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In the first trimester of human pregnancy, low oxygen tension or hypoxia is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multiple cell types, the relationship between hypoxia and Notch in first trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human first trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a γ-secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed the second trimester chorionic villous sampling (CVS) samples and third trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.

Rickettsia is a genus of Gram-negative bacteria that has for centuries caused large-scale morbidity and mortality. In recent years, the resurgence of rickettsial diseases as a major cause of pyrexias of unknown origin, bioterrorism concerns, vector movement, and concerns over drug resistance is driving a need to identify novel treatments for these obligate intracellular bacteria. Utilizing an uvGFP plasmid reporter, we developed a screen for identifying anti-rickettsial small molecule inhibitors using Rickettsia canadensis as a model organism. The screening data were utilized to train a Bayesian model to predict growth inhibition in this assay. This two-pronged methodology identified anti-rickettsial compounds, including duartin and JSF-3204 as highly specific, efficacious, and noncytotoxic compounds. Both molecules exhibited in vitro growth inhibition of R. prowazekii, the causative agent of epidemic typhus. These small molecules and the workflow, featuring a high-throughput phenotypic screen for growth inhibitors of intracellular Rickettsia spp. and machine learning models for the prediction of growth inhibition of an obligate intracellular Gram-negative bacterium, should prove useful in the search for new therapeutic strategies to treat infections from Rickettsia spp. and other obligate intracellular bacteria.

Objective To assess the role of STAT4 activation in driving pathogenic follicular helper T (Tfh) cell secretion of the cytokines interleukin-21 (IL-21) and interferon-γ (IFNγ) in murine and human lupus. Methods The effect of STAT4-dependent Tfh cell signaling on cytokine production and autoreactive B cell maturation was assessed temporally during the course of lupus in a murine model, with further assessment of Tfh cell gene transcription performed using RNA-Seq technology. STAT4-dependent signaling and cytokine production were also determined in circulating Tfh-like cells in patients with systemic lupus erythematosus (SLE), as compared to cells from healthy control subjects, and correlations with disease activity were assessed in the Tfh-like cells from SLE patients. Results IL-21- and IFNγ-coproducing Tfh cells expanded prior to the detection of potentially pathogenic IgG2c autoantibodies in lupus-prone mice. Tfh cells transcriptionally evolved during the course of disease with acquisition of a STAT4-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon STAT4 signaling, driven by type I IFNs. Circulating Tfh-like cells from patients with SLE also secreted IL-21 and IFNγ, with STAT4 phosphorylation enhanced by IFNβ, in association with the extent of clinical disease activity. Conclusion We identified a role for type I IFN signaling in driving STAT4 activation and production of IL-21 and IFNγ by Tfh cells in murine and human lupus. Enhanced STAT4 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that STAT4 guides pathogenic cytokine and immunoglobulin production in SLE, demonstrating a potential therapeutic target to modulate autoimmunity.

Asthma involves chronic airway inflammation and airway smooth muscle (ASM) cell contraction. Treatment include agonists of the beta 2-AR, a GPCR that induces the Gs/cAMP pathway leading to ASM relaxation. These agonists can also promote severe side effects which have been correlated with beta-arrestins (barr) activation. Therefore, biased ligands selective for the Gs/cAMP pathway over the barr-induced side effects should be beneficial. To test this, we have used high-throughput screening to identify Gs-biased agonists. The initial lead candidates were further analyzed for their ability to modulate Gs and Gi interaction, cAMP production, and barr interaction. We identified three compounds which showed minimal barr recruitment as well as decreased barr-mediated outputs including receptor internalization and ERK activation. They also showed reduced GRK-mediated phosphorylation of the receptor as well as decreased agonist-promoted receptor desensitization in human ASM cells. These Gs-biased agonists may contribute to develop more effective drugs for asthma and may help to determine the structure determinants of receptor mediated biased signaling. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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Type 2 cytokine responses promote parasitic immunity and initiate tissue repair; however, they can also result in immunopathologies when not properly restricted. Although basophilia is recognized as a common feature of type 2 inflammation, the roles basophils play in regulating these responses are unknown. Here, we demonstrate that helminth-induced group 2 innate lymphoid cell (ILC2) responses are exaggerated in the absence of basophils, resulting in increased inflammation and diminished lung function. Additionally, we show that ILC2s from basophil-depleted mice express reduced amounts of the receptor for the neuropeptide neuromedin B (NMB). Critically, NMB stimulation inhibited ILC2 responses from control but not basophil-depleted mice, and basophils were sufficient to directly enhance NMB receptor expression on ILC2s. These studies suggest that basophils prime ILC2s to respond to neuron-derived signals necessary to maintain tissue integrity. Further, these data provide mechanistic insight into the functions of basophils and identify NMB as a potent inhibitor of type 2 inflammation.

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A

The acquisition of a metastatic phenotype is the critical event that determines patient survival from breast cancer. Several receptor tyrosine kinases have functions both in promoting and inhibiting metastasis in breast tumors. Although the insulin-like growth factor 1 receptor (IGF-1R) has been considered a target for inhibition in breast cancer, low levels of IGF-1R expression are associated with worse overall patient survival. To determine how reduced IGF-1R impacts tumor phenotype, we used weighted gene correlation network analysis (WGCNA) of METABRIC patient data and identified gene modules specific to cell cycle, adhesion, and immune cell signaling inversely correlated with IGF-1R expression in human breast cancers. Integration of human patient data with data from mouse tumors revealed similar pathways necessary for promoting metastasis in basal-like tumors with reduced signaling or expression of the IGF-1R. Functional analyses revealed the basis for the enhanced metastatic phenotype including alterations in E- and P-cadherins.

Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) serve as a first line of defense against luminal microbes. Although the presence of an intact microbiota is dispensable for γδ IEL development, several microbial factors contribute to the maintenance of this sentinel population. However, whether specific commensals influence population of the γδ IEL compartment under homeostatic conditions has yet to be determined. We identified a novel γδ IEL hyperproliferative phenotype that arises early in life and is characterized by expansion of multiple Vγ subsets. Horizontal transfer of this hyperproliferative phenotype to mice harboring a phenotypically normal γδ IEL compartment was prevented following antibiotic treatment, thus demonstrating that the microbiota is both necessary and sufficient for the observed increase in γδ IELs. Further, we identified two guilds of small intestinal or fecal bacteria represented by 12 amplicon sequence variants (ASV) that are strongly associated with γδ IEL expansion. Using intravital microscopy, we find that hyperproliferative γδ IELs also exhibit increased migratory behavior leading to enhanced protection against bacterial infection. These findings reveal that transfer of a specific group of commensals can regulate γδ IEL homeostasis and immune surveillance, which may provide a novel means to reinforce the epithelial barrier.

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IELs) serve as a first line of defense against luminal microbes. Although the presence of an intact microbiota is dispensable for {gamma}{delta} IEL development, several microbial factors contribute to the maintenance of this sentinel population. However, whether specific commensals influence population of the {gamma}{delta} IEL compartment under homeostatic conditions has yet to be determined. We identified a novel {gamma}{delta} IEL hyperproliferative phenotype that arises early in life and is characterized by expansion of multiple V{gamma} subsets. Horizontal transfer of this hyperproliferative phenotype to mice harboring a phenotypically normal {gamma}{delta} IEL compartment was prevented following antibiotic treatment, thus demonstrating that the microbiota is both necessary and sufficient for the observed increase in {gamma}{delta} IELs. Further, we identified a group of unique gut bacteria represented by 5 amplicon sequence variants (ASV) which are strongly associated with {gamma}{delta} IEL expansion. Using intravital microscopy, we find that hyperproliferative {gamma}{delta} IELs also exhibit increased migratory behavior leading to enhanced protection against bacterial infection. These findings reveal that transfer of a specific group of commensals can regulate {gamma}{delta} IEL homeostasis and immune surveillance, which may provide a novel means to reinforce the epithelial barrier.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), kills 1.6 million people annually. To bridge the gap between structure- and cell-based drug discovery strategies, we are pionee...

Non-small cell lung cancer (NSCLC) is a complex disease in need of new methods of therapeutic intervention. Recent interest has focused on using microRNAs (miRNAs) as a novel treatment method for various cancers. miRNAs negatively regulate gene expression post-transcriptionally, and have become attractive candidates for cancer treatment because they often simultaneously target multiple genes of similar biological function. One such miRNA is miR-146a-5p, which has been described as a tumor suppressive miRNA in NSCLC cell lines and tissues. In this study, we performed RNA-Sequencing (RNA-Seq) analysis following transfection of synthetic miR-146a-5p in an NSCLC cell line, A549, and validated our data with Gene Ontology and qRT-PCR analysis of known miR-146a-5p target genes. Our transcriptomic data revealed that miR-146a-5p exerts its tumor suppressive function beyond previously reported targeting of EGFR and NF-κB signaling. miR-146a-5p mimic transfection downregulated arachidonic acid metabolism genes, the RNA-binding protein HuR, and many HuR-stabilized pro-cancer mRNAs, including TGF-β, HIF-1α, and various cyclins. miR-146a-5p transfection also reduced expression and cellular release of the chemokine CCL2, and this effect was mediated through the 3ʹ untranslated region of its mRNA. Taken together, our work reveals that miR-146a-5p functions as a tumor suppressor in NSCLC by controlling various metabolic and signaling pathways through direct and indirect mechanisms.

This study shows that Vochysia guatemalensis tree plantations were associated with enhanced soil biotic and abiotic characteristics in previously cleared forests in the northern zone of Costa Rica, suggesting the possible use of this practice as a restoration strategy for local land owners. Soil samples from a primary forest, secondary forest, and a 13‐year‐old plantation of V. guatemalensis had greater relative abundances of DNA sequences of microbial genera critical for carbon‐use (C‐use) efficiency (i.e. the saprobe, complex C and wood rot/lignin decomposer fungi, and bacterial lignin and other complex C degraders), and greater levels of total organic carbon, C‐biomass, and microbial quotients as indicators of enhanced C‐use efficiency, than found in soils of adjacent 5‐year‐old V. guatemalensis plantations and abandoned non‐productive pasture/grasslands (GRs). The major research conclusions were that (1) conversion of forested land into abandoned pasture/GRs decreased the C‐use efficiency in the soils and the microbial groups associated with C‐use efficiency; (2) soils in plantations of V. guatemalensis were associated with increased abundances of the DNA of these same microbial groups and enhanced C‐use efficiency; (3) DNA‐based taxonomic analysis of microbes and analysis of the microbial quotient values can be used to monitor soil ecosystems for assessment of the efficacy of restoration activities. Thus, planting V. guatemalensis on damaged lands in the Maquenque National Wildlife Refuge should be encouraged to provide a sustainable forestry crop that can be harvested rotationally, while improving soil ecosystem health and reducing the pressure to harvest other forest sites.

Animal models that recapitulate human diseases and disorders are widely used to investigate etiology, diagnosis, and treatment of those conditions in people. Disorders during pregnancy are particularly difficult to explore as interventions in pregnant women are not easily performed. Therefore, models that allow for pre-conception investigations are advantageous for elucidating the mechanisms involved in adverse pregnancy outcomes that are responsible for both maternal and fetal morbidity, such as preeclampsia. The Blood Pressure High (BPH)/5 mouse model has been used extensively to study the pathogenesis of preeclampsia. The female BPH/5 mouse is obese with increased adiposity and borderline hypertension, both of which are exacerbated with pregnancy making it a model of superimposed preeclampsia. Thus, the BPH/5 model shares traits with a large majority of women with pre-existing conditions that predisposes them to preeclampsia. We sought to explore the genome of the BPH/5 female mouse and determine the genetic underpinnings that may contribute to preeclampsia-associated phenotypes in this model. Using a whole genome sequencing approach, we are the first to characterize the genetic mutations in BPH/5 female mice that make it unique from the closely related BPH/2 model and the normotensive background strain, C57Bl/6. We found the BPH/5 female mouse to be uniquely different from BPH/2 and C57Bl/6 mice with a genetically complex landscape. The majority of non-synonymous consequences within the coding region of BPH/5 females were missense mutations found most abundant on chromosome X when comparing BPH/5 and BPH/2, and on chromosome 8 when comparing BPH/5 to C57Bl/6. Genetic mutations in BPH/5 females largely belong to immune system-related processes, with overlap between BPH/5 and BPH/2 models. Further studies examining each gene mutation during pregnancy are warranted to determine key contributors to the BPH/5 preeclamptic-like phenotype and to identify genetic similarities to women that develop preeclampsia.

OBJECTIVE: To assess the role of STAT4 activation in driving pathogenic follicular helper T (Tfh) cell secretion of the cytokines IL-21 and IFN-γ during murine and human lupus. METHODS: We temporally assessed STAT4-dependent Tfh cell signaling with cytokine production and autoreactive B cell maturation during the course of murine lupus, with further assessment of Tfh cell gene transcription using RNA-seq. STAT4-dependent signaling and cytokine production were also determined in circulating Tfh-like cells in patients with SLE, compared to cells from controls, with correlation to disease activity in the former. RESULTS: IL-21 and IFN-γ co-producing Tfh cells expanded prior to the detection of potentially pathogenic IgG2c autoantibodies in lupus-prone mice. Tfh cells transcriptionally evolved during the course of disease with acquisition of a STAT4-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon STAT4 signaling, driven by type I interferons. Circulating Tfh-like (cTfh) cells from patients with SLE also secreted IL-21 and IFN-γ, with STAT4 phosphorylation enhanced by IFN-β, in association with clinical disease activity. CONCLUSION: We identified a role for IFN-I signaling in driving STAT4 activation and production of IL-21 and IFN-γ by Tfh cells in murine and human lupus. Enhanced STAT4 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that STAT4 guides pathogenic cytokine and immunoglobulin production in SLE, providing a potential therapeutic target to modulate autoimmunity.

Multicellular intestinal nematode parasites can cross the epithelial barrier potentially causing tissue damage and release of danger associated molecular patterns (DAMPs) that may promote type 2 responses and host protective immunity. We investigated whether adenosine specifically binding the A2B adenosine receptor on epithelial cell played an important role in driving intestinal immunity. Specific blockade of epithelial cell A2B adenosine receptor inhibited the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri (Hpb), including disruption of granuloma development at the host:parasite interface during the transient tissue dwelling larval stage. Memory T cell development was blocked during the primary response and transcriptional analyses revealed profound impairment of epithelial cell activation and reduced type 2 markers by 24 hours after inoculation. Extracellular ATP was visualized at 24 hours after inoculation and shown in CD39 deficient mice to be critical for the adenosine production mediating initiation of type 2 immunity. Our studies indicate a potent adenosine-mediated epithelial cell pathway that along with the tuft cell circuit is critical for activation of type 2 immunity.

Tbet+CD11c+ B cells comprise a distinct subset that arises during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Their developmental reliance upon T cell help and relationship to germinal center (GC) B cells are unclear. We examined Tbet+CD11c+ B cells induced by acute LCMV infections, finding that T follicular helper (Tfh), not T helper 1 (Th1), cells drove their generation prior to GC formation. Genetic fate-tracking and lineage tracing revealed that most Tbet+CD11c+ B cells were not GC-derived and developed independently of cell-intrinsic Bcl6 expression. They localized to the marginal zone where their splenic retention depended upon integrins LFA-1 and VLA-4. After viral clearance, Tbet+CD11c+ B cells formed an uncommon but competitive memory subset, contributing to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet+CD11c+ B cells are predominantly generated independently of the GC response, yet their development is dependent upon help delivered by Tfh cells.

Background & Aims: Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) are actively involved in the shedding of enterocytes into the lumen. Methods: Intravital microscopy was performed on GFP γδ T cell reporter mice treated with intraperitoneal lipopolysaccharide (10 mg/kg) for 90 minutes to induce tumor necrosis factor–mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). Granzyme A and granzyme B release from ex vivo–stimulated γδ IELs was quantified by enzyme-linked immunosorbent assay. Immunostaining for γδ T cell receptor and CC3 was performed on duodenal and ileal biopsies from controls and patients with Crohn's disease. Results: Intravital microscopy of lipopolysaccharide-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, and CD103 knockout or blockade significantly reduced lipopolysaccharide-induced shedding. Furthermore, we found that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by γδ IELs both constitutively and after CD103/E-cadherin ligation. Moreover, we found that the frequency of γδ IEL localization to CC3-positive enterocytes is increased in Crohn's disease biopsies compared with healthy controls. Conclusions: Our results uncover a previously unrecognized role for γδ IELs in facilitating tumor necrosis factor–mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release.

Inga edulis and Pentaclethra macroloba are dominant N-fixing forest trees in Costa Rica, likely important for recovery of soil N and C after deforestation, yet little is known of their soil microbiomes nor how land use impacts them. Soils from both trees in a primary and secondary forest were assessed for N-cycle metrics and DNA sequence-based composition of total bacterial, potential N-fixing bacterial, and potential ammonium oxidizing bacterial genera. The compositions of the functional groups of bacteria, but not their total relative abundance of DNA, were different across the soils. The P. macroloba soils had greater NO3&minus, levels and richness of both functional groups, while I. edulis soils had greater NH4+ levels, consistent with its NH4+ preference for root nodule development. The bacterial communities were different by habitat, as secondary forest I. edulis microbiomes were less rich, more dominant, possibly more affected by the disturbance, or reached equilibrium status quicker than the richer, less dominant P. macroloba microbiomes, which may be developing slower along with secondary forest succession, or were less affected by the disturbance. Functional redundancy and switching of 10 N-cycle bacterial genera was evident between the primary and secondary forest soils, likely to maintain stable levels of N-cycle activity following disturbance. In summary, the two tree soil microbiomes are different, land use differentially affects them, and, thus, both tree species should be used during forest regeneration strategies in this region.

Mutations in integral membrane protein 2B (ITM2b/BRI2) gene cause familial British and Danish dementia (FBD and FDD), autosomal dominant disorders characterized by progressive cognitive deterioration. Two pathogenic mechanisms, which may not be mutually exclusive, have been proposed for FDD and FBD: 1) loss of BRI2 function; 2) accumulation of amyloidogenic mutant BRI2-derived peptides, but the mechanistic details remain unclear. We have previously reported a physiological role of BRI2 in excitatory synaptic transmission at both presynaptic termini and postsynaptic termini. To test whether pathogenic ITM2b mutations affect these physiological BRI2 functions, we analyzed glutamatergic transmission in FDD and FBD knock-in mice, which carry pathogenic FDD and FBD mutations into the mouse endogenous Itm2b gene. We show that in both mutant lines, spontaneous glutamate release and AMPAR-mediated responses are decreased, while short-term synaptic facilitation is increased, effects similar to those observed in Itm2bKO mice. In vivo and in vitro studies show that both pathogenic mutations alter maturation of BRI2 resulting in reduced levels of functional mature BRI2 protein at synapses. Collectively, the data show that FDD and FBD mutations cause a reduction of BRI2 levels and function at synapses, which results in reduced glutamatergic transmission. Notably, other genes mutated in Familial dementia, such as APP, PSEN1/PSEN2, are implicated in glutamatergic synaptic transmission, a function that is altered by pathogenic mutations. Thus, defects in excitatory neurotransmitter release may represent a general and convergent mechanism leading to neurodegeneration. Targeting these dysfunction may offer a unique disease modifying method of therapeutic intervention in neurodegenerative disorders.

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-like macrophage (AM) phenotype, expressing both Siglec-F and CD11c, surround invading parasitic larvae and preferentially kill parasites in vitro. Monocyte-derived AMs (Mo-AMs) express type 2-associated markers and show distinct remodeling of the chromatin landscape relative to tissue-derived AMs. In particular, they express high amounts of Arg1 (arginase-1), which we demonstrate mediates helminth killing through L-arginine depletion. These studies indicate that recruited monocytes are selectively programmed in the pulmonary environment to express AM markers and an anti-helminth phenotype.

Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrow-resident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1-reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes., Author summary Helminth parasites infect approximately 2 billion people and represent a significant public health concern. Helminths undertake complex developmental life cycles through multiple organs and as a result cause substantial tissue damage. To combat this, mammals have evolved mechanisms to initiate balanced immune responses that promote inflammation needed to seclude parasites in granulomas, reduce parasitic burdens and mitigate the consequences of helminth-induced wounds. Despite their clinical importance, the mechanisms that regulate these events remain poorly defined. Here we have uncovered a unique progenitor cell that supports both proinflammatory mast cell responses and red blood cell development, thereby simultaneously initiating both of these host-protective responses. Collectively, these studies reveal unappreciated events initiated by the host to combat pathogens that infect billions of individuals worldwide.

We examined the activation and effector functions of lung macrophages in mediatingimmunity against helminth parasites. Using fate mapping mice, we showed thatmonocytes recruited to the lung assume an alveolar macrophage phenotype andcomprise as many as 10% of alveolar macrophages by 7 days after inoculation.Monocyte-derived alveolar macrophages assume distinct transcriptional and metabolicprofiles that include high levels of arginase expression and preferentially mediatehelminth damage, both of which are dependent on neutrophil help. In further studies,arginase was shown to mediate helminth killing through localized depletion of arginine.