bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lung αβ T-cells secrete IL-17A independent of ROR-γt expression and contribute to neutrophil-dependent lung damage during respiratory mycoplasma infection
Authors: Mize Maximillion Tobias , Simecka Jerry 
Published: January 2023

Abstract
How Mycoplasma pneumoniae promotes airway inflammation is not fully understood. Experimental vaccines induce host damage [1]. Airway inflammation, caused by neutrophils and T-cells, is often seen in infants. Children represent 20% of the hospitalized M. pneumoniae cases reported annually in the United States [2]. Secreted by T-cells, IL-17A promotes neutrophil activation. In humans, IL-17A+ T-cells and IL-17A increase during infection with M. pneumoniae [3]. Lung lesions caused by Mycoplasma mycoides are linked to IL-17A in cattle [4]. No reports link IL-17A to neutrophil-mediated host damage. Understanding how IL-17A functions will aid in developing effective vaccines.
We identify that CD3+ T-cells produce IL-17A during murine infection with Mycoplasma pulmonis. T-cells secreting IL-17A exist in the lungs before infection. These cells may contribute to neutrophil recruitment into the respiratory tract after infection. T-cells from the lungs and respiratory lymph nodes produced IL-17A alone, or together with IFN-γ. Expression of ROR-γt was not required for IL-17A production by respiratory αβ T-cells. Neutralizing IL-17A reduced host damage without impacting bacterial burden. Neutrophil-dependent lung lesions were lower in mice receiving αIL-17A antibodies. Depletion of neutrophils was more effective at reducing pathology when compared to IL-17A neutralization. The simultaneous neutralization and depletion of IL-17A and neutrophils failed to further reduce the disease characteristics studied. Neutrophils and IL-17A promote pathogenesis during respiratory mycoplasma disease.
Neutrophil recruitment is not entirely dependent upon IL-17A. Exacerbated pathology may occur if IL-17A directly binds neutrophils.
Genetic Transmission Networks Reveal the Transmission Patterns of HIV-1 CRF01_AE in China
Authors: Li Xiaoshan 
Published: January 2023

Abstract
The epidemic of HIV-1 CRF01_AE has become one of major public health issues in China. We sought to characterize the transmission patterns of networks for this strain nationwide and elucidate possible opportunities for prevention. All available CRF01_AE pol sequences (n = 4, 704) from China in the HIV LANL were isolated and conducted genetic transmission network analysis. A total of 1, 391 (29.6%) sequences were identified as belonging to 400 separate networks. Of men who have sex with men (MSM) in networks, 93.8% were linked to other MSM and only 2.4% were linked to heterosexual women. However, 11.8% heterosexual women in networks were linked to MSM. The lineages mainly composed of MSM had a higher transmission than those major consisted of heterosexuals. Of the 1, 391 individuals in networks, 36.9% (513) were linked to cases diagnosed in different provinces. The proportions of individuals involved in inter-province links by province was interrelated with the number of migrant people (Spearman r =0.738, P =0.001). This study could help improve our ability to understand HIV transmission among various regions and risk groups in China, and highlighted the importance of targeting MSM and migrants by prevention and intervention efforts.
Metformin suppressed human cytomegalovirus (hCMV) replication and its potential molecular mechanisms in human fibroblasts
Authors: Li Huifen , Ning Xiaoxuan , Liu Hans , Chen Yiyin , Ding Xiang , Zhang Haiyan , leng Sean X 
Published: January 2023

Abstract

Background
Chronic hCMV infection may contribute to T-cell immunosenenscence and chronic inflammation, and is shown to be associated with frailty and mortality in old adults. Metformin is a first-line treatment for type 2 diabetes mellitus. Emerging data have shown its additional beneficial effects including cardiovascular protection as well as anti-inflammatory, anti-cancer, and anti-aging activities. The objective of this study was to investigate the effect of metformin on hCMV infection in human fibroblasts and its underlying mechanisms.

Methods
Metformin was added (at concentration of 0, 1mM, 3mM, or 5mM) 2 h before inoculation of hCMV (Towne strain) at multiplicity of infection (MOI) of 0.01 or 0.1 to 80% confluent MRC-5 culture. Cells were cultured for additional 24h to 96 h. Viral plaques were observed under microscope, replication measured by qPCR (primers targeted to hCMV UL123 gene), cell cycle effect determined using flow cytometer, and hCMV protein expression (IE1/IE2, pp28, ICP36) and signaling pathway molecules analyzed by Western blot.

Results and discussion
Metformin at 3mM potently suppressed hCMV viral plaque formation, replication, and protein production. While hCMV infection promoted MRC-5 cells from G2 to M and S phase, metformin treatment led to G0/G1 arrest. Metformin suppressed expression of cyclin D, CDK4, and p21. It had no effect on CK2 or CDk6 expression. While AMPK pathway antagonist compound C suppressed AMPKa phosphorylation from both hCMV and metformin, it did not antagonize suppressive effect of metformin on hCMV protein expression. Taken together, metformin may suppress hCMV infection in MRC-5 cells via cell cycle regulation and molecular mechanisms independent of AMPK pathway.
Non-cytopathic Clearance of a CNS Viral Infection Following Blockade of Type I Interferon Signaling
Authors: Gossa Selamawit , McGavern Dorian B 
Published: January 2023

Abstract
Viral infections that enter the central nervous system (CNS) can drive immune-mediated neurological disorders such as meningitis, encephalitis, and meningoencephalitis. Developing therapeutic interventions to ameliorate these disorders is an important area of clinically relevant research. To gain insights into the immunopathogenesis of CNS viral infection, we study the fatal meningitis induced by lymphocytic choriomeningitis virus (LCMV). We have recently shown that this disease is induced by the pathogenic cooperation between virus-specific CD8+ T cells and innate myelomonocytic cells that damage CNS blood vessels. In addition, genomic studies revealed that the onset of disease is associated with a profound local type I interferon (IFN-I) signature that triggers massive immune extravasation into the meninges. In the present study, we explored approaches to therapeutically treat this disorder. Importantly, we observed that a single injection of a therapeutic antibody directed against the IFN-I receptor (IFNAR) prevented fatal disease as well as the development of symptoms in infected mice. Using a recombinant virus expressing iCre recombinase, we conducted in vivo fate mapping studies in IFNAR blocked fluorescent protein reporter mice. These studies revealed evidence of non-cytopathic viral clearance throughout meninges and glial limitans. Mechanistically, microarray studies uncovered that IFNAR blockade promoted noncytopathic viral clearance through widespread reduction of immune signaling within the CNS without altering the composition of the immune infiltrate. These studies demonstrate that it is possible to mitigate a fatal virus-induced CNS disease via modulation of innate immune signaling pathways.
Early morphine exposure reduced viral burden in the periphery and induced regional difference in brains of LP-BM5 MAIDS model
Authors: Wakley Alexa A , Arabatzis Taxia J , McLane Virginia D , Rau Sanjay , Cao Ling 
Published: January 2023

Abstract
Intravenous opioid use contributes to 11% of HIV infections in the U.S.A. Morphine suppresses the immune system while exacerbating the progression of HIV. To investigate morphine effects on HIV-associated neurocognitive disorders (HAND), we used the LP-BM5 infection murine AIDS (MAIDS) model. Previously, we found that morphine exposure at 7 wks post-infection (p.i.) enhanced cognitive impairment associated with MAIDS, increased hippocampal viral loads, and decreased CCL5 expression in examined brain regions, without affecting peripheral immunodeficiency. Because many HIV+ patients are exposed to opioids before infection, we examined these parameters after exposing the animals to morphine before and immediately after infection. Male mice were implanted with two placebo or 25mg morphine pellets for 6 days, with infection occurring on post-pellet implantation day 3. At 7 wks p.i., cognitive impairment was assessed by the spontaneous alternation T-maze task. At wk 8, blood, spleen and brain regions (hippocampus, striatum and frontal lobe) were harvested. LP-BM5 induced splenomegaly and higher levels of serum IgG2a and IgM, regardless of morphine treatment. Morphine significantly decreased body weight-normalized spleen weight. Morphine did not alter viral BM5Def RNA in spleen or any brain region examined. Morphine appeared to reduce LP-BM5-induced CCL5 expression in the striatum and frontal lobe. LP-BM5 alone appeared to increase the expression of both IFN-α and IFN-β in the frontal lobe only. Infection or morphine exposure did not affect animals’ performance in the T-maze task. Together with our previous results, these results suggest that timing of morphine exposure can alter the modulation and progression of MAIDS and HAND.
IL-22 signaling contributes to modulate the pathogenesis of Zika virus infection
Authors: Yi Panpan , Liang Yuejin , Chen Jinling , Hood Brandon , Azar Sasha , Rossi Shannan , Sun Jiaren 
Published: January 2023

Abstract
The recent outbreaks of Zika virus (ZIKV) in multiple countries are linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is entirely unknown. Here, we infected 3-week-old Ifnar1−/− mice with ZIKV (Cambodian isolate, 1.0×105 pfu/mouse), and found that ZIKV infection resulted in weight loss, paralysis, and mortality at 5 to 6 days post-infection (dpi). This was accompanied by tissue injuries, neutrophil influx, and CD8+ T cell expansion in multiple organs, especially in the brain. The infection significantly up-regulated gene expression of multiple inflammatory cytokines, including IL-6, IL-1β, and TNF-α. Importantly, ZIKV infection elicited a tenfold increase in IL-22 production from non-T cells compared with that of uninfected animals. To investigate the effects of IL-22 on ZIKV infection, we challenged 1-day-old WT and IL-22−/− mice with ZIKV (4.0×103 pfu/mouse). WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 dpi, and ultimately succumbed to the infection on 16–19 dpi. Surprisingly, IL-22 deficiency lessened the weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. In fact, around 90% of the IL-22−/− mice recovered from the insult on the nervous system at 20 dpi. Thus, our data revealed an obvious systemic inflammation in multiple organs induced by ZIKV, and demonstrated a novel role of IL-22 in determining the disease outcome.
Fusion of Fc domain to Factor IX (FIX) modulates the Th2 biased response to FIX and triggers Th1 immunity in hemophilia B treated mice.
Authors: Levin Ditza , Lagasse H.A. Daniel , Burch Erin , Strome Scott , Tan Siyuan , Jiang Haiyan , Sauna Zuben E. , Golding Basil 
Published: January 2023

Abstract
Fusion of the IgG1 constant region domain (Fc) to therapeutic proteins increases the plasma half-life of drugs via binding to the neonatal Fc receptor (FcRn). However, potential interactions with Fc gamma-receptors (FcγR) expressed by immune cells may effect the immunogenicity of these drugs. The coagulation factors VIII (FVIII) and IX (FIX) for the treatment of hemophilia A & B (HA & HB) are the only drugs available with and without Fc fusion and offer an opportunity to experimentally study the effect of Fc fusion. Anti FVIII & FIX antibodies (ADAs) and rare cases of anaphylaxis in HB patients, are serious safety concerns. Using a mouse model for HB, we compared the immune responses to infusions of recombinant human FIX (hFIX) and hFIX fused to mouse IgG2a-Fc (hFIX-mFc). The mFc allowed species-specific Fc-FcγR interactions and prevented immune response to the foreign hFc. Treatment with hFIX-mFc caused earlier onset of anti-FIX IgG and elicited higher FIX-neutralizing antibody levels. Treatment with hFIX triggered Th2 biased immunity i.e., elevated plasma IgE titers, and Th2 cytokine profile of FIX-specific CD4 T cells and a few anaphylactic events. The fusion of Fc altered the response to a Th1 type with increased plasma IFN-γ levels, and IFN-γ secretion by effector CD4 T cells. hFIX-mFc binds to soluble FcγRs and FcγRs on natural killer cells (which also secrete IFNγ) and antigen presenting cells (dendritic cells, and macrophages source of IL-12). We show that Fc fusion enhances the presentation of hFIX to CD4 T cells. We propose that high plasma availability and targeting of APC provide plausible mechanisms by which the Fc fusion may modulate the CD4 T cell response to hFIX towards a Th1 like response, thus avoiding allergic responses.
IL-4 and IL-13 modulate natural killer cell responses under inflammatory conditions
Authors: Ohayon David E , Krishnamurthy Durga , Brusilovsky Michael , Waggoner Stephen N 
Published: January 2023

Abstract
Natural killer (NK) cells are critical producers of IFN-g and mediators of cytotoxicity in response to type 1 inflammatory cytokine (e.g. IL-12) rich environments. Conventional thinking therefore holds that type 2 cytokines (e.g. IL-4 and IL-13) that counter production of IL-12 would inhibit NK cell effector functions and thereby limit the antiviral role of NK cells. In contrast, IL-4 unexpectedly synergized with IL-12 to enhance IFN-g production by mouse NK cells. We now extend this observation to human NK cells, where we find that stimulation with either IL-4 or IL-13 resulted in dose-dependent enhancement of IFN-g and TNF-a expression in response to IL-12. Neither IL-4 nor IL-13 stimulated IFN-g release in the absence of IL-12, suggesting that these type 2 cytokines modulate IL-12 signaling or NK cell responsiveness to IL-12. In contrast to the effect of IL-4 on IL-12 responsiveness, IL-4 (but not IL-13) markedly reduced the expression of IFN-g and TNF-a by human NK cells following engagement of the natural cytotoxicity receptor, NKp46. Likewise, IL-4-treated NK cells demonstrated reduced cytotoxicity towards K562 cells. Our results reveal that IL-4 and IL-13 modulate NK cells in a complex manner, enhancing responsiveness to inflammatory cytokines like IL-12 while diminishing activation via natural cytotoxicity receptors. We speculate that this could have important consequences for NK cell lysis of eosinophils, IFN-g-mediated airway hyperresponsiveness, and other features of allergic or asthmatic diseases associated with aberrant type 2 cytokine production.
Keratinocyte-specific deletion of STAT3 promotes elevated serum IgE in response to Staphylococcus aureus exposure: relevance to hyper-IgE syndrome
Authors: Liu Haiyun , Archer Nathan K , Dillen Carly A , Wang Yu , Ashbaugh Alyssa G , Ortines Roger V , Lee Steven K , Kao Tracy , Miller Lloyd S 
Published: January 2023

Abstract
Autosomal dominant hyper-IgE syndrome is caused by STAT3 loss-of-function mutations, which results in a constellation of clinical features, including highly elevated serum IgE levels, a severe eczema-like skin eruption, and an increased susceptibility to Candida albicans and Staphylococcus aureus skin infections. However, the mechanism by which these individuals have elevated IgE levels is not well understood. To evaluate the role of defective STAT3 signaling in contributing to IgE production, we used a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous exposure to S. aureus in cre/lox mice with cell specific deletion of STAT3. Unexpectedly, STAT3 deletion in keratinocytes (K5-creERT2 × STAT3fl/fl mice) but not in T cells (CD4-creERT2 × STAT3fl/fl mice) resulted in a substantial elevation of serum IgE levels. The increase in serum IgE involved concomitant increase in IgG and IgA levels that were also significantly higher in the keratinocyte-specific STAT3-deficient mice compared with wildtype mice. CD4+ T cells were required for the IgE production, since CD4+ T cell depletion resulted in significantly reduced level of serum IgE in the K5-creERT2 × STAT3fl/fl mice. Taken together, these results indicate that keratinocytes can modulate serum antibody levels, especially in the absence of STAT3 signaling. These results provide an explanation of the increased serum IgE levels in autosomal dominant hyper-IgE syndrome and more broadly into the mechanisms that promote antibody production in response to epicutaneous exposure to microbes and inflammation.
Significance of VIP and VIP receptor interaction in promoting pathogenesis of Eosinophilic esophagitis
Authors: Verma Alok Kumar , Venkateshaiah Sathisha Upparahalli , Manohar Murli , Mishra Anil 
Published: January 2023

Abstract
Vasoactive intestinal peptide (VIP) is shown to have a role in the esophageal sphincter contraction and relaxation, and its role in pathogenesis of eosinophil associated allergic diseases like asthma and rhinitis is reported. Therefore, we tested the hypothesis that VIP may have an important role in the eosinophils accumulation in the esophagus that promote the pathogenesis of eosinophilic esophagitis (EoE). Accordingly, we performed flow cytometer analysis for VIP receptors expression in the blood eosinophils and real time PCR for VIP transcript analysis in the biopsies of human EoE. Herein, we show that human eosinophils highly express VIP associated receptor CRTH2, not VAPC1 or VAPC2. Further, VIP mRNA and protein is induced in esophageal biopsies of human EoE compare to the normal individuals. Additionally, we show that in vitro VIP has a similar chemoattractant activity for eosinophils as eotaxin. Further, we show that in vivo CRTH2 expressed eosinophils accumulated around the VIP producing nerves in the esophageal biopsies of EoE patients. Interestingly, we also observed VIP receptor VPAC2 on mast cells and their accumulation near the nerve cells in EoE biopsies. Taken together, we show the significance of VIP and its receptors interaction in the recruitment of eosinophils and mast cells that may have an important role in promoting chronic EoE pathogenesis in human.
Overexpression of tIK ameliorates DNCB-induced allergic contact dermatitis in BALB/c mice
Authors: Son JeHee , Jang Hyun-Young , Lee Sang-Myeong 
Published: January 2023

Abstract
Allergic contact dermatitis (ACD) is a delayed type hypersensitivity reaction that is mediated by hapten-specific T cells. Dinitrochlorobenzene (DNCB)-induced contact hypersensitivity of the skin is a commonly-used mice model for studying the pathogenesis of contact dermatitis. IK cytokine is known to suppress IFN-γ induced expression of MHC class II molecules on B cells by increasing cAMP. Recently, we reported that truncated IK (tIK) cytokine-expressed transgenic (Tg) mouse ameliorated inflammatory arthritis symptoms by suppressing the differentiation of TH1 and TH17 cells and the activation of macrophages. However, there are still limited studies showing the functionality of this cytokine in inflammatory diseases such as ACD. Here, we investigated whether tIK cytokine expressing Tg mice are less susceptible for DNCB induced ACD. DNCB treatment caused severe dermatitis symptoms in wild type (WT) including weight loss, increased ear thickness and scratching behavior but those symptoms are significantly reduced in tIK Tg mice. The weights of draining lymph node (dLN) and spleen were also much less in tIKTg mice. In addition, tIK overexpression decreased IgE serum level, mRNA transcript of mast cell associated factors in Tg mice compared to WT mice. Analyzing T cell subpopulation in dLN revealed that Th2 and Th17 cell differentiation were suppressed by tIK expression while Tregs and Th1 differentiation were not affected. Taken together, our results presented here suggest that tIK expression effectively attenuate DNCB induced allergic contact dermatitis lesions by modulation Th cell differentiation. Futher studies are needed to elucidate immunological and molecular mechanisms by which tIK functions on this disease model.
Regulation of IL-17-producing subsets of NKT and γδ-T cells by syndecan-1 and relevance to psoriasis
Authors: Jaiswal Anil Kumar , Sadasivam Mohanraj , Archer Nate , Miller Lloyd S , Hamad Abdel Rahim A 
Published: January 2023

Abstract
IL-17 is a potent proinflammatory cytokine that protects the host against extracellular bacteria and fungi and it also drives psoriasis in humans and in the imiquimod-treated mouse model of psoriasiform dermatitis. Although IL-17A contributes to disease pathogenesis in psoriasis as two IL-17A neutralizing mAbs have recently been approved for treatment of moderate to severe psoriasis, less is known about the mechanisms that regulate the numbers of IL-17A-producing cells. Production of IL-17 by innate-like T cells and Th17 cells provides a challenge and an opportunity for identification and selective targeting of appropriate cellular source(s). Here we show that the heparan sulfate proteoglycan syndecan-1 (sdc1) is a major regulator of IL-17A production by γδ-T cells and NKT cells. Sdc1 is selectively expressed on IL-17A-producing subsets of NKT (NKT17) and γδ-T cells in the thymus and in the periphery. Lack of sdc1 significantly increases frequency and absolute numbers of NKT17 and IL-17A+ γδ-T cells in the thymus and the periphery in sdc1 knockout mice. In Sdc1KO B6 mice, a population of IL-17A-producing γδ-T cells are significantly increased in the dermis and epidermis. Using the imiquimod-induced psoriasiform dermatitis model in C57BL/6 mice, we found that imiquimod treatment led to a significantly higher percentage of IL-17A+ γδ-T cells and Th17 cells and more severe skin disease. Insights into the underlying mechanisms and therapeutic implications are being investigated and will be presented at the meeting
Differential role of oxidative stress pathways and microbiota in the development of allergen specific IgE following chronic ingestion of low doses of cadmium
Authors: Kim Eunsoo , Lembert Melanie M. , Opiyo Stephen O. , Ahmer Brian M. , Cormet-Boyaka Estelle , Boyaka Prosper N 
Published: January 2023

Abstract
Chronic ingestion of low doses of cadmium is becoming a major public health issue due to the presence of this heavy metal in contaminated water and its accumulation in leafy vegetables, fish and grains. Environmental pollutants are believed to contribute to the increased incidence of allergy diseases, but underlying mechanisms remain poorly understood. We found that C57BL/6 mice chronically exposed to low doses of cadmium through drinking water develop higher titer of antigen-specific IgE responses upon oral sensitization. Cadmium-treated mice also exhibited higher IL-17 and Th1 responses in the airways and displayed more severe signs of airway allergic responses, upon nasal antigen challenge. Analysis of innate responses in the intestine revealed that ingestion of low doses of cadmium activated both the canonical and the non-canonical NF-κB pathway and promoted proinflammatory cytokine and antimicrobial responses through activation of oxidative signaling pathways including Duox2 and Nrf2. Chronic ingestion of low doses of cadmium also resulted in a dysbiosis of the intestinal microbial community, which persisted long after exposure was interrupted. Germ-free C57BL/6 mice exposed to cadmium and sensitized under the same conditions failed to develop elevated allergen-specific IgE responses. Finally, when transferred into untreated mice, the fecal microbe of cadmium-treated mice increased the allergen-specific IgE responses in the recipients confirming the central role the dysbiosis in the induction of allergic responses. Microbial products mediating the allergy-promoting effect of cadmium are being identified in ongoing studies.