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The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.Stravalaci et al. examined recognition of SARS-CoV-2 by human soluble innate pattern recognition receptor. They report that pentraxin 3 and mannose-binding protein recognize viral nucleoprotein and spike, respectively. Mannose-binding lectin has antiviral activity, and human genetic polymorphisms of MBL2 are associated with more severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.Kanneganti and Diamond review the key role played by innate immunity in the control and immunopathology of COVID-19.

In mammals, cyclic GMP–AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide 2′3′-cGAMP in response to cytosolic DNA and this triggers an antiviral immune response. cGAS belongs to a large family of cGAS/DncV-like nucleotidyltransferases that is present in both prokaryotes 1 and eukaryotes 2 – 5 . In bacteria, these enzymes synthesize a range of cyclic oligonucleotides and have recently emerged as important regulators of phage infections 6 – 8 . Here we identify two cGAS-like receptors (cGLRs) in the insect Drosophila melanogaster . We show that cGLR1 and cGLR2 activate Sting- and NF-κB-dependent antiviral immunity in response to infection with RNA or DNA viruses. cGLR1 is activated by double-stranded RNA to produce the cyclic dinucleotide 3′2′-cGAMP, whereas cGLR2 produces a combination of 2′3′-cGAMP and 3′2′-cGAMP in response to an as-yet-unidentified stimulus. Our data establish cGAS as the founding member of a family of receptors that sense different types of nucleic acids and trigger immunity through the production of cyclic dinucleotides beyond 2′3′-cGAMP. Two cGAS-like receptors, cGLR1 and cGLR2, identified in Drosophila melanogaster are shown to induce antiviral immunity in response to RNA or DNA virus infections through the production of 2′3′-cGAMP and 3′2′-cGAMP.

Plants rely on cell-surface-localized pattern recognition receptors to detect pathogen- or host-derived danger signals and trigger an immune response 1 – 6 . Receptor-like proteins (RLPs) with a leucine-rich repeat (LRR) ectodomain constitute a subgroup of pattern recognition receptors and play a critical role in plant immunity 1 – 3 . Mechanisms underlying ligand recognition and activation of LRR-RLPs remain elusive. Here we report a crystal structure of the LRR-RLP RXEG1 from Nicotiana benthamiana that recognizes XEG1 xyloglucanase from the pathogen Phytophthora sojae . The structure reveals that specific XEG1 recognition is predominantly mediated by an amino-terminal and a carboxy-terminal loop-out region (RXEG1(ID)) of RXEG1. The two loops bind to the active-site groove of XEG1, inhibiting its enzymatic activity and suppressing Phytophthora infection of N. benthamiana . Binding of XEG1 promotes association of RXEG1(LRR) with the LRR-type co-receptor BAK1 through RXEG1(ID) and the last four conserved LRRs to trigger RXEG1-mediated immune responses. Comparison of the structures of apo-RXEG1(LRR), XEG1–RXEG1(LRR) and XEG1–BAK1–RXEG1(LRR) shows that binding of XEG1 induces conformational changes in the N-terminal region of RXEG1(ID) and enhances structural flexibility of the BAK1-associating regions of RXEG1(LRR). These changes allow fold switching of RXEG1(ID) for recruitment of BAK1(LRR). Our data reveal a conserved mechanism of ligand-induced heterodimerization of an LRR-RLP with BAK1 and suggest a dual function for the LRR-RLP in plant immunity. A structural analysis focusing on plant immunity reveals how LRR-containing receptor-like proteins recognize pathogenic ligands and consequently become activated, with the data suggesting that these proteins target pathogens through two different mechanisms.

Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions.

Receptor-like kinases (RLKs) and Receptor-like proteins (RLPs) play crucial roles in plant immunity, growth, and development. Plants deploy a large number of RLKs and RLPs as pattern recognition receptors (PRRs) that detect microbe- and host-derived molecular patterns as the first layer of inducible defense. Recent advances have uncovered novel PRRs, their corresponding ligands, and mechanisms underlying PRR activation and signaling. In general, PRRs associate with other RLKs and function as part of multiprotein immune complexes at the cell surface. Innovative strategies have emerged for the rapid identification of microbial patterns and their cognate PRRs. Successful pathogens can evade or block host recognition by secreting effector proteins to “hide” microbial patterns or inhibit PRR-mediated signaling. Furthermore, newly identified pathogen effectors have been shown to manipulate RLKs controlling growth and development by mimicking peptide hormones of host plants. The ongoing studies illustrate the importance of diverse plant RLKs in plant disease

Summary Plants face a relentless onslaught from a diverse array of pathogens in their natural environment, to which they have evolved a myriad of strategies that unfold across various temporal scales. Cell surface pattern recognition receptors (PRRs) detect conserved elicitors from pathogens or endogenous molecules released during pathogen invasion, initiating the first line of defence in plants, known as pattern‐triggered immunity (PTI), which imparts a baseline level of disease resistance. Inside host cells, pathogen effectors are sensed by the nucleotide‐binding/leucine‐rich repeat (NLR) receptors, which then activate the second line of defence: effector‐triggered immunity (ETI), offering a more potent and enduring defence mechanism. Moreover, PTI and ETI collaborate synergistically to bolster disease resistance and collectively trigger a cascade of downstream defence responses. This article provides a comprehensive review of plant defence responses, offering an overview of the stepwise activation of plant immunity and the interactions between PTI‐ETI synergistic signal transduction.

Phytohormone signalling pathways have an important role in defence against pathogens mediated by cell-surface pattern recognition receptors and intracellular nucleotide-binding leucine-rich repeat class immune receptors 1 , 2 (NLR). Pathogens have evolved counter-defence strategies to manipulate phytohormone signalling pathways to dampen immunity and promote virulence 3 . However, little is known about the surveillance of pathogen interference of phytohormone signalling by the plant innate immune system. The pepper ( Capsicum chinense ) NLR Tsw, which recognizes the effector nonstructural protein NSs encoded by tomato spotted wilt orthotospovirus (TSWV), contains an unusually large leucine-rich repeat (LRR) domain. Structural modelling predicts similarity between the LRR domain of Tsw and those of the jasmonic acid receptor COI1, the auxin receptor TIR1 and the strigolactone receptor partner MAX2. This suggested that NSs could directly target hormone receptor signalling to promote infection, and that Tsw has evolved a LRR resembling those of phytohormone receptors LRR to induce immunity. Here we show that NSs associates with COI1, TIR1 and MAX2 through a common repressor—TCP21—which interacts directly with these phytohormone receptors. NSs enhances the interaction of COI1, TIR1 or MAX2 with TCP21 and blocks the degradation of corresponding transcriptional repressors to disable phytohormone-mediated host immunity to the virus. Tsw also interacts directly with TCP21 and this interaction is enhanced by viral NSs. Downregulation of TCP21 compromised Tsw-mediated defence against TSWV. Together, our findings reveal that a pathogen effector targets TCP21 to inhibit phytohormone receptor function, promoting virulence, and a plant NLR protein has evolved to recognize this interference as a counter-virulence strategy, thereby activating immunity. The tomato spotted wilt orthotospovirus nonstructural protein NSs interferes with phytohormone signalling in plants to compromise plant defences by interacting with plant TCP21—this effect of the viral protein is counteracted by the plant NLR immune receptor protein Tsw.

Key Points Candida albicans is the most important fungal pathogen in humans, and it causes both mucosal and systemic fungal infections. Innate immune recognition by pattern recognition receptors (PRRs) is the first step for activation of host defence mechanisms during Candida infections. C-type lectin receptors (CLRs) are the main family of PRRs involved in recognition of Candida species, but Toll-like receptors, NOD-like receptors and RIG-I-like receptors are also involved in the antifungal response. Neutrophils, monocytes and macrophages are the main immune cell populations responsible for host defence against systemic candidiasis, whereas T helper 1 (T H 1) cells, T H 17 cells and innate lymphoid cells are mainly responsible for protection against Candida infections at mucosal surfaces. C. albicans and components from its cell wall, particularly β-glucans, have the capacity to induce epigenetic reprogramming of innate immune cells, generating a de facto innate immune memory that has been termed 'trained immunity'. Systems biology approaches combining innovative genomic, microbiome and functional data open new possibilities for identifying key mechanisms in the pathophysiology of fungal infections. Future efforts need to combine cutting-edge molecular and cell-biological techniques with translational approaches in order to gain a better understanding of the host immune response to Candida infections and enable the design of novel antifungal strategies. This Review describes the host immune response to Candida fungal infections. The authors detail the innate and adaptive immune mechanisms, as well as the non-immune mechanisms, that are involved in the antifungal response. They also discuss emerging evidence suggesting that both innate and adaptive immune cells contribute to immune memory against Candida species. The immune response to Candida species is shaped by the commensal character of the fungus. There is a crucial role for discerning between colonization and invasion at mucosal surfaces, with the antifungal host defence mechanisms used during mucosal or systemic infection with Candida species differing substantially. Here, we describe how innate sensing of fungi by pattern recognition receptors and the interplay of immune cells (both myeloid and lymphoid) with non-immune cells, including platelets and epithelial cells, shapes host immunity to Candida species. Furthermore, we discuss emerging data suggesting that both the innate and adaptive immune systems display memory characteristics after encountering Candida species.

Key Points Autophagy is a fundamental eukaryotic homeostatic pathway that affects innate and adaptive immunity. Autophagic responses are integrated with pattern recognition receptor and cytokine signalling. Autophagic receptors, termed sequestosome 1-like receptors, target intracellular microorganisms for autophagy via ubiquitin and galectin tags, and they represent a new class of pattern recognition receptors. Intracellular pathogens have evolved elaborate strategies to prevent, neutralize or commandeer autophagy to support their own survival. Autophagy is a potent anti-inflammatory process that inhibits inflammasome activation and that modulates type I interferon responses. Autophagy affects the secretion of inflammatory and antimicrobial mediators. Autophagy enhances conventional phagosome maturation, affects antigen presentation, and influences T cell homeostasis and T helper cell polarization. Genetic predisposition and physiological links exist between autophagy and infectious, inflammatory and autoimmune diseases in humans. It is increasingly understood that autophagy is an ancient defence mechanism that has become incorporated into numerous immunological pathways. As discussed in this Review, its immunological roles include the elimination of microorganisms, the control of inflammation, the regulation of antigen presentation and lymphocyte homeostasis, and the secretion of immune mediators. Autophagy is a fundamental eukaryotic pathway that has multiple effects on immunity. Autophagy is induced by pattern recognition receptors and, through autophagic adaptors, it provides a mechanism for the elimination of intracellular microorganisms. Autophagy controls inflammation through regulatory interactions with innate immune signalling pathways, by removing endogenous inflammasome agonists and through effects on the secretion of immune mediators. Moreover, autophagy contributes to antigen presentation and to T cell homeostasis, and it affects T cell repertoires and polarization. Thus, as we discuss in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity.