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Although the production time (11 months) of the messenger RNA vaccines against SARS-CoV-2 infection set a record, the preclinical research undergirding them spanned decades and was challenged by lack of funding. The 2021 Lasker–DeBakey Clinical Medical Research Award goes to Drs. Drew Weissman and Katalin Karikó, pioneer researchers of modified RNA.

Lynda Stuart and colleagues discuss the ability of animals to sense perturbations in host cells caused by pathogen effectors. On the basis of recent mechanistic evidence, they suggest that such effector-triggered immunity might be as widespread in animals as in plants. A fundamental question regarding any immune system is how it can discriminate between pathogens and non-pathogens. Here, we discuss how this discrimination can be mediated by a surveillance system distinct from pattern-recognition receptors that recognize conserved microbial patterns. It can be based instead on the ability of the host to sense perturbations in host cells induced by bacterial toxins or 'effectors' that are encoded by pathogenic microorganisms. Such 'effector-triggered immunity' was previously demonstrated mainly in plants, but recent data confirm that animals can also use this strategy.

Key Points Phagocytosis, the internalization of particles by cells, is involved in development, tissue homeostasis and host defence. Aspects of this process are highly conserved between species and hence studies in model organisms, such as Drosophila melanogaster , have been informative. Particle internalization is not simply a mechanism of waste disposal but rather essential for the formation of the phagosome, the organelle that is generated around the internalized particle. As in mammals, D. melanogaster phagosomes are highly complex compartments and are central to many of the effector functions of phagocytes. Phagocytosis is triggered after ligation of cell-surface receptors. Similar to mammals, D. melanogaster uses multiple mechanisms of bacterial recognition, such as complement-like opsonization and scavenger receptors. In addition, studies in D. melanogaster have highlighted a new family of phagocytic receptors that use epidermal growth factor (EGF)-like repeats to bind ligands. Fruit flies have an alternative to the highly variable antibodies found in mammals and instead use DSCAM (Down syndrome cell-adhesion molecule), an immunoglobulin-superfamily member that shows remarkable variability, that may act as both an opsonin and a cell-surface receptor. RNA-interference-based screens have shown that much of the machinery downstream of the cell-surface receptors are common between flies and humans. Studies in D. melanogaster have also suggested roles for the coatamer protein complex and the exocyst complex in the process of phagocytosis. In addition, studies in D. melanogaster have added to our understanding of the role of phagocytosis in pathogen sensing. Furthermore, D. melanogaster phagocytes may potentially be involved in immune adaptation and the processing of internalized antigens. Studies in Drosophila melanogaster are proving fruitful for our understanding of phagocytosis in development, tissue homeostasis and host defence. In this Review, parallels are drawn between phagocytosis in flies and mammals, providing insight into its complexity and the evolutionary origins of immunity. Phagocytosis, the engulfment of material by cells, is a highly conserved process that arose before the development of multicellularity. Phagocytes have a key role in embryogenesis and also guard the portals of potential pathogen entry. They discriminate between diverse particles through the array of receptors expressed on their surface. In higher species, arguably the most sophisticated function of phagocytes is the processing and presentation of antigens derived from internalized material to stimulate lymphocytes and long-lived specific immunity. Central to these processes is the generation of a phagosome, the organelle that forms around internalized material. As we discuss in this Review, over the past two decades important insights into phagocytosis have been gleaned from studies in the model organism Drosophila melanogaster .

The molecular mechanisms behind recognition of altered self remain unclear. Moore and co-workers show that oxidized low-density lipoprotein (LDL) and β-amyloid trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-β triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-β trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-β stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.

Particulate crystals can activate the NLRP3 inflammasome. Moore and colleagues show that the scavenger protein CD36 contributes to sterile inflammation via uptake of soluble cholesterol and amyloid peptides that nucleate into intracellular crystals. Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.

The NLRP3 inflammasome is primarily known for producing inflammatory cytokines and inducing pyroptosis. Stuart and colleagues identify an additional role for NLRP3 in driving down the pH of phagosomes. Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense.

Lipid-engorged macrophages accumulate in atherosclerotic plaques where chronic inflammation ensues. Moore and colleagues show that macrophage migration to chemokines and egress is arrested by netrin-1, which is secreted in the plaque lesions. Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic inflammation, remain unknown. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin-1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation.

Integrin signalling triggers cytoskeletal rearrangements, including endocytosis and exocytosis of integrins and other membrane proteins. In addition to recycling integrins, this trafficking can also regulate intracellular signalling pathways. Here we describe a role for αv integrins in regulating Toll-like receptor (TLR) signalling by modulating intracellular trafficking. We show that deletion of αv or β3 causes increased B-cell responses to TLR stimulation in vitro , and αv-conditional knockout mice have elevated antibody responses to TLR-ligand-associated antigens. αv regulates TLR signalling by promoting recruitment of the autophagy component LC3 (microtubule-associated proteins 1 light chain 3) to TLR-containing endosomes, which is essential for progression from NF-κB to IRF signalling, and ultimately for traffic to lysosomes where signalling is terminated. Disruption of LC3 recruitment leads to prolonged NF-κB signalling and increased B-cell proliferation and antibody production. This work identifies a previously unrecognized role for αv and the autophagy components LC3 and atg5 in regulating TLR signalling and B-cell immunity. Integrins can regulate antigen-specific and innate immune receptor signalling, thereby affecting immune cell function. Here the authors show that avß3 integrin controls Toll-like receptor (TLR) signalling by regulating its trafficking to limit TLR-mediated B-cell proliferation and antibody production.

Mitochondria can contribute to an increase in the amount of phagosomal reactive oxygen species and thereby promote the effective killing of bacteria. Study of mice deficient in Mst1 and Mst2 reveals a role for these kinases in recruiting mitochondria to phagosomes.

Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through TLRs on B cells promotes many aspects of GC B cell responses, including affinity maturation, class switching, and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here, we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αv integrins and noncanonical autophagy. Using B cell-specific αv-KO mice, we show that loss of αv-mediated TLR regulation increased GC B cell expansion, somatic hypermutation, class switching, and generation of long-lived plasma cells after immunization with virus-like particles (VLPs) or antigens associated with TLR ligand adjuvants. Furthermore, targeting αv-mediated regulation increased the magnitude and breadth of antibody responses to influenza virus vaccination. These data therefore identify a mechanism of regulation of GC B cells that can be targeted to enhance antibody responses to vaccination.