bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pivotal role for the non-receptor tyrosine kinase SRMS in IRF3-dependent innate antiviral immune response in murine cells
Authors: Wang Ruixue , Zhang Yunzhi , Li Nan L , Yang Darong , Wang Dang , Zhou Zhi , Potts Malia B , Li Kui 
Published: August 2023

Abstract
Upon viral infections, RIG-I-like receptors (RLRs) sense cytosolic viral RNAs and initiate signaling pathways culminating in the activation of IRF3 and subsequent type I interferon (IFN) antiviral response. This intrinsic protective mechanism is orchestrated by a host of positive and negative regulators, which collectively govern the magnitude and duration of antiviral signaling. SRMS is an understudied non-receptor tyrosine kinase frequently overexpressed in breast cancers. SRMS restrains autophagy and promotes tumor growth, although its physiological function is unclear. We report here that SRMS is critical for IRF3-dependent innate antiviral response in murine cells. Depletion of SRMS impaired virus- or dsRNA-induced expression of type I and III IFNs and ISGs in mouse embryonic fibroblasts (MEFs), mouse hepatoma hepa1–6 cells, and primary mouse lung fibroblasts, concomitant with heightened viral replication. Mechanistically, SRMS loss led to diminished phosphorylations of TBK1 and IRF3, IRF3 dimerization and nuclear translocation. The kinase activity of SRMS, however, was dispensable. Reconstituting the expression of SRMS of mouse or human origin, be it wild-type or kinase-dead protein, in SRMS-null MEFs restored antiviral signaling. Autophagy regulation was not involved, either. Interestingly, antiviral gene expression via the RLRs in human U2OS and MDA-MB-231 cells was not impacted by SRMS deletion, suggesting signaling redundancy in human cells. Altogether, our data uncover a novel role of SRMS in controlling IRF3-dependent innate antiviral responses and describe a non-canonical, kinase- and autophagy-independent regulatory mechanism that operates differentially between mouse and human species.
R21 AI142044
Differential role of TLR7 signaling in SARS-CoV-2-induced antiviral and inflammatory responses
Authors: Ghimire Roshan , Patton Titus , Shrestha Rakshya , Chanda Debarati , More Sunil , Channappanavar Rudragouda 
Published: August 2023

Abstract
Since its emergence in 2019, SARS-CoV-2 has caused significant morbidity and mortality in humans. SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses drive acute lung injury and severe pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and pathogenic inflammatory responses are not well defined. Since CoVs are single-stranded RNA (ssRNA) viruses that make double-stranded RNA (dsRNA) intermediates during replication, we assessed the antiviral and pro-inflammatory roles of ssRNA and dsRNA mimics in mouse macrophages. We show that R837-TLR7 signaling induced excessive inflammation, while PolyIC-TLR3/MDA activation caused robust IFN production. Since R837-TLR7 induced high levels of inflammatory cytokines, using a novel mouse-adapted SARS-COV-2, we examined the role of TLR7 signaling in COVID-19 pathogenesis. Our results show that TLR7 KO mice were more susceptible to SARS-CoV-2 infection as compared to WT mice. Further investigation of SARS-CoV-2 infected lungs showed significantly reduced mRNA levels of antiviral interferons (IFNα/β/λ), ISGs (ISG15 and CXCL10), and several pro-inflammatory cytokine/chemokines in TLR7 KO lungs compared to WT. Interestingly, immunolabelling of cells isolated from infected WT and TLR7 KO lungs showed a high neutrophil count in TLR7 KO mice compared to WT mice. Furthermore, reduced lung IFN levels and increased mortality correlated with high lung viral titer in TLR7 KO mice. In summary, our findings conclusively establish that TLR7 signaling is protective during SARS-CoV-2 infection, and despite TLR7-mediated robust inflammatory cytokine production, TLR7-induced IFN and ISG responses play a key role in host protection.
Role of Caspase-11 in house dust mites-mediated lung inflammation
Authors: Khweek Arwa Abu , Joldrichsen Marisa R R , Boyaka Prosper N , Amer Amal O 
Published: August 2023

Abstract
Asthma is a long-term recurring inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, chronic airway inflammation and bronchial hyper-responsiveness. House dust mites (HDM), such as Dermatophagoides pteronyssinus, are an unsurpassed cause of atopic sensitization and the major causes of allergic asthma worldwide. The multiprotein complexness of the canonical and noncanonical inflammasomes assemble in response to pathogen or danger-associated molecular patterns (PAMPs or DAMPs). We have shown that caspase-11 expression is induced in vitro in response to HDM. Treatment with TH2 cytokines such as IL-4 and IL-13 mediates caspase-11 expression. Additionally, caspase-11−/− macrophages show reduced release of IL-6, IL-12, and KC, and express lower levels of costimulatory molecules (e.g., CD40, CD86 and MHCII) in response to HDM stimulation. Notably, similar level of IgE responses and similar degree of hypothermia in response to nasal HDM challenge were seen in WT and caspase-11−/− mice following HDM sensitization. However, altered inflammatory responses and reduced neutrophilia in bronchiolar alveolar lavage fluid (BALF) and in representative histopathological lung tissues were seen in the caspase-11−/− mice. Therefore, caspase-11 is a regulator of airway inflammation in response to HDM exposure.
PTEN regulation of AcetyCoA/HAT activity regulates macrophage activation during Staphylococcus aureus infection
Authors: Shili Cedrick Ndhumba , Salina Ana , Faneuf Eden , Eddie Alex , Serezani Henrique 
Published: August 2023

Abstract
Sepsis is a life-threatening condition characterized by systemic inflammation, multiple organ failure, and death. Macrophage metabolism and actions play a critical role in sepsis pathogenesis. Fatty acid metabolism was identified as one of the most promising metabolic predictors for survival in sepsis. The phosphatase and tensin homolog (PTEN) is a critical regulator of cell growth and metabolism and influences different arms of the innate immune response. Here, we seek to investigate whether PTEN is a bridge between immunometabolism and gene expression in macrophages during S. aureus infection, WT (PTENfl/fl) and KO (PTENfl/fl_LysMCre) were infected i.v. with methicillin-resistant Staphylococcus aureus (MRSA) and kidney and blood were collected on day three. PTEN deficiency decreased MRSA kidney bacterial loads, as evidenced by IVIS. Bulk RNAseq analysis of kidney macrophages from infected WT and PTEN KO mice showed reduced expression of genes involved in fat acids synthesis, such as (FASN), which correlated with decreased levels of cellular acetyl-coenzyme A in MRSA-infected macrophages. Acetyl-CoA is a substrate for the epigenetic enzyme histone acetyltransferase (HAT) and favors gene expression. Infected PTEN KO macrophages showed lower nuclear p300/CBP HAT activity than cells from WT mice and decreased H3K9 and H3K18 acetylation (involved in open chromatin) in infected macrophages. Studies underpinning the role of the PTEN/HAT axis in MRSA infection are underway. These data suggest that PTEN is required for gene expression of genes involved in fatty acid metabolism, which might reduce the cytokine storm seen during sepsis.
Maternal Antibiotic Treatment Dysregulates Goblet Cell Associated Antigen Passages in Neonatal Mice
Authors: McDonald Keely G , Schill Ellen M , Joyce Elisabeth , Floyd Alexandria N , Newberry Rodney D 
Published: August 2023

Abstract
Maternal antibiotic treatment (MAT) disrupts the development of the neonatal microbiome, intestinal immune development and increases susceptibility to sepsis in mouse models. Mechanisms by which MAT disrupts neonatal intestinal immune function will facilitate the development of novel strategies to reduce neonatal sepsis risk. Intestinal goblet cell associated antigen passages (GAPs) are portals for physiologic exposure of the immune system to commensal gut bacteria and luminal antigens. GAPs are inhibited by epidermal growth factor receptor (EGFR) signaling, colonic GAPs are closed prior to postnatal day (P) 10 in mice when luminal EGF levels from breast milk are high, then open after P10 when breast milk EGF levels decline. When colonic GAPs are opened inappropriately due to low levels of EGF prior to P10 or dysbiosis of the gut microbiota after weaning, they can facilitate pathological bacterial translocation. Pups of dams treated with ampicillin and neomycin in their drinking water from pup P1–8 had significantly more open GAPs in the small intestine (SI) compared to controls. These data suggest that MAT creates a permissive environment for SI GAPs in the neonatal period which could allow pathologic bacterial translocation. MAT pups weighed significantly less and were significantly hypoglycemic compared to pups from control dams, after weaning MAT pups recover to a normal weight. We hypothesize that MAT pups have reduced intestinal EGFR signaling, leading to stunted growth and irregular opening of GAPs in the SI and colon. These data suggest maternal antibiotic treatment may be a risk factor for sepsis and growth failure in premature neonates.
Acquired resistance against skin penetration by Strongylodies ratti is dependent on IL-33 expressing APCs
Authors: Jean E Evonne , Herbert De’Broski 
Published: August 2023

Abstract
Interleukin 33 (IL-33) is an alarmin cytokine released from damaged epithelia that is essential for protection against gastrointestinal (GI) helminth (worm) infection, but whether IL-33 serves any role in cutaneous immunity against parasites remains unclear. While epithelial cells are considered the predominant source of IL-33, our recent work demonstrates that CD11c+ myeloid antigen presenting cells can express IL-33 to shape Type 2 immunity. We developed a percutaneous infection model using Strongylodies ratti, a rodent-specific GI helminth, to better understand mechanisms of host protection and the potential role for IL-33. Data show that C57BL/6 mice develop resistance to percutaneous infection upon secondary challenge, but IL-33 deficient mice lack this capacity. Surprisingly, mice with a selective IL-33 deficiency only in myeloid APC (CD11cCre) also failed to develop secondary resistance to S. ratti, suggesting myeloid-derived IL-33 is essential for cutaneous immunity. Mechanistically, we find that loss of myeloid IL-33 impairs recruitment of gd T cells that express the IL-33 receptor ST2 and gene deficient mice that lack all gd T cells show defective protective immunity against S. ratti. Moreover, we propose that IL-33 drives a noncanonical Type 2 immunity, because mice lacking the Type 2 transcription factor STAT6 (Signal transducer and activator of transcription 6), have no defects in primary or secondary cutaneous immunity. Our work implies that myeloid APCs are a necessary source of IL-33 that drives acquired immunity against helminths, potentially through regulating gd T cell effector function(s). Ongoing studies seek to understand how myeloid APC derived IL-33 controls gd T cells to promote cutaneous immunity.
NIH (R01 AI095289 and R01 GM083204) NSF GFRP
Mathematical Modelling of Neutrophil Responses to Aspergillus
Authors: Wheeler Matthew , Yang Ning , Whitten Spencer , Goddard Yana , Vieira Luis Sordo , Scindia Yogesh , Laubenbacher Reinhard , Mehrad Borna 
Published: August 2023

Abstract
Invasive aspergillosis is a dangerous infection commonly affecting immunocompromised patients. The spores of the fungal pathogen, Aspergillus, are found ubiquitously in the environment and are inhaled daily by all humans. These spores are cleared quickly and effectively healthy hosts without developing infection. On the other hand, patients with impaired immunity, can develop an invasive pneumonia with poor outcomes. Neutrophils are essential to the host defense against aspergillosis, both in direct fungal killing and as modulators of immunity against the pathogen. To better understand this role, we conducted a transcriptomic time series comparing the responses of human neutrophils to Aspergillus. Differential gene expression analysis as well as gene enrichment analysis indicated an up regulation of number of transcriptional markers and pathways including NFkB, NR4A, TNF, as well as neutrophil degranulation, cytokine-mediated signaling, chemokine signaling, and TREM1 signaling among others. Combining this data with known mechanisms and pathways from the literature, we built a mathematical model describing the intracellular pathways which determine the neutrophil’s response after detecting Aspergillus. Very few mathematical models have been built modeling intracellular mechanisms of a neutrophil and none that we know of which relates to the interaction between neutrophils and this organism. We intend to use our model to make predictions on the effects of altering different pathways within the cell. Moreover we intend to use this model in a larger systems model describing the immune system response to invasive pulmonary aspergillosis.
Supported by: R01AI135128, U01EB024501, Keck Foundation Medical Research Grant 994413.
Vaccine Immunology in the context of COVID-19
Authors: Sika-Paotonu Dianne 
Published: August 2023

Abstract
Evidence at the start of the pandemic indicated that Māori and Pacific peoples were vulnerable to being disproportionately impacted and affected by COVID-19, indicating prioritisation with respect to COVID-19 vaccination and prevention efforts would be needed. Significant health inequities already existed for Māori and Pacific peoples prior to the COVID-19 outbreak, with the pandemic exacerbating pre-existing health inequities for vulnerable groups including Māori and Pacific peoples. An elimination strategy was pursued at the start of the COVID-19 pandemic in Aotearoa/New Zealand, a suppression strategy was then followed later. The initial lockdown periods helped keep the SARS-CoV-2 virus away while trying to get people vaccinated once the COVID-19 vaccines became available in Aotearoa/New Zealand. Efforts to spread mis/disinformation about the SARS-CoV-2 virus and COVID-19 vaccines were initiated early during the COVID-19 outbreak. The purpose of this work was to focus upon the immunological areas pertaining to the COVID-19 vaccines, to ensure appropriate scientific communication approaches that would support the COVID-19 vaccination roll-out. This work involved the utilisation of an online videoconferencing tool to support urgent communication efforts for the general public and lay audiences that would also support the countering of mis/disinformation about the COVID-19 vaccines in particular. Those who participated responded positively and indicating this approach helped demystify COVID-19 vaccines, explained how they worked, and encouraged vaccination. This work showed how appropriately presented COVID-19 vaccine information in the online setting could help counter mis/disinformation efforts.
Wellington School of Medicine & Health Sciences, University of Otago.
Cross-reactive seasonal coronavirus antibody responses contribute to antibody-mediated effector functions against SARS-CoV-2 in individuals in Kenya
Authors: Ulusan Sinem , Bai Shuangyi , Murrell Amelie , Osoro Eric , Dawa Jeanette , Ngere Isaac , Langat Robert , Robinson James , Norton Elizabeth , Njenga M Kariuki , Gunn Bronwyn 
Published: August 2023

Abstract
Much of sub-Saharan Africa has fared the SARS-CoV-2 pandemic with reduced disease and death even with low uptake of vaccines, little to no infection mitigation strategies, and clear serologic evidence of infection. While warmer weather, a youthful population, and microbiome have been posited to explain the differences in Africa compared to Americas, we aimed to determine if there was a unique humoral immune response to SARS-CoV-2. To do this, we analyzed SARS-CoV-2 seropositive and seronegative samples from Nairobi, Kenya and compared to a cohort collected in the US in late 2020. We measured the levels of antibodies (Abs) against SARS-CoV-2 Spike [S], receptor binding domain [RBD], and nucleocapsid [N] and hCoVs (229E, NL63, OC43, HKU1) S using a multiplexed Luminex-based assay, and we measured induction of antiviral Ab functions including Ab-dependent cellular phagocytosis (ADCP), neutrophil phagocytosis (ADNP), neutralization, NK cell activation (ADNKA), and complement deposition (ADCD). Correlation network analysis revealed that Ab effector functions were strongly associated with SARS-CoV-2 S, RBD and N-specific Abs in both Kenyan- and US-based cohorts. Surprisingly, we observed that hCoV-specific Abs were correlated with the effector functions against SARS-CoV-2 in the Kenyan samples, but not in the US samples. A subset of Kenyan seronegative subjects displayed ADCP and ADNP against SARS-CoV-2, which was reduced when HKU1-specific IgG was depleted from samples, suggesting cross-reactive Ab responses from hCoVs may augment SARS-CoV-2 immunity. Thus, together these data suggests that unique Ab-mediated functions induced by hCoVs in Africa may help explain the disparity in COVID-19 severity observed across the globe.
Robust T cell responses to the Pfizer/BioNTech vaccine compared to infection and evidence of attenuated CD8+ T cell responses due to COVID-19
Authors: Gao Fei , Mallajoysula Vamsee , Altman John D , Wang Taia T , Nadeau Kari C , Boyd Scott D , Pulendran Bali , Davis Mark M 
Published: August 2023

Abstract
The COVID-19 pandemic has resulted in rapid development of several novel vaccine platforms, including the mRNA-based Pfizer/BioNTech vaccine. As of October 2022, more than 3.8 billion Pfizer/BioNTech vaccines were administrated to people in 180 countries. Meanwhile, the total number of COVID-19 cases has reached 627 million globally.
We recently developed a new antigen-specific T cell staining tool— ”spheromer” that is able to label T cells more efficiently and capture a broader swath of the repertoire than any other available platform. Using spheromers loaded with SARS-CoV-2 peptides, we applied a panel covers 49 epitopes spanning the entire genome to characterize the magnitude and durability of antigen-specific T cell responses at single-epitope resolution.
Using very sensitive “spheromer” peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in very robust peripheral blood responses to predicted SARS-CoV-2 spike peptides bound to either class-I or class-II MHC alleles. These peaked at 9.8% and 7.5% for the dominant CD4+ (HLA-DRB1*15:01/S191) and CD8+ (HLA-A*02/S691) T cell epitopes. Interestingly, the antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring one week post the second vaccination (boost), whereas CD8+ T cells didn’t peak until two weeks later. These responses were much higher than in COVID-19 patients. We also found that prior SARS-CoV-2 infection decreased the CD8+ T cell response post vaccination by 2.4 to 41.4-fold at peak, and that the remaining cells were less responsive, suggesting that the virus can profoundly damage an individuals’ CD8+ T cell response.
1. Howard Hughes Medical Institute and NIAID grant AI057229 to Mark.M.Davis; 2. Bill and Melinda Gates Foundation grant OPP1113682, Center for Human Systems Immunology, to Mark.M.Davis; 3. U01 AI140498 to to Mark.M.Davis.
Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19
Authors: Laurent Paoline , Yang Chao , Rendeiro Andre L , Nilsson-Payant Benjamin , Carrau Lucia , Chandar Vasuretha , Bram Yaron , tenOever Benjamin , Elemento Olivier , Ivashkiv Lionel , Schwartz Robert , Barrat Franck J 
Published: August 2023

Abstract
Lung-infiltrating macrophages create a marked inflammatory milieu in a subset of patients with COVID-19 by producing a cytokine storm, which correlates with increased lethality. However, these macrophages are largely not infected by SARS-CoV-2, so the mechanism underlying their activation in the lung is unclear. Type I interferons (IFN-I) contribute to protecting the host against SARS-CoV-2 but may also have some deleterious effect, and the source of IFN-I in the lungs of infected patients is not well defined. Plasmacytoid dendritic cells (pDCs), a key cell type involved in antiviral responses, can produce IFN-I in response to SARS-CoV-2. We observed the infiltration of pDCs in the lungs of SARS-CoV-2–infected patients, which correlated with strong IFN-I signaling in lung macrophages. In patients with severe COVID-19, lung macrophages expressed a robust inflammatory signature, which correlated with persistent IFN-I signaling at the single-cell level. Hence, we observed the uncoupling in the kinetics of the infiltration of pDCs in the lungs and the associated IFN-I signature, with the cytokine storm in macrophages. We observed that pDCs were the dominant IFN-α–producing cells in response to the virus in the blood, whereas macrophages produced IFN-α only when in physical contact with infected epithelial cells. We also showed that IFN-α produced by pDCs, after the sensing of SARS-CoV-2 by TLR7, mediated changes in macrophages at both transcriptional and epigenetic levels, which favored their hyperactivation by environmental stimuli. Together, these data indicate that the priming of macrophages can result from the response by pDCs to SARS-CoV-2, leading to macrophage activation in patients with severe COVID-19.
Supported by NCI grant T32CA203702. Supported by NIH grant 1R01AI132447, the Scleroderma Research Foundation, the Scleroderma Foundation, and a grant from the HSS Research Institute to study the role of pDCs in SARS-CoV-2 pathogenesis. Supported by NIH grants AI046712 and AR050401. Supported by NIH grants UL1TR002384, R01CA194547, and P01CA214274; LLS SCOR grants 180078-01 and 7021-20; and Starr Cancer Consortium grant I11-0027. Supported by NIDDK R01DK121072, NIDDK R01DK119667, NCI R01CA234614, and NIAID R01AI107301. Supported as an Irma Hirschl Trust Research Award Scholar.