inflammatory cell response that contracts sooner, leading to faster clearance of the pathogenic virus while reducing immune-mediated pathology.
Influenza-specific ASC development is controlled by a T follicular helper cell dependent T-bet controlled feedforward loop.
Authors: Risley Chris A , Stone Sara L , Lund Frances E 
Published: January 2023

Abstract
Understanding the factors that drive differentiation of long-lived plasma cells (LLPCs) remains a significant roadblock en route to rationale vaccine design. Our lab previously described a prominent role for the cytokine-induced transcription factor, T-bet, in driving LLPC differentiation during a pulmonary viral infection. We observed that T-bet is upregulated by a significant proportion of virus-specific germinal center B cells (GCBs), which are the precursors of LLPCs. However, the cells and signals responsible for inducing T-bet and the T-bet transcriptional program in B cells remain unknown. It is likely that the interaction between the T follicular helper cells (TFHs) and the GCBs is primarily responsible for this programming. Drawing from research done with human samples, a subset of TFHs that express the T-bet regulated gene, CXCR3, has been described. We therefore hypothesize that these CXCR3+ TFHs express T-bet and are responsible for inducing T-bet expression by the GCBs and initiating T-bet transcriptional programming in the B cells. Studying the role of these CXCR3+ TFHs in mice gives us a unique opportunity to study the interaction between TFHs and GCBs, and determine how this specific interaction drives LLPC differentiation. Elucidation of these mechanisms will, in the future, allow us to address whether we can develop better and longer-lasting vaccines by choosing adjuvants that activate T-bet-dependent transcriptional programming in B cells.
Human parainfluenza virus type 3 encoded C protein antagonizes inflammasome activity
Authors: Shil Niraj Kanti , Pokharel Swechha Mainali , Thapa Bhim Bahadur , Bose Santanu 
Published: January 2023

Abstract
Human parainfluenza virus type 3 (HPIV3) is a negative-sense RNA virus in the paramyxovirus family and is the second leading viral cause of acute respiratory tract illness and hospitalization among infants and children worldwide. Interleukin-1β (IL-1β) is an important pro-inflammatory cytokine regulating innate immune response during infection. Inflammasome activation is required for IL-1β production. Inflammasome is a multi-protein complex platform that cleaves pro-caspase-1 to yield enzymatically active caspase-1. Caspase-1 in turn is involved in cleavage of pro-IL-1β into mature IL-1β. We recently showed activation of NLRP3/ASC inflammasome by HPIV3. NLRP3/ASC inflammasome activation triggered IL-1β production from HPIV3 infected macrophages. During our studies we identified HPIV3 encoded C protein as an inflammasome antagonist. C protein is an accessory protein originating from the over-lapping open reading frame of HPIV3 phosphoprotein (P) gene mRNA. Expression of C protein in human THP-1 macrophages led to diminished inflammasome activation and IL-1β production following treatment with LPS and nigericin. Similar result was observed following reconstitution of inflammasome in HEK293 cells expressing HPIV3 C protein. Mechanistically, our study revealed HPIV3 C protein regulating NLRP3 protein stability. Expression of C protein drastically reduced NLRP3 protein levels in THP-1 cells. Similar loss of NLRP3 protein was noted in HEK293 cells co-expressing C protein and NLRP3. However, C protein expression did not affect NLRP3 mRNA levels. Thus our studies have identified HPIV3 C protein as an inflammasome antagonist that directly modulates inflammasome activity by promoting NLRP3 protein degradation.
Host-immune responses to RSV infection and associated lung injury is modulated by Osteopontin (OPN) in age-dependent fashion
Authors: Durre Kainath , Qureshi Nagib , Qureshi Mahboob 
Published: January 2023

Abstract
RSV bronchiolitis and pneumonia causes significant mortality in young infants every year. The survivors become susceptible to asthma. In our present study, using a mouse model of BALB/C and NKT−/− mice, we examined the pulmonary responses to RSV infection in the very young hosts as opposed to relatively older hosts. We also examined the effects of exogenous osteopontin (OPN) administration on the alveolar cellular constitution by direct microscopy and flowcytometry and the role of NKT cells in this process. Pulmonary damage was assessed by measuring the Lactic Dehydrogenase (LDH) levels in the BALF by ELISA and histopathological examination by microscopy. Microscopy revealed a decreased lymphocyte response in the bronchoalevolar lavage fluid (BALF) of RSV-infected-4-day- old pups as compared to that of -14- and -20-day-old mice; but an enhanced neutrophil response, which was associated with increased LDH levels. Flowcytometry revealed that administration of OPN had downregulatory effects on lung lymphocyte (CD4+ and CD8+) responses in all age groups with proportional upregulation of lung macrophage (CD11bmed/hi, CD11Clo/−) responses. This effect was less pronounced in the older age groups. Additionally, activation of macrophages, as indicated by MHCII expression, was NKT dependent. Moreover, RSV- infection significantly inhibited lung CD8+ T cell activation as indicated by decreased CD44 expression, which was recovered by OPN administration. Understanding the underlying mechanisms of RSV-infection induced differential immune responses and OPN-mediated differential immunomodulation in different age groups may help develop newer therapeutic strategies.