Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.

Age-related inflammation or inflammaging is a key mechanism that increases disease burden and may control lifespan. How adipose tissue macrophages (ATMs) control inflammaging is not well understood in part because the molecular identities of niche-specific ATMs are incompletely known. Using intravascular labeling to exclude circulating myeloid cells and subsequent single-cell sequencing with orthogonal validation, we define the diversity and alterations in niche resident ATMs through lifespan.

Vagal TRPV1 sensory neurons regulate myeloid cell dynamics and protect against influenza virus infection.

Influenza viruses are a major global cause of morbidity and mortality. Vagal TRPV1 nociceptive sensory neurons, which innervate the airways, are known to mediate defenses against harmful agents. However, their function in lung antiviral defenses remains unclear.

Dietary and water restriction leads to increased susceptibility to antimicrobial resistant pathogens.

Dehydration and malnutrition are common and often underdiagnosed in hospital settings. Multidrug-resistant bacterial infections result in more than 35,000 deaths a year in nosocomial patients. The effect of temporal dietary and water restriction (DWR) on susceptibility to multidrug-resistant pathogens is unknown.

Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients.

Introduction: Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study.

Material And Methods: We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days).

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in mutant lung cancer.

Loss-of-function mutations in frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of mutant tumors.

Recruitment and Maintenance of CX3CR1+CD4+ T Cells during Helminth Infection.

Distinct subsets of T lymphocytes express CX3CR1 under inflammatory conditions, but little is known about CX3CR1+CD4+ T cells during type 2 inflammation in helminth infections. In this study, we used a fate-mapping mouse model to characterize CX3CR1+CD4+ T cells during both acute Nippostrongylus brasiliensis and chronic Schistosoma mansoni murine models of helminth infections, revealing CX3CR1+CD4+ T cells to be an activated tissue-homing subset with varying capacity for cytokine production. Tracking these cells over time revealed that maintenance of CX3CR1 itself along with a TH2 phenotype conferred a survival advantage in the inflamed tissue.

Mouse genome rewriting and tailoring of three important disease loci.

Genetically engineered mouse models (GEMMs) help us to understand human pathologies and develop new therapies, yet faithfully recapitulating human diseases in mice is challenging. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences, which control spatiotemporal gene expression patterns and splicing in many human diseases. Including regulatory extensive genomic regions, which requires large-scale genome engineering, should enhance the quality of disease modelling.

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment.

Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth.

Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of -mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1 interstitial macrophages and SiglecF neutrophils.

Single-Cell Analysis of CX3CR1+ Cells Reveals a Pathogenic Role for BIRC5+ Myeloid Proliferating Cells Driven by Staphylococcus aureus Leukotoxins.

Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage-tracing cells derived from CX3CR1+ precursors in mice during infection and profiling by single-cell RNA sequencing, in this study, we identify a cluster of BIRC5+ myeloid cells that expanded in the liver during chronic infection with either the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus. In the absence of tissue-damaging toxins, S.

A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8.

Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2.

Age-dependent differences in efferocytosis determine the outcome of opsonophagocytic protection from invasive pathogens.

In early life, susceptibility to invasive infection skews toward a small subset of microbes, whereas other pathogens associated with diseases later in life, including Streptococcus pneumoniae (Spn), are uncommon among neonates. To delineate mechanisms behind age-dependent susceptibility, we compared age-specific mouse models of invasive Spn infection. We show enhanced CD11b-dependent opsonophagocytosis by neonatal neutrophils improved protection against Spn during early life.

Single-cell analysis of CX3CR1 cells reveal a pathogenic role for BIRC5 myeloid proliferating cells driven by leukotoxins.

Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage tracing cells derived from CX3CR1 precursors in mice during infection and profiling by scRNA-seq, here we identify a cluster of BIRC5 myeloid cells that expanded in the liver during either chronic infection with the parasite or the bacterial pathogen . In the absence of tissue damaging toxins, infection does not elicit these BIRC5 cells.

CD169+ macrophage intrinsic IL-10 production regulates immune homeostasis during sepsis.

Macrophages facilitate critical functions in regulating pathogen clearance and immune homeostasis in tissues. The remarkable functional diversity exhibited by macrophage subsets is dependent on tissue environment and the nature of the pathological insult. Our current knowledge of the mechanisms that regulate the multifaceted counter-inflammatory responses mediated by macrophages remains incomplete.

Galectin-9 protects humanized-ACE2 immunocompetent mice from SARS-CoV-2 infection.

SARS-CoV-2 remains a global health crisis even with effective vaccines and the availability of FDA approved therapies. Efforts to understand the complex disease pathology and develop effective strategies to limit mortality and morbidity are needed. Recent studies reveal circulating Galectin-9 (gal-9), a soluble beta-galactoside binding lectin with immunoregulatory properties, are elevated in SARS-CoV-2 infected individuals with moderate to severe disease.

A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8.

Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets . Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2 .

Helminth resistance is mediated by differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion.

Macrophages are known to mediate anti-helminth responses, but it remains uncertain which subsets are involved or how macrophages actually kill helminths. Here, we show rapid monocyte recruitment to the lung after infection with the nematode parasite Nippostrongylus brasiliensis. In this inflamed tissue microenvironment, these monocytes differentiate into an alveolar macrophage (AM)-like phenotype, expressing both SiglecF and CD11c, surround invading parasitic larvae, and preferentially kill parasites in vitro.

Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation.

Beyond neutralization for BNT162b2 mRNA vaccination.

Mounting a robust immune response against SARS-CoV-2 requires neutralization as well as effector T cell functions. In this issue of Cell Host Microbe, Tauzin et al. characterize the humoral and T cell responses after a single dose of BNT162b2 mRNA vaccine in individuals with or without previous exposure to SARS-CoV-2.

Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice.

Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59).

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation.