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Ehrlichia chaffeensis is an obligately intracellular bacterium that causes human monocytic ehrlichiosis and survives within mononuclear phagocytes by manipulating key cell signaling pathways. Unlike most Gram-negative bacteria, E. chaffeensis lacks classical pathogen-associated molecular patterns such as lipopolysaccharide and peptidoglycan, yet it stimulates strong chemokine production during infection; however, the molecular patterns, receptors and signaling pathways involved in inducing chemokine expression are unknown. Here, we uncover a cell signaling strategy whereby E. chaffeensis , through TRP120 Wnt ligand mimicry, co-opts the noncanonical Wnt/Ca 2+ signaling to selectively activate NFATc1 and drive chemokine expression. This pathogen-driven NFAT activation promotes monocyte recruitment, revealing a previously unrecognized chemokine induction mechanism.

The effect of the production of IFN-I upon infection by Chlamydia trachomatis is not well understood. We showed that IFN-I exacerbated Chlamydia -induced inflammation in epithelial cells. This synergy was mediated by the IFN-induced upregulation of Toll-like receptor 3 (TLR3) expression, which facilitated sensing of Chlamydia and amplified the inflammatory response. We identified the signaling cascades involved upstream and downstream of TLR3 signaling. By exacerbating the pro-inflammatory response of epithelial cells, IFN-I might contribute to the hyperinflammation experienced by some individuals. The signaling pathways we uncovered can serve as a starting point for novel therapeutic strategies to alleviate tissue damage upon Chlamydia infection.

Lipid rafts, also known as microdomains, are important components of cell membranes and are enriched in cholesterol, glycophospholipids and receptors. They are involved in various essential cellular processes, including endocytosis, exocytosis and cellular signaling. Receptors are concentrated at lipid rafts, through which cellular signaling can be transmitted. Pathogens exploit these signaling mechanisms to enter cells, proliferate and egress. However, lipid rafts also play an important role in initiating antimicrobial responses by sensing pathogens via clustered pathogen-sensing receptors and triggering downstream signaling events such as programmed cell death or cytokine production for pathogen clearance. In this review, we discuss how both host and pathogens use lipid rafts and associated proteins in an arms race to survive. Special attention is given to the involvement of the major vault protein, the main constituent of a ribonucleoprotein complex, which is enriched in lipid rafts upon infection with vaccinia virus.

Key Points Host defence peptides (HDPs) display substantial immunomodulatory properties in vitro and in vivo , and these features are becoming increasingly appreciated in the literature. The immune response is a highly complex process, involving multiple interconnected signalling pathways. HDPs influence the entire signalling network of the immune response and, as a result, their effects on biological processes are also complex. The ability of HDPs to influence many different cell types and pathways has implications in various immune-associated diseases. In addition to direct antimicrobial activity and immunomodulatory activities, HDPs may have a role in biological functions such as anticancer activity, wound healing and angiogenesis. In this Review, the authors detail the diverse roles of host defence peptides (HDPs) in innate immunity and their association with inflammatory diseases. They highlight the complexity of the immune signalling pathways that are influenced by natural and synthetic HDPs and show that systems biology approaches are important to understand this complexity. Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications.

Small noncoding RNAs (sncRNAs) play important regulatory roles in bacterial physiological processes and host-pathogen interactions. Meanwhile, bacterial outer membrane vesicles (OMVs), as naturally secreted outer membrane structures, play a vital role in the interaction between bacteria and their living environment, including the host environment. However, most current studies focus on the biological functions of sncRNAs in bacteria or hosts, while neglecting the roles and regulatory mechanisms of the OMVs that encapsulate these sncRNAs. Therefore, this review aims to summarize the intracellular regulatory roles of bacterial sncRNAs in promoting pathogen survival by regulating virulence, modulating bacterial drug resistance, and regulating iron metabolism, and their extracellular regulatory function for influencing host immunity through host-pathogen interactions. Additionally, we introduce the key role played by OMVs, which serve as important cargoes in bacterial sncRNA–host interactions. We propose emerging pathways of sncRNA action to further discuss the mode of host-pathogen interactions, highlighting that the inhibition of sncRNA delivery by OMVs may prevent the occurrence of infection to some extent. Hence, this review lays the foundation for future prophylactic treatments against bacterial infections and strategies for addressing bacterial drug resistance. Key points •sncRNAs have intracellular and extracellular regulatory functions in bacterial physiological processes and host-pathogen interactions. •OMVs are potential mediators between bacterial sncRNAs and host cells. •OMVs encapsulating sncRNAs have more potential biological functions.

The global healthcare system faces increasing threats from emerging and re-emerging pathogens. Current understanding of host-pathogen interactions and underlying immune mechanisms remains incomplete, which hinders the development of effective diagnostic tools and therapeutic strategies. The receptor for activated C kinase 1 (RACK1) is a multifunctional scaffolding protein that integrates diverse signaling pathways, modulates translation, and regulates key cellular processes. Despite accumulating evidence implicating RACK1 in host immune response to infections, its multifaceted roles and mechanisms remain poorly defined. Hence, this review systematically discusses the involvement of RACK1 in host defense against bacterial and viral pathogens, with a focus on its regulation of inflammatory signaling, inflammasome activation, hormone-mediated immune regulation, reactive oxygen species production, adaptive immunity, and different pathogen infections. Together, current evidence suggests that RACK1 links signaling and translation to shape immune responses in different infectious settings and may provide a basis for host-directed therapeutic strategies.

Tuberculosis (TB), caused by (Mtb), remains a leading cause of mortality worldwide. A crucial factor in virulence is the ESX-5 secretion system, which transports PE/PPE proteins such as PE18 and PPE26. These proteins modulate host-pathogen interactions, immune responses, and intracellular survival mechanisms. Despite their importance, the roles and molecular interactions of PE18 and PPE26 in pathogenesis require further investigation. We explored the roles of PE18 and PPE26 using recombinant ( ) as a model organism. Protein-protein interactions were analyzed biochemically to identify partners within the ESX-5 secretion system, including EspG5 and other PE/PPE proteins. Subcellular localization of these proteins was assessed via cell fractionation studies. Functional assays, including cytokine production and antigen presentation studies, were performed using TLR2/Myd88 knockout and wild-type macrophages. experiments were conducted to assess effector T-cell activation and intracellular survival. Mechanistic insights into endosome-phagosome maturation and actin cytoskeleton dynamics were obtained through fluorescence microscopy. Our biochemical analyses confirmed interactions between PE18/PPE26, PE18/PPE27, PE19/PPE25, and EspG5/PPE, highlighting their involvement in ESX-5-mediated secretion. Cell fractionation studies revealed that PE/PPE proteins predominantly localize to the cell wall, with PE18 also secreted extracellularly. In vitro and experiments demonstrated that PE18 and PPE26 activate cytokine production and antigen presentation via TLR2/Myd88-dependent signaling pathways, inducing robust effector memory T-cell responses. Recombinant expressing PE18, PPE26, or their combination exhibited enhanced intracellular survival by disrupting endosome-phagosome maturation, likely through interference with actin cytoskeletal organization. Our findings elucidate the pivotal roles of PE18 and PPE26 in pathogenesis, emphasizing their contributions to immune modulation and intracellular persistence. The observed disruption of actin dynamics and endosome-phagosome maturation underscores a novel mechanism by which evades host defenses. The ability of PE18 and PPE26 to induce effector T-cell responses highlights their potential as targets for host-directed therapies or vaccine development against TB. Further studies focusing on their structure-function relationships and interactions with host proteins could accelerate the development of innovative therapeutic strategies.

Key Points Virtually all bacterial and eukaryotic cells, as well as many viruses, display surface carbohydrates, which have a crucial role in the establishment of host–microorganism complex interactions through their recognition by protein receptors, mainly known as lectins. Lectin–glycan interactions are ubiquitous and essential to biological systems, not simply as the 'glue' between cells, but as the initiators of a functional crosstalk that modulates their physiology and homeostatic balance. Microbial lectins, including viral haemagglutinins, bacterial adhesins and parasite lectins, are involved in host colonization, whereas some animal lectins can function as pattern recognition receptors in immune responses against microbial pathogens and parasites. Among the various lectin families, the galectins are proteins that are characterized by a unique binding-site sequence motif, affinity for β-galactosides and wide taxonomic distribution. Most metazoans are endowed with a complex galectin repertoire, with members exhibiting multiple isoforms and subtle variations in carbohydrate specificity, which together with a certain level of plasticity in sugar binding suggests they have substantial diversity in recognition properties. Galectins were initially thought to only bind endogenous 'self' glycans and mediate developmental processes, including cell differentiation and tissue organization, and more recently, regulation of immune homeostasis. In the past few years, however, it has become clear that galectins also bind non-self glycans on the surface of potentially pathogenic microorganisms (viruses, bacteria, protista and fungi) and parasitic worms, and mediate recognition and effector functions in innate immunity. Some pathogens and parasites subvert the roles of galectins as PRRs to either attach to suitable epithelia in their insect vector or final host, or to enter the host cells to proliferate and disseminate systemically. Furthermore, galectins from parasites might contribute directly or indirectly to host invasion, or downregulation of the host immune response. In summary, the recent evidence discussed in this Review indicates that host galectins can function as recognition receptors that target non-self glycans on the surfaces of viruses, bacteria, protista and helminth pathogens and parasites, and either prevent or facilitate infection. Because galectins also bind self glycans on the host cell surface as the first step in immunoregulation and developmental processes, galectins do not fit current models of innate immune self or non-self recognition or defence. Gaps in our knowledge about the diversity of the host galectins, their subcellular compartmentalization and secretion, and structural and biophysical aspects of their interactions with the microbial carbohydrate moieties warrant further investigation. The novel insights provided by the realization that galectins are directly involved in pathogen recognition has opened new avenues of research aimed at disrupting their roles in parasite–vector interactions or host invasion. Galectins are important for recognition of carbohydrate ligands during embryogenesis, development and immune regulation. In addition, recent work has shown that galectins also function as receptors for glycans expressed on the surface of potentially pathogenic microorganisms. In this Review, Gerardo Vasta discusses the roles of galectins in host immunity and how pathogens have evolved to evade or subvert galectin-mediated immune responses. Galectins, which were first characterized in the mid-1970s, were assigned a role in the recognition of endogenous ('self') carbohydrate ligands in embryogenesis, development and immune regulation. Recently, however, galectins have been shown to bind glycans on the surface of potentially pathogenic microorganisms, and function as recognition and effector factors in innate immunity. Some parasites subvert the recognition roles of the vector or host galectins to ensure successful attachment or invasion. This Review discusses the role of galectins in microbial infection, with particular emphasis on adaptations of pathogens to evasion or subversion of host galectin-mediated immune responses.

As a member of the Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) protein kinase subfamily, FERONIA (FER) has emerged as a versatile player regulating multifaceted functions in growth and development, as well as responses to environmental factors and pathogens. With the concerted efforts of researchers, the molecular mechanism underlying FER-dependent signaling has been gradually elucidated. A number of cellular processes regulated by FER-ligand interactions have been extensively reported, implying cell type-specific mechanisms for FER. Here, we provide a review on the roles of FER in male-female gametophyte recognition, cell elongation, hormonal signaling, stress responses, responses to fungi and bacteria, and present a brief outlook for future efforts.

Cirrhotic portal hypertension is characterised by development of the decompensating events of ascites, encephalopathy, portal hypertensive bleeding and hepatorenal syndrome, which arise in a setting of cirrhosis-associated immune dysfunction (CAID) and define morbidity and prognosis. CAID describes the dichotomous observations that systemic immune cells are primed and display an inflammatory phenotype, while failing to mount robust responses to pathogen challenge. Bacterial infections including spontaneous bacterial peritonitis are common complications of advanced chronic liver disease and can precipitate variceal haemorrhage, hepatorenal syndrome and acute-on-chronic liver failure; they frequently arise from gut-derived organisms and are closely linked with dysbiosis of the commensal intestinal microbiota in advanced chronic liver disease.Here, we review the links between cirrhotic dysbiosis, intestinal barrier dysfunction and deficits of host-microbiome compartmentalisation and mucosal immune homoeostasis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies targeted at restoring intestinal eubiosis, augmenting gut barrier function and ameliorating the mucosal and systemic immune deficits that characterise and define the course of decompensated cirrhosis.