Pulmonary-Resident Memory Lymphocytes: Pivotal Orchestrators of Local Immunity Against Respiratory Infections

There is increasing evidence that lung-resident memory T and B cells play a critical role in protecting against respiratory reinfection. With a unique transcriptional and phenotypic profile, resident memory lymphocytes are maintained in a quiescent state, constantly surveying the lung for microbial intruders. Upon reactivation with cognate antigen, these cells provide rapid effector function to enhance immunity and prevent infection. Immunization strategies designed to induce their formation, alongside novel techniques enabling their detection, have the potential to accelerate and transform vaccine development. Despite most data originating from murine studies, this review will discuss recent insights into the generation, maintenance and characterisation of pulmonary resident memory lymphocytes in the context of respiratory infection and vaccination using recent findings from human and non-human primate studies

Density-and trait-mediated effects of a parasite and a predator in a tri-trophic food web

1. Despite growing interest in ecological consequences of parasitism in food webs, relatively little is known about effects of parasites on long-term population dynamics of non-host species or about whether such effects are density- or trait- mediated. 2. We studied a tri-trophic food chain comprised of: (i) a bacterial basal resource (Serratia fonticola), (ii) an intermediate consumer (Paramecium caudatum), (iii) a top predator (Didinium nasutum), and (iv) a parasite of the intermediate consumer (Holospora undulata). A fully-factorial experimental manipulation of predator and parasite presence/absence was combined with analyses of population dynamics, modelling, and analyses of host (Paramecium) morphology and behavior. 3. Predation and parasitism each reduced the abundance of the intermediate consumer (Paramecium), and parasitism indirectly reduced the abundance of the basal resource (Serratia). However, in combination, predation and parasitism had non-additive effects on the abundance of the intermediate consumer, as well as on that of the basal resource. In both cases, the negative effect of parasitism seemed to be effaced by predation. 4. Infection of the intermediate consumer reduced predator abundance. Modelling and additional experimentation revealed that this was most likely due to parasite reduction of intermediate host abundance (a density-mediated effect), as opposed to changes in predator functional or numerical response. 5. Parasitism altered morphological and behavioural traits, by reducing host cell length and increasing the swimming speed of cells with moderate parasite loads. Additional tests showed no significant difference in Didinium feeding rate on infected and uninfected hosts, suggesting that the combination of these modifications does not affect host vulnerability to predation. However, estimated rates of encounter with Serratia based on these modifications were higher for infected Paramecium than for uninfected Paramecium. 6. A mixture of density-mediated and trait-mediated indirect effects of parasitism on non- host species creates rich and complex possibilities for effects of parasites in food webs that should be included in assessments of possible impacts of parasite eradication or introduction

Valuation of Country Food in Nunavut Based on Energy and Protein Replacement

Communicating value across the pluralities of Indigenous Peoples’ food systems requires attention to economy and environment, food and wildlife, and the health of the people and that of the land. Valuation of distinct entities is always difficult but often essential to describe collective wealth and well-being, to quantify trade-offs, and to consider compensation when one is compromised for another. Here we estimate the replacement value of Nunavut country food by combining information on the amount and nutritional composition of harvested country food with the nutritional content and local price of store-bought food. Comparing the five-year average of energy and protein available in reported harvest to recommended dietary allowances indicates that 17 of 21 Nunavut communities harvest enough country food to satisfy the protein requirements of all community members. Nunavut’s country food system annually harvests five million kg of protein-rich food from across the territory, which would cost $198 million to purchase as store-bought protein, with a replacement value between$13.19 and $39.67 per kg depending on energy versus protein replacement and the inclusion versus exclusion of store-bought food subsidies. These valuations are higher than most previous estimates of local food value because they are more reflective of the energy and nutrient richness of country food and the high price of store-bought food in northern communities. The country food system is priceless in many, profound ways; better awareness of its energy and protein cost of replacement, together with the breadth of its nutritional and cultural value, may help to ensure local food systems are prioritized in northern food security and economic development initiatives. La communication de la valeur à travers les pluralités des systèmes alimentaires des peuples autochtones doit tenir compte de l’économie et de l’environnement, de l’alimentation et de la faune, de la santé des gens et de celle de la terre. L’évaluation d’entités distinctes est toujours difficile, mais souvent essentielle pour décrire la richesse et le bien-être collectifs, pour quantifier les concessions et pour considérer une compensation lorsqu’un système est compromis en raison d’un autre. Dans cet article, nous estimons la valeur de remplacement de la nourriture traditionnelle du Nunavut en combinant des données sur la quantité et la composition nutritionnelle des aliments récoltés sur le terroir, ainsi que sur le contenu nutritionnel et le prix local de la nourriture achetée en magasin. La comparaison de la moyenne quinquennale des données en valeur énergétique et protéique provenant des récoltes déclarées aux apports nutritionnels recommandés permet de constater que 17 des 21 collectivités du Nunavut récoltent suffisamment de nourriture traditionnelle pour satisfaire aux besoins en protéines de tous les membres des collectivités. Annuellement, le système alimentaire traditionnel du Nunavut donne lieu à des récoltes de cinq millions de kilogrammes de nourriture riche en protéines à l’échelle du territoire, ce qui représenterait des achats d’aliments protéinés en magasin d’une valeur de 198 millions de dollars, moyennant une valeur de remplacement s’échelonnant entre 13,19$ et 39,67 $ le kilogramme, selon que le remplacement est calculé en fonction de la valeur énergétique ou protéique, et avec inclusion ou exclusion des subventions au titre de la nourriture achetée en magasin. Ces évaluations sont plus élevées que la plupart des estimations antérieures de la valeur de la nourriture locale parce qu’elles tiennent davantage compte de la valeur énergétique et de la richesse en nutriments de la nourriture traditionnelle ainsi que du prix élevé de la nourriture achetée en magasin dans les collectivités nordiques. À bien des égards importants, le système alimentaire traditionnel a une valeur inestimable. Le fait de prendre davantage conscience du coût de remplacement de la valeur énergétique et protéique des aliments, en plus de l’ampleur de la valeur culturelle et nutritionnelle du système, pourrait aider à faire en sorte que les systèmes alimentaires locaux soient priorisés par les initiatives de sécurité alimentaire et de développement économique dans le Nord.

Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

Rationale: Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury. Methods:LgalS3(fl/fl) mice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yield LysM-cre (+/-) /LgalS3 (fl/fl) and Pdgfrb-cre (+/-) /LgalS3 (fl/fl) mice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficient Gal-3 (−/−) mice. Results: Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed in Pdgfrb-cre (+/-) /LgalS3 (fl/fl) mice. Conclusions: Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation

Galectin-3 inhibitor GB0139 protects against acute lung injury by inhibiting neutrophil recruitment and activation

Rationale: Galectin-3 (Gal-3) drives fibrosis during chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Effective pharmacological therapies available for ALI are limited; identifying novel concepts in treatment is essential. GB0139 is a Gal-3 inhibitor currently under clinical investigation for the treatment of idiopathic pulmonary fibrosis. We investigate the role of Gal-3 in ALI and evaluate whether its inhibition with GB0139 offers a protective role. The effect of GB0139 on ALI was explored in vivo and in vitro. Methods: The pharmacokinetic profile of intra-tracheal (i.t.) GB0139 was investigated in C57BL/6 mice to support the daily dosing regimen. GB0139 (1–30 µg) was then assessed following acute i.t. lipopolysaccharide (LPS) and bleomycin administration. Histology, broncho-alveolar lavage fluid (BALf) analysis, and flow cytometric analysis of lung digests and BALf were performed. The impact of GB0139 on cell activation and apoptosis was determined in vitro using neutrophils and THP-1, A549 and Jurkat E6 cell lines. Results: GB0139 decreased inflammation severity via a reduction in neutrophil and macrophage recruitment and neutrophil activation. GB0139 reduced LPS-mediated increases in interleukin (IL)-6, tumor necrosis factor alpha (TNFα) and macrophage inflammatory protein-1-alpha. In vitro, GB0139 inhibited Gal-3-induced neutrophil activation, monocyte IL-8 secretion, T cell apoptosis and the upregulation of pro-inflammatory genes encoding for IL-8, TNFα, IL-6 in alveolar epithelial cells in response to mechanical stretch. Conclusion: These data indicate that Gal-3 adopts a pro-inflammatory role following the early stages of lung injury and supports the development of GB0139, as a potential treatment approach in ALI

Chemical modulation of <i>in vivo</i> macrophage function with subpopulation-specific fluorescent prodrug conjugates

Immunomodulatory agents represent one of the most promising strategies for enhancing tissue regeneration without the side effects of traditional drug-based therapies. Tissue repair depends largely on macrophages, making them ideal targets for proregenerative therapies. However, given the multiple roles of macrophages in tissue homeostasis, small molecule drugs must be only active in very specific subpopulations. In this work, we have developed the first prodrug–fluorophore conjugates able to discriminate closely related subpopulations of macrophages (i.e., proinflammatory M1 vs anti-inflammatory M2 macrophages), and employed them to deplete M1 macrophages <i>in vivo</i> without affecting other cell populations. Selective intracellular activation and drug release enabled simultaneous fluorescence cell tracking and ablation of M1 macrophages <i>in vivo</i>, with the concomitant rescue of a proregenerative phenotype. <i>Ex vivo</i> assays in human monocyte-derived macrophages validate the translational potential of this novel platform to develop chemical immunomodulatory agents as targeted therapies for immune-related diseases