Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

AbstractEarly events in the host response to SARS-CoV-2 are thought to play a major role in determining disease severity. During pulmonary infection, the virus encounters both myeloid and epithelioid lineage cells that can either support or restrict pathogen replication as well as respond with host protective versus detrimental mediators. In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer non-specific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here we demonstrate that prior intravenous, but not subcutaneous, administration of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 and results in reduced viral loads in non-transgenic animals infected with an alpha variant. The observed increase in host resistance was associated with reductions in SARS-CoV-2-induced tissue pathology, inflammatory cell recruitment and cytokine production that multivariate analysis revealed to be only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and the ensuing immunopathology.

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Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

Journal of Experimental Medicine ◽

10.1084/jem.20211862 ◽

2021 ◽

Vol 219 (2) ◽

Author(s):

Kerry L. Hilligan ◽

Sivaranjani Namasivayam ◽

Chad S. Clancy ◽

Danielle O’Mard ◽

Sandra D. Oland ◽

...

Keyword(s):

Host Resistance ◽

Myeloid Cell ◽

Transgenic Animals ◽

Lethal Challenge ◽

Nonspecific Resistance ◽

Cellular Compartment ◽

Cell Recruitment ◽

Viral Loads ◽

Pediatric Tuberculosis ◽

And Function

In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer nonspecific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here, we demonstrate that intravenous, but not subcutaneous, inoculation of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 (SCV2) and results in reduced viral loads in non-transgenic animals infected with an α variant. The observed increase in host resistance was associated with reductions in SCV2-induced tissue pathology, inflammatory cell recruitment, and cytokine production that multivariate analysis revealed as only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and ensuing immunopathology. While intravenous BCG vaccination is not a clinically acceptable practice, our findings provide an experimental model for identifying mechanisms by which nonspecific stimulation of the pulmonary immune response promotes host resistance to SCV2 lethality.

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Circulating Non-Classical Monocytes are Reduced in Patients with Active IBD but Increase after Vedolizumab: A Role for α4β7 in Myeloid Cell Recruitment to the Inflamed Intestine

Gastroenterology ◽

10.1016/s0016-5085(17)33405-4 ◽

2017 ◽

Vol 152 (5) ◽

pp. S1003-S1004

Author(s):

Hannah Gordon ◽

Inva Hoti ◽

James O. Lindsay ◽

Andrew J. Stagg

Keyword(s):

Myeloid Cell ◽

Cell Recruitment ◽

Classical Monocytes

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miR‐223 promotes regenerative myeloid cell phenotype and function in the demyelinated central nervous system

Glia ◽

10.1002/glia.23576 ◽

2018 ◽

Vol 67 (5) ◽

pp. 857-869 ◽

Cited By ~ 11

Author(s):

Dylan A. Galloway ◽

Stephanie N. Blandford ◽

Tangyne Berry ◽

John B. Williams ◽

Mark Stefanelli ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Myeloid Cell ◽

Cell Phenotype ◽

And Function

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High diversity in Delta variant across countries revealed via genome-wide analysis of SARS-CoV-2 beyond the Spike protein

10.1101/2021.09.01.458647 ◽

2021 ◽

Author(s):

Pritha Ghosh ◽

Rohit Suratekar ◽

Michiel J.M. Niesen ◽

Praveen Anand ◽

Gregory Donadio ◽

...

Keyword(s):

Amino Acid ◽

Spike Protein ◽

P Value ◽

Missense Mutations ◽

Systematic Analysis ◽

Viral Loads ◽

Amino Acid Mutations ◽

Mechanistic Basis ◽

Alpha Variant ◽

High Diversity

The highly contagious Delta variant of SARS-CoV-2 has emerged as the new dominant global strain, and reports of reduced effectiveness of COVID-19 vaccines against the Delta variant are highly concerning. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike protein, the mutational landscape of the rest of the SARS-CoV-2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS-CoV-2 proteins from nearly 2 million SARS-CoV-2 genomes from 176 countries/territories. Six highly-prevalent missense mutations in the viral life cycle-associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant (cosine similarity: meanAlpha = 0.94, S.D.Alpha = 0.05; meanDelta = 0.86, S.D.Delta = 0.1; Cohen's dAlpha-Delta = 1.17, p-value < 0.001). Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of targetable amino acid mutations in the Delta variant's proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.

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Agrin is required for survival and function of monocytic cells

Blood ◽

10.1182/blood-2011-09-382812 ◽

2012 ◽

Vol 119 (23) ◽

pp. 5502-5511 ◽

Cited By ~ 21

Author(s):

Cristina Mazzon ◽

Achille Anselmo ◽

Cristiana Soldani ◽

Javier Cibella ◽

Cristina Ploia ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Synapse Formation ◽

Myeloid Cell ◽

Heparan Sulfate Proteoglycans ◽

Extracellular Matrix Protein ◽

Monocytic Cells ◽

Hematopoietic System ◽

Extracellular Signal ◽

And Function

Abstract Agrin, an extracellular matrix protein belonging to the heterogeneous family of heparan sulfate proteoglycans (HSPGs), is expressed by cells of the hematopoietic system but its role in leukocyte biology is not yet clear. Here we demonstrate that agrin has a crucial, nonredundant role in myeloid cell development and functions. We have identified lineage-specific alterations that affect maturation, survival and properties of agrin-deficient monocytic cells, and occur at stages later than stem cell precursors. Our data indicate that the cell-autonomous signals delivered by agrin are sensed by macrophages through the α-DC (DG) receptor and lead to the activation of signaling pathways resulting in rearrangements of the actin cytoskeleton during the phagocytic synapse formation and phosphorylation of extracellular signal-regulated kinases (Erk 1/2). Altogether, these data identify agrin as a novel player of innate immunity.

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Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer

Cancers ◽

10.3390/cancers12123631 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3631

Author(s):

Krystal Villalobos-Ayala ◽

Ivannie Ortiz Rivera ◽

Ciara Alvarez ◽

Kazim Husain ◽

DeVon DeLoach ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Responses ◽

Suppressor Cells ◽

Myeloid Cell ◽

Tumor Burden ◽

Sh2 Domain ◽

Src Homology 2 ◽

Src Homology ◽

And Function ◽

Deficient Mice

Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5′-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.

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Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice

Nature Communications ◽

10.1038/s41467-021-25590-8 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Kanchan Bisht ◽

Kenneth A. Okojie ◽

Kaushik Sharma ◽

Dennis H. Lentferink ◽

Yu-Yo Sun ◽

...

Keyword(s):

Myeloid Cell ◽

Structure And Function ◽

Pannexin 1 ◽

Vascular Physiology ◽

Blood Flow Increase ◽

Bona Fide ◽

Spatio Temporal ◽

And Function ◽

The Brain

AbstractMicroglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12−/− and PANX1−/− mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.

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Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans

European Heart Journal ◽

10.1093/eurheartj/ehaa484 ◽

2020 ◽

Vol 41 (31) ◽

pp. 2938-2948

Author(s):

Annelie Shami ◽

Dorothee Atzler ◽

Laura A Bosmans ◽

Holger Winkels ◽

Svenja Meiler ◽

...

Keyword(s):

Immune Checkpoint ◽

Myeloid Cell ◽

Tumour Necrosis Factor Receptor ◽

Cell Recruitment ◽

Atherosclerosis Progression ◽

Fibrous Cap ◽

Plaque Area ◽

Asymptomatic Patients ◽

Cerebrovascular Events ◽

Plaque Phenotype

Abstract Aims GITR—a co-stimulatory immune checkpoint protein—is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD). Methods and results GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr−/−Apoe−/− mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr−/−Apoe−/− and Apoe−/− monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr−/−Apoe−/− monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity. Conclusion Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.

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The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Experimental Biology and Medicine ◽

10.1177/1535370219867269 ◽

2019 ◽

Vol 244 (15) ◽

pp. 1273-1302 ◽

Cited By ~ 3

Author(s):

Steven R. Goodman ◽

Daniel Johnson ◽

Steven L. Youngentob ◽

David Kakhniashvili

Keyword(s):

Cell Surface ◽

Intracellular Signaling ◽

Cellular Protein ◽

Human Diseases ◽

Scaffolding Protein ◽

Eukaryotic Cells ◽

Cellular Functions ◽

Cellular Compartment ◽

Atlas Data ◽

And Function

We provide a review of Spectrin isoform function in the cytoplasm, the nucleus, the cell surface, and in intracellular signaling. We then discuss the importance of Spectrin’s E2/E3 chimeric ubiquitin conjugating and ligating activity in maintaining cellular homeostasis. Finally we present spectrin isoform subunit specific human diseases. We have created the Spectrinome, from the Human Proteome, Human Reactome and Human Atlas data and demonstrated how it can be a useful tool in visualizing and understanding spectrins myriad of cellular functions. Impact statement Spectrin was for the first 12 years after its discovery thought to be found only in erythrocytes. In 1981, Goodman and colleagues 1 found that spectrin-like molecules were ubiquitously found in non-erythroid cells leading to a great multitude of publications over the next thirty eight years. The discovery of multiple spectrin isoforms found associated with every cellular compartment, and representing 2-3% of cellular protein, has brought us to today’s understanding that spectrin is a scaffolding protein, with its own E2/E3 chimeric ubiquitin conjugating ligating activity that is involved in virtually every cellular function. We cover the history, localized functions of spectrin isoforms, human diseases caused by mutations, and provide the spectrinome: a useful tool for understanding the myriad of functions for one of the most important proteins in all eukaryotic cells.

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