bluuebunny/crossref_metadata_2025_split huggingface dataset:
Candida albicans Induces Foaming and Inflammation in Macrophages through FABP4: Its Implication for Atherosclerosis
Authors: Alrashed Fatema , Haider Mohammed , Albaqsumi Zahraa , Alobaid Khalid , Alqabandi Rawan , Al-Mulla Fahd , Ahmad Rasheed 
Published: January 2023

Abstract
Atherosclerosis is a chronic degenerative disorder characterized by lipid-dense plaques and low-grade inflammation affecting arterial walls. Foamy macrophages are important in the formation of atherosclerotic plaques and the induction of low-grade inflammation. Candida albicans is the major cause of candidiasis in immunocompromised patients, including those with diabetes mellitus. However, the role played by C. albicans in macrophage foaming and the associated inflammation is poorly understood. We investigated whether C. albicans induces foaming along with inflammation in macrophages and, if so, by which mechanism(s). We incubated THP-1 macrophages with heat-killed C. albicans (HKCA). HKCA-induced lipid accumulation in macrophages along with increased expression of inflammatory markers, including CD11b and CD11c or expression and secretion of IL-1β. HKCA also increased the expression of PPAR, CD36, and FABP4 in macrophages. Mechanistically, we found that the foamy and inflammatory macrophage phenotype induced by HKCA requires FABP4 because disruption of FABP4 in macrophages either by chemical inhibitor BMS309404 or small interfering RNA (siRNA) abrogated foam cell formation and expression of inflammatory markers CD11b, CD11c, and IL-1β. Furthermore, HKCA-treated macrophages displayed high expression and secretion of MMP-9. Inhibition of FABP4 resulted in suppression of HCKA-induced MMP-9 production. Overall, our results demonstrate that C. albicans induces foam cell formation, inflammation, and MMP-9 expression in macrophages via the upregulation of FABP4, which may constitute a novel therapeutic target for treating C. albicans-induced atherosclerosis.
Supported by Kuwait Foundation for the Advancement of Sciences (KFAS) (RA CB-2019-002)
A rare case of Liraglutide-induced iatrogenic amyloidosis
Authors: Aujla Sumeet K , Jasti Pallavi 
Published: January 2023

Abstract
Iatrogenic amyloidosis has been linked to injectable drugs such as Enfuvirtide and insulin, which can cause cutaneous deposition of insoluble proteins. We present a rare case in which Liraglutide injections resulted in an iatrogenic amyloidosis.
Our patient is a 63 year-old female with a 12-year history of type 2 diabetes mellitus complicated by peripheral neuropathy, on Liraglutide for 10 years, who presented with a 4-month history of developing abdominal subcutaneous masses. She underwent abdominal soft tissue mass excision and biopsy, which revealed Congo red stain positive for amyloid and apple green birefringence on polarization. Lab work and skeletal survey showed no abnormalities. Serum protein electrophoresis revealed no monoclonal protein. Mass spectrometry of amyloid tissue at Mayo clinic revealed Liraglutide detection by immunohistochemistry using glucagon antibodies, dense amyloid deposits typical of amyloid caused by injectable drugs, and a peptide profile inconclusive for an amyloid type-all confirming a diagnosis of iatrogenic amyloidosis caused by Liraglutide injection.
This case highlights a very rare side effect of Liraglutide injections. If biopsy confirms amyloid deposits, further workup is absolutely necessary to differentiate the forms of amyloidosis, as the treatment varies based on the kind of amyloidosis. Diabetic patients who are on Liraglutide can have other signs and symptoms which overlap with symptoms of AL amyloidosis. Hence further workup including mass spectroscopy to type the amyloid are vital.
Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA–cGAS–STING Signaling Axis
Authors: Torres-Odio Sylvia , Lei Yuanjiu , Gispert Suzana , Maletzko Antonia , Key Jana , Menissy Saeed , Wittig Ilka , Auburger Georg , West A Phillip 
Published: January 2023

Abstract
Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease that degrades damaged or misfolded mitochondrial proteins. CLPP-null mice exhibit growth retardation, deafness, and sterility, resembling human Perrault syndrome (PS). Absence of CLPP also leads to immune system alterations but the molecular mechanisms and underlying signaling pathways remain unclear. In this study, we report the steady-state activation of type I IFN signaling and antiviral gene expression in CLPP-deficient cells and tissues, resulting in marked resistance to RNA and DNA virus infection. Depletion of the cyclic GMP-AMP (cGAS)-stimulator of IFN genes (STING) DNA sensing pathway reduces steady-state IFN-I signaling and abrogates the broad antiviral phenotype of CLPP-null cells. We report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations, a phenotype also observed in CLPP mutant fibroblasts from PS patient. Our work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have implications for understanding PS and other human diseases involving CLPP dysregulation and proteostasis.
Office of the Assistant Secretary of Defense for Health Affairs, U.S. Department of Defense (W81XWH-17-1-0052; W81XWH-20-1-0150); National Heart, Lung, and Blood Institute, National Institutes of Health (R01HL148153)
Leukocyte associated immunoglobulin-like receptor 1 (LAIR1) is immunoprotective in S. aureus skin infection
Authors: Dorando Hannah K , Tomaszewski Kelly , Tian Ling , Wurtz Mellisa , Quinn Chaz , Mutic Evan , Wardenburg Juliane Bubeck , Payton Jacqueline 
Published: January 2023

Abstract

Background
Inhibitory immune receptors are important for maintaining immune homeostasis. We recently identified a member of this group, LAIR1, in advanced cutaneous T-cell lymphoma, a cancer of skin-invasive T cells associated with recurrent and often fatal S. aureus skin and soft tissue infections. Based on these data, we predicted that LAIR1 plays a role in immune response to S. aureus infection.

Objective
Determine the impact of LAIR1 loss on S. aureus skin infection.

Methods
Wild type (WT) and Lair1 knock-out (KO) mice were subjected to subcutaneous S. aureus skin infection. In skin lesions, we measured size, bacterial clearance, immune cell recruitment (flow cytometry), and cytokine production (ELISA). We compared changes in gene expression (qRT-PCR), cytokine production (ELISA), and complement-mediated phagocytosis (flow cytometry) in WT and Lair1 KO bone marrow-derived macrophages (BMDMs) infected with S. aureus. Finally, we conducted RNAseq from S. aureus skin lesions and bone marrow neutrophils and monocytes 2 and 5 days post-infection (dpi), and from in vitro-infected BMDMs.

Results
Lair1 KO mice had significantly larger areas of abscess and dermonecrosis by 1 dpi and decreased bacterial clearance at 2 dpi. BMDMs showed defects in proinflammatory cytokine production and complement-mediated phagocytosis.

Conclusions
Taken together, these data support a previously unrecognized role for LAIR1 in myeloid response to bacterial infection.
Lactic acid bacteria derived-bioactive molecules condition an in vitro cell model into a tolerogenic dendritic-like cell phenotype
Authors: Saleem Lin , Jeffrey Michael P , Clarke Sandra T , Green-Johnson Julia M 
Published: January 2023

Abstract
Retinoic acid (RA) is a vitamin A metabolite; CD103+ dendritic cells (DCs) acquire a tolerogenic phenotype through an RA-dependent mechanism, driving the differentiation of gut-homing regulatory T cells in the gut mucosa. Growing evidence shows bioactive molecules derived from lactic acid bacteria exhibit immunomodulatory activity by interacting with antigen presenting cells (APCs), stimulating their differentiation and altering their phenotype to further shape adaptive immunity. We utilized the monocytic THP-1 cell line as an in vitro model to examine the impact of the Lacticaseibacillus rhamnosus secretome (LrS) and interactions with RA on APC differentiation into a tolerogenic dendritic-like cell (DLC) phenotype. THP-1 monocytes were treated with Phorbol 12-myristate 13-acetate to drive differentiation into macrophages, then conditioned with the LrS and/or RA for 24, 48 or 72 hours. Expression of key DC markers CD11b, CD11c, DC-SIGN, CD83, CD80 and CD103 increased, while expression of proinflammatory marker CD64, co-stimulatory marker CD86 and MHC class II molecule HLA-DR was reduced. Cytokine profiling revealed LrS + RA co-treatment increased the production of immunoregulatory cytokines IL-10 and IL-1RA. Expression of NFKB1 and NFKB2, key genes involved in the activation of the NF-κB canonical and non-canonical pathways was induced by 48 hours of LrS conditioning, accompanied by increased expression of CD40 and IDO1, indicating an ability to drive DLC maturation and induce co-stimulatory capacity. Deciphering the mechanisms behind these types of microbiota-host interactions gives insight into how microbial metabolites can influence immune maturation and maintain immune homeostasis.
Supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2017-05237
Innate Memory Following Intravenous BCG in Neonatal Pigs
Authors: Byrne Kristen A , Hill Dana C , Loving Crystal L 
Published: January 2023

Abstract
In adults and rodents, Bacillus Calmette-Guerin (BCG) inoculation alters innate immune cells via epigenetic and metabolic modifications resulting in heightened responses to subsequent microbial exposure (innate memory). Neonatal BCG vaccination can correlate to improved disease resistance in some human populations, but studies with human infants are extremely limited. Pigs are a relevant biomedical model for human disease and offer a path to directly asses neonatal innate memory to improve disease resilience. BCG administration in a weaned (3 week old) pig model elicited monocyte memory only with intravenous (IV) but not subcutaneous administration. Therefore, to evaluate induction of innate memory in neonates, 3–5 day old piglets received intravenous (IV) BCG or mock and ex vivo monocyte memory was assessed. At 3 and 6 weeks post-BCG, monocytes from the IV-BCG group had elevated TNF but not IL-1β production in response to LPS stimulation ex vivo, indicating neonatal BCG exposure induced innate memory. Interestingly, broncho-alveolar lavage cells from IV-BCG group had minimal differences compared to mock group in response to LPS, suggesting IV-BCG alters responses in peripheral monocytes differently than tissue resident myeloid-lineage cells. Overall, IV-BCG administration induced monocyte memory in neonatal pigs, highlighting piglets as a valuable model for continued study on the utility of BCG induced innate memory to improve disease resilience.
This work was funded by USDA-NIFA AFRI grant # 2019-07511 as part of the joint USDA-NIFA-NIH Dual Purpose with Dual Benefit: Research in Biomedicine and Agriculture Using Agriculturally Important Domestic Animal Species Program and USDA-ARS CRIS project 5030-32000-225-000D
In vitro assessment of neutrophil response to proteins and antibodies of SARS-CoV-2
Authors: Almeida Nathalie Bonatti Franco , Fantone Kayla Marie , Sarr Demba , Grenfell Rafaella Fortini Queiroz , Rada Balazs 
Published: January 2023

Abstract
The SARS-CoV-2 virus caused a worldwide epidemic of respiratory disease (COVID-19). Acute respiratory distress syndrome (ARDS) has been associated with severe COVID-19. Activation of neutrophils have been linked to ARDS in COVID-19. While emerging results indicate that SARS-CoV-2 leads to neutrophil activation, it remains unknown which components of the virus are responsible for this. We assessed in vitro how the spike (S) protein and anti-spike antibodies affect neutrophils. Human neutrophils were isolated from healthy donors. Different concentrations of recombinant S protein, a monoclonal antibody (mAb) produced against the S protein and their immunocomplex were used to stimulate neutrophils. Unstimulated and PMA-treated neutrophils were used as negative and positive controls. Reactive oxygen species (ROS) production was measured by Diogenes chemiluminescence, and cell death was measured by fluorescence. While no significant increase of cell death was observed, neutrophils responded with a dose-dependent increase in the production of ROS when stimulated with either the S protein or the mAb. Neutrophils produced significantly (p&lt;0.05) more ROS when activated by 1,000 ng of the mAb. Immune complex stimulation (1,000 ng each component) of human neutrophils also lead to significantly (p&lt;0.005) enhanced ROS production compared to stimulations by the protein or the mAb alone. Neutrophil cell death was also significantly enhanced when stimulated by the immune complex (500 ng and 1,000 ng each component) (p&lt;0.05, p&lt;0.005, respectively). Our work indicates that the S protein and its immune complex formed with mAb could stimulate neutrophils in vitro and contribute to neutrophil-mediated tissue damage in COVID-19 patients.
Supported by grants from: Oswaldo Cruz Foundation, International Graduate Programme (PrInt FIOCRUZ-CAPES), University of Georgia and NIH.
Type III IFNs (IFNλs) expressed in tuberculosis (TB) granulomas enhance anti-mycobacterial activity of macrophages
Authors: Talukdar Priyanka , Junecko Beth Fallert , Mattila Joshua T 
Published: January 2023

Abstract
Granulomas are the pathologic hallmark of Mycobacterium tuberculosis (Mtb) infection. How a granuloma functions at limiting Mtb growth depends on the qualitative balance of pro- and anti-inflammatory cytokines in these lesions. Understanding which cytokines constitute protective and detrimental inflammation in TB is important for the improvement of current TB therapeutics. The type III interferon (IFN) family is composed of four isoforms and includes IL-29, IL-28A, IL-28B, and IFNλ4. These cytokines may be important regulators of inflammation in TB, yet little is known about their relation with TB or whether they have different properties in granulomas than type I IFN (IFNα/β), which is associated with severe TB. We identified that IFNλ is expressed at a significantly higher level in TB granulomas than non-disease lung, and negatively correlates with the CFU/granuloma. IHC characterization of IFNλ expression in granulomas revealed neutrophils and macrophages expressing IFNλ1 and IFNλ4, with neutrophils having a higher percentage of IFNλ expression. IFNλ1 and IFNλ4 differed in their intracellular localization, IFNλ4 having a significantly higher nuclear localization in macrophages than IFNλ1. IFNλ1 treatment of monocyte-derived macrophages induced the expression of different proinflammatory genes at the transcript level and costimulatory molecules like CD86 at the protein level. Further, pretreatment of macrophages with IFNλ1 inhibited the transcriptional activity in a reporter Mtb strain and follow-up experiments suggested this was accompanied by increased acidification of macrophage lysosomes. Our findings suggest that IFNλs may have unappreciated roles in regulating inflammation at the site of disease in TB.
Supported by Grant from NIH entitled Pitt HIV-TB Research and Training Program in India (grant number: D43 TW010039)
Leptospira spp. are a potent activator of Type I IFN responses via the cGAS-STING pathway
Authors: Gupta Suman , Matsunaga James , Cassel Suzanne L , Haake David A , Sutterwala Fayyaz S 
Published: January 2023

Abstract
Leptospirosis is a widespread zoonotic disease which can be potentially fatal in infected humans and dogs. The spirochetal bacteria Leptospira interrogans is the major causative agent of leptospirosis. Rodents serve as reservoir hosts for L. interrogans and once colonized they continue to shed bacteria in their urine. The host immune response to Leptospira spp. remains poorly defined. Leptospiral lipopolysaccharide and lipoproteins can activate TLR4 and TLR2. In addition, leptospires have been shown to activate the NLRP3 inflammasome in macrophages. We observed that when compared to other Gram-negative bacteria, L. interrogans induced a poor inflammasome response with little or no notable pyroptosis. In contrast, L. interrogans induced a robust type I IFN responses in both mouse macrophages and human monocytes. The L. interrogans-induced type I IFN response was dependent on both cGAS and STING and resulted in rapid phosphorylation of TBK1 and IRF3. Furthermore, supernatants from infected macrophages were capable of inducing IFNβ expression in uninfected macrophages, suggesting paracrine signaling from infected cells. These studies demonstrate that L. interrogans can drive a cGAS-STING dependent type I IFN response that may contribute to the host defense against this pathogen.
Role of foxn1 in Xenopus laevis thymopoiesis.
Authors: Dimitrakopoulou Dionysia dionysia , Bellin Eleanor , Horb Marko , Robert Jacques 
Published: January 2023

Abstract
The transcription factor forkhead box N1 (FOXN1) plays a pivotal role in differentiation of thymic epithelial cells (TECs) essential for intrathymic T cell education and keratinocyte development. Mutations in murine foxn1 are associated with T− B+ NK+ nude/severe combined immunodeficiency (SCID) phenotype. In humans FOXN1 mutations also lead to thymic aplasia or hypoplasia, hair loss and dysmorphic nails. In the amphibian Xenopus tropicalis, foxn1−/− line exhibited loss of thymi formation and absence of mature T-cells, similar with Foxn1−/− murine line. Due to expanded resources in immunobiology of X. laevis (a close relative of X. tropicalis), we generated a novel foxn1-deficient X. laevis model by using the CRISPR/Cas9. foxn1 crispants shows a high mutational efficiency (30–90%) and about 25% of tadpoles (stage 55–56), exhibit hypoplastic thymi. foxn1 disruption resulted in significant reduction of T-cell markers transcript levels, detected by RT-PCR. Furthermore, spleen of foxn1 crispants had markedly reduced CD3e staining compared to controls. Interestingly, Mycobacterium marinum (M. marinum) infection of tadpoles results in noninflammatory CD8 negative- and iT cell–mediated response, while foxn1 mutations in X. laevis appeared to affect tolerigenic innate immune response of infected tadpoles. This foxn1-deficient transgenic line will empower X. laevis as nonmammalian alternative experimental organism for studying host interaction with to non-tuberculosis mycobacteria. Currently, we are investigating mechanisms by which foxn1 mutation alter innate immunity of M. marinum inoculated tadpoles and evaluating tolerance/resistance by analysing the inflammatory/anti-inflammatory cytokine profile.
NLRC3 Localizes to the Endoplasmic Reticulum via Interactions with a Novel ER-Resident Protein
Authors: Davis Beckley K , Chapman Elisabeth , Gawon Kalida , Petrecca Izzy , Baker Taylor , Rechnitzer Alma 
Published: January 2023

Abstract
Nucleotide binding domain, leucine rich repeat CARD containing protein 3 (NLRC3) is a member of the NLR gene family. Members of this family have been associated with human inflammatory diseases such as Crohn’s disease and cryopyrin-associated periodic syndrome. Although NLRC3 (and others) are not associated with human diseases, it is expressed preferentially in the immune system and functions in pathogen recognition. NLRC3 is an intracellular protein involved in the sensing of lipopolysaccharide and cytosolic nucleic acids. NLRC3 is hypothesized to act as a negative regulator in response to bacterial and viral infection, suggesting that the vertebrate immune system has evolved specific inhibitors to limit the inflammatory response. We performed an unbiased yeast two-hybrid screen using an amino terminal fragment of NLRC3 to identify putative interacting proteins that might help elucidate the mechanism by which NLRC3 might inhibit inflammatory responses. To this end, we identified several interacting proteins. One protein in particular localizes to the endoplasmic reticulum (ER) and might serve as a localization-dependent anchor for NLRC3, thus facilitating its interaction with STING and TBK1. Here we show NLRC3 is distributed to the ER where it can interact with several important signaling molecules involved in type I interferon production.
Supported by a grant from the NIH (R15 GM134430)
Myosin 18A is a novel checkpoint regulator in B cell differentiation and antibody-mediated immunity
Authors: Gupta Neetu , Cheung Michael B , Enyindah-Asonye Gospel M , Matsui Ken , Kosik Ivan , Dvorina Nina , Baldwin William M , Yewdell Jonathan W 
Published: January 2023

Abstract
The B cell antibody response is tightly regulated to facilitate pathogen-specific immunity and prevent self-reactivity, with actin cytoskeleton dynamics playing an important role in regulating B cell activation. The newly discovered unconventional myosin family protein Myosin 18A (Myo18A) is most closely related to Myo2A, and regulates important cellular processes in non-lymphoid cells. Myo18A is expressed in both precursor and mature B cells, and interacts with ezrin, Myo2A and tyrosine phosphorylated proteins suggesting that it may regulate physiological functions of B cells. We investigated the function of Myo18A in antibody-mediated immunity by generating B cell-conditional Myo18A-deficient mice. Basally, Myo18A deficiency led to expansion of both bone marrow progenitor B cells, and mature B cells in secondary lymphoid organs. Myo18A-deficient mice displayed serum IgM hyperglobulinemia with greater levels of splenic IgM secreting cells, with older mice switching to IgG1 hyperglobulinemia and autoantibody development. Immunization of Myo18A-deficient mice with inactivated influenza virus led to development of more potent neutralizing antibodies against the major antigen hemagglutinin, associated with early expansion and persistent accumulation of antigen-specific germinal center B cells. In vitro stimulation with TLR7 and BCR ligands revealed a greater ability of Myo18A-deficient B cells to differentiate into antibody secreting cells, and induce Blimp-1 expression. Overall, our study demonstrates that Myo18A is a novel negative regulator of B cell homeostasis, differentiation, self-tolerance and humoral immunity.
Supported by an NIH grant (R21 AI117350) to Neetu Gupta