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Trace metals are essential micronutrients required for survival across all kingdoms of life. From bacteria to animals, metals have critical roles as both structural and catalytic cofactors for an estimated third of the proteome, representing a major contributor to the maintenance of cellular homeostasis. The reactivity of metal ions engenders them with the ability to promote enzyme catalysis and stabilize reaction intermediates. However, these properties render metals toxic at high concentrations and, therefore, metal levels must be tightly regulated. Having evolved in close association with bacteria, vertebrate hosts have developed numerous strategies of metal limitation and intoxication that prevent bacterial proliferation, a process termed nutritional immunity. In turn, bacterial pathogens have evolved adaptive mechanisms to survive in conditions of metal depletion or excess. In this Review, we discuss mechanisms by which nutrient metals shape the interactions between bacterial pathogens and animal hosts. We explore the cell-specific and tissue-specific roles of distinct trace metals in shaping bacterial infections, as well as implications for future research and new therapeutic development.Trace metals are essential micronutrients required for survival across all kingdoms of life. In this Review, Murdoch and Skaar discuss the strategies whereby vertebrate hosts limit metal or induce excess metal to prevent bacterial proliferation, a process termed nutritional immunity, and they discuss adaptive mechanisms that bacterial pathogens have evolved to survive in conditions of metal depletion or excess.

Invasive Staphylococcus aureus infections are common, causing high mortality, compounded by the propensity of the bacterium to develop drug resistance. S. aureus is an excellent case study of the potential for a bacterium to be commensal, colonizing, latent or disease-causing; these states defined by the interplay between S. aureus and host. This interplay is multidimensional and evolving, exemplified by the spread of S. aureus between humans and other animal reservoirs and the lack of success in vaccine development. In this Review, we examine recent advances in understanding the S. aureus–host interactions that lead to infections. We revisit the primary role of neutrophils in controlling infection, summarizing the discovery of new immune evasion molecules and the discovery of new functions ascribed to well-known virulence factors. We explore the intriguing intersection of bacterial and host metabolism, where crosstalk in both directions can influence immune responses and infection outcomes. This Review also assesses the surprising genomic plasticity of S. aureus, its dualism as a multi-mammalian species commensal and opportunistic pathogen and our developing understanding of the roles of other bacteria in shaping S. aureus colonization.In this Review, Howden and co-workers examine and integrate recent key advances in understanding the mechanisms that Staphylococcus aureus uses to cause infections.

Osteomyelitis remains one of the greatest risks in orthopaedic surgery. Although many organisms are linked to skeletal infections, Staphylococcus aureus remains the most prevalent and devastating causative pathogen. Important discoveries have uncovered novel mechanisms of S. aureus pathogenesis and persistence within bone tissue, including implant-associated biofilms, abscesses and invasion of the osteocyte lacuno-canalicular network. However, little clinical progress has been made in the prevention and eradication of skeletal infection as treatment algorithms and outcomes have only incrementally changed over the past half century. In this Review, we discuss the mechanisms of persistence and immune evasion in S. aureus infection of the skeletal system as well as features of other osteomyelitis-causing pathogens in implant-associated and native bone infections. We also describe how the host fails to eradicate bacterial bone infections, and how this new information may lead to the development of novel interventions. Finally, we discuss the clinical management of skeletal infection, including osteomyelitis classification and strategies to treat skeletal infections with emerging technologies that could translate to the clinic in the future.Osteomyelitis is an infection of bone that arises when a pathogen colonizes bone tissue owing to injury or surgery. In this Review, Masters and colleagues explore the microbial pathogenesis, immunity and clinical management of bone infections.

Host–microbiota interactions are fundamental for the development of the immune system. Drastic changes in modern environments and lifestyles have led to an imbalance of this evolutionarily ancient process, coinciding with a steep rise in immune-mediated diseases such as autoimmune, allergic and chronic inflammatory disorders. There is an urgent need to better understand these diseases in the context of mucosal and skin microbiota. This Review discusses the mechanisms of how the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases in the context of a genetically prone host. It is timely owing to the wealth of new studies that recently contributed to this field, ranging from metagenomic studies in humans and mechanistic studies of host–microorganism interactions in gnotobiotic models and in vitro systems, to molecular mechanisms with broader implications across immune-mediated diseases. We focus on the general principles, such as breaches in immune tolerance and barriers, leading to the promotion of immune-mediated diseases by gut, oral and skin microbiota. Lastly, the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis will be explored.In this Review, Ruff, Greiling and Kriegel discuss the mechanisms through which the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases, and explore the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis.

Microorganisms engage in complex interactions with other organisms and their environment. Recent studies have shown that these interactions are not limited to the exchange of electron donors. Most microorganisms are auxotrophs, thus relying on external nutrients for growth, including the exchange of amino acids and vitamins. Currently, we lack a deeper understanding of auxotrophies in microorganisms and how nutrient requirements differ between different strains and different environments. In this Opinion article, we describe how the study of auxotrophies and nutrient requirements among members of complex communities will enable new insights into community composition and assembly. Understanding this complex network over space and time is crucial for developing strategies to interrogate and shape microbial communities.

The innate immune system recognizes microbial products using germline-encoded receptors that initiate inflammatory responses to infection. The bacterial cell wall component peptidoglycan is a prime example of a conserved pathogen-associated molecular pattern (PAMP) for which the innate immune system has evolved sensing mechanisms. Peptidoglycan is a direct target for innate immune receptors and also regulates the accessibility of other PAMPs to additional innate immune receptors. Subtle structural modifications to peptidoglycan can influence the ability of the innate immune system to detect bacteria and can allow bacteria to evade or alter host defences. This Review focuses on the mechanisms of peptidoglycan recognition that are used by mammalian cells and discusses new insights into the role of peptidoglycan recognition in inflammation, metabolism, immune homeostasis and disease.

Key Points Outer membrane vesicles (OMVs) are bacterial nanoparticles that are naturally produced during bacterial growth both in vitro and in vivo . OMVs can interact with many host cell types — including mucosal epithelial cells, myeloid cells and cells distal to the site of OMV entry — and thus have a range of inflammatory outcomes. Clinical studies have demonstrated the presence of OMVs in host tissues, suggesting that they have potentially pathogenic roles in various infectious diseases, particularly in those of a chronic nature. OMVs may also be important as previously unrecognized mediators of the inflammatory pathologies that accompany certain infectious diseases of idiopathic origin. OMVs can enter non-phagocytic human epithelial cells via multiple mechanisms including lipid raft-dependent and lipid raft-independent endocytosis, in addition to dynamin-dependent and dynamin-independent mechanisms. When they are present inside cells, OMVs migrate to early endosomes and are detected by the host intracellular immune receptor nucleotide-binding oligomerization domain-containing protein 1 (NOD1), which results in the induction of autophagy and the generation of a pro-inflammatory response. When OMVs are within epithelial cells, their protein cargo is processed and OMV peptides are released in exosomes. These peptide-laden exosomes can then be taken up by professional antigen-presenting cells and presented to T cells, resulting in the generation of antigen-specific adaptive immune responses. In addition to their pro-inflammatory effects, OMVs can modulate or even suppress immune cell responses through their direct effects on host cells. Evidence is also emerging that OMVs produced by commensal bacteria may have roles in immune tolerance and other physiological functions of benefit to the host. OMVs are highly stable, non-infectious and genetically tractable nanoparticles that contain the major immunogenic proteins of the parent bacterium and are able to elicit responses from both arms of the immune system, thus making them highly suited as vaccines and adjuvants. Outer membrane vesicles (OMVs) are produced by bacteria and can interact with leukocytes and other host cells to shape the immune response during infection. OMVs can have both pro-inflammatory and anti-inflammatory effects; in this Review, the authors discuss how they may contribute to human diseases and also their potential as vaccine adjuvants. Gram-negative bacteria shed extracellular outer membrane vesicles (OMVs) during their normal growth both in vitro and in vivo . OMVs are spherical, bilayered membrane nanostructures that contain many components found within the parent bacterium. Until recently, OMVs were dismissed as a by-product of bacterial growth; however, findings within the past decade have revealed that both pathogenic and commensal bacteria can use OMVs to manipulate the host immune response. In this Review, we describe the mechanisms through which OMVs induce host pathology or immune tolerance, and we discuss the development of OMVs as innovative nanotechnologies.

Key Points Emergency granulopoiesis is defined as the well-orchestrated de novo generation of neutrophils in response to systemically disseminated infection. The overall goal of this process is to enhance neutrophil output from the bone marrow to meet the higher demand for neutrophils during severe infection when these cells are consumed in large quantities during the innate immune response. Emergency granulopoiesis can be dissected into three phases: pathogen sensing is followed by translation of this signal into enhanced granulocytic cell production in the bone marrow, and then the subsequent re-establishment of homeostatic steady-state conditions once the infection has been cleared. Pathogen sensing mainly occurs in non-haematopoietic cells through Toll-like receptor signalling and leads to the subsequent initiation of emergency granulopoiesis through the release of granulopoietic cytokines. In addition, pathogen sensing by haematopoietic stem and progenitor cells themselves might contribute to the overall granulopoietic response directly by promoting proliferation and myeloid cell differentiation, and also indirectly through the release of cytokines by early haematopoietic cells that signal in a paracrine and autocrine manner. The biological relevance of direct pathogen sensing by haematopoietic stem and progenitor cells in acute and chronic inflammation remains to be determined. Granulocyte colony-stimulating factor is the major granulopoietic cytokine regulating both steady-state and emergency granulopoiesis. At the transcriptional level, CCAAT-enhancer-binding protein-α (C/EBPα) drives steady-state granulopoiesis, whereas C/EBPβ is the master regulator of emergency granulopoiesis. The mechanisms that restrain emergency granulopoiesis and orchestrate the return to steady-state conditions are incompletely understood but are known to involve suppressor of cytokine signalling proteins. A summary of the molecular and cellular events that coordinate the markedly increased de novo production of neutrophils in response to systemic microbial infection. Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo production of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the molecular and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.

Key Points Pathogens have to overcome colonization resistance by the microbiota to colonize the gut and to cause disease. The microbiota modulates the immune system to limit pathogen colonization but also inadvertently helps certain pathogens to colonize, for example, by making electron acceptors and carbon sources available. Pathogens are quickly sensed by innate pattern-recognition receptors (for example, Toll-like receptors (TLRs) and NOD-like receptors (NLRs)) on various cell types, which results in a pro-inflammatory response, for example, activation of the inflammasome. Activation of innate receptors triggers an inflammatory response (for example, the interleukin-23–T helper 17 cell axis) that for some pathogens initially promotes colonization but ultimately results in clearance of pathogens. Recruitment of high numbers of neutrophils to the site of infection is a hallmark of inflammatory diarrhoea and is generally beneficial to the host as it controls pathogens. Secretory IgA antibodies are important to maintain the mucosal barrier and to protect against pathogens, for example, Vibrio cholerae or Salmonella spp. Enteric bacterial infections are a major cause of morbidity and mortality. In this Review, the authors describe the different types of mucosal defences — including innate and adaptive immune cells, epithelial cells and commensal microorganisms — that protect us against bacterial pathogens in the intestines. The intestinal mucosa is a particularly dynamic environment in which the host constantly interacts with trillions of commensal microorganisms, known as the microbiota, and periodically interacts with pathogens of diverse nature. In this Review, we discuss how mucosal immunity is controlled in response to enteric bacterial pathogens, with a focus on the species that cause morbidity and mortality in humans. We explain how the microbiota can shape the immune response to pathogenic bacteria, and we detail innate and adaptive immune mechanisms that drive protective immunity against these pathogens. The vast diversity of the microbiota, pathogens and immune responses encountered in the intestines precludes discussion of all of the relevant players in this Review. Instead, we aim to provide a representative overview of how the intestinal immune system responds to pathogenic bacteria.

Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia. Sepsis and physical trauma can increase the susceptibility of patients to pneumonia. Roquilly and colleagues demonstrate that sepsis results in durable impairment of alveolar phagocytic function that is dependent on the localized expression of the inhibitory receptor SIRPα.