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Immunological memory is critical for immune protection, particularly at epithelial sites, which are under constant risk of pathogen invasions. To counter invading pathogens, CD8 + memory T cells develop at the location of infection: tissue-resident memory T cells (T RM ). CD8 + T-cell responses are associated with type-1 infections and type-1 regulatory T cells (T REG ) are important for CD8 + T-cell development, however, if CD8 + T RM cells develop under other infection types and require immune type-specific T REG cells is unknown. We used three distinct lung infection models, to show that type-2 helminth infection does not establish CD8 + T RM cells. Intracellular (type-1) and extracellular (type-3) infections do and rely on the recruitment of response type-matching T REG population contributing transforming growth factor-β. Nevertheless, type-1 T REG cells remain the most important population for T RM cell development. Once established, T RM cells maintain their immune type profile. These results may have implications in the development of vaccines inducing CD8 + T RM cells. Type-1 regulatory T cells promoted the generation of CD8+ tissue-resident memory T (TRM) cells during intracellular infections in the gut. Here, the authors show that the establishment TRM cells more broadly depends on the presence of regulatory T cells matching the type of infection.

Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with soluble factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory molecules). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.

CD4 + T cells are critical to fighting pathogens, but a comprehensive analysis of human T-cell specificities is hindered by the diversity of HLA alleles (>20,000) and the complexity of many pathogen genomes. We previously described GLIPH, an algorithm to cluster T-cell receptors (TCRs) that recognize the same epitope and to predict their HLA restriction, but this method loses efficiency and accuracy when >10,000 TCRs are analyzed. Here we describe an improved algorithm, GLIPH2, that can process millions of TCR sequences. We used GLIPH2 to analyze 19,044 unique TCRβ sequences from 58 individuals latently infected with Mycobacterium tuberculosis ( Mtb ) and to group them according to their specificity. To identify the epitopes targeted by clusters of Mtb -specific T cells, we carried out a screen of 3,724 distinct proteins covering 95% of Mtb protein-coding genes using artificial antigen-presenting cells (aAPCs) and reporter T cells. We found that at least five PPE (Pro-Pro-Glu) proteins are targets for T-cell recognition in Mtb . The T-cell response to tuberculosis is examined by clustering T-cell receptor sequences to identify shared specificities, along with whole-genome antigen screening.

Co-infection with Mycobacterium tuberculosis is the leading cause of death in individuals infected with HIV-1. It has long been known that HIV-1 infection alters the course of M. tuberculosis infection and substantially increases the risk of active tuberculosis (TB). It has also become clear that TB increases levels of HIV-1 replication, propagation and genetic diversity. Therefore, co-infection provides reciprocal advantages to both pathogens. In this Review, we describe the epidemiological associations between the two pathogens, selected interactions of each pathogen with the host and our current understanding of how they affect the pathogenesis of TB and HIV-1/AIDS in individuals with co-infections. We evaluate the mechanisms and consequences of HIV-1 depletion of T cells on immune responses to M. tuberculosis. We also discuss the effect of HIV-1 infection on the control of M. tuberculosis by macrophages through phagocytosis, autophagy and cell death, and we propose models by which dysregulated inflammatory responses drive the pathogenesis of TB and HIV-1/AIDS.

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8 + T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8 + T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A , remain ‘epigenetically scarred.’ T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells. The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8 + T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen.

In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8 + T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor–progeny relationship between memory-like and terminally exhausted HCV-specific CD8 + T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8 + T cell response. However, an exhausted core signature of memory-like CD8 + T cells was still detectable, including, to a smaller extent, in HCV-specific CD8 + T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8 + T cells even after the cessation of chronic antigen stimulation. Thimme and colleagues identify a molecular signature of T cell exhaustion resembling a ‘chronic scar’ that is imprinted in hepatitis C virus–specific CD8 + T cells and cannot simply be reversed by viral clearance.

Key Points Antibiotic treatment disrupts the native intestinal microbiota and favours infection with and the proliferation of antibiotic-resistant intestinal pathogens. Clinically important antibiotic-resistant pathogens include vancomycin-resistant Enterococcus spp., various Enterobacteriaceae and Clostridium difficile . The intestinal microbiota influences the development, the maintenance and the function of the innate and adaptive immune systems. Host immune function is decreased in the intestines following antibiotic therapy, and antibiotic-treated hosts are susceptible to intestinal infection. Microbiota-derived bacterial populations and products that enhance immune defence against intestinal pathogens are being identified. However, the precise bacterial sources of many immunomodulatory molecules remain unclear and, conversely, the molecular mechanisms by which most probiotics restore immunity have yet to be elucidated. In addition to indirectly enhancing colonization resistance by stimulating host immune defences, bacterial populations can directly suppress intestinal pathogens by competitive exclusion and by antimicrobial activities. The commensal populations that are responsible for direct antagonism of pathogens and indirect, immune-mediated colonization resistance may be closely related and difficult to distinguish. Microbiota-derived bacterial populations and products, a subset of which enhance immune defence, can also promote intestinal inflammation, whereas other microbiota components restrain effector responses and promote tolerance. Manipulation of the intestinal microbiota to prevent and to treat some intestinal infections, such as C. difficile , shows promise in human patients and animal models of infection. However, the specific contributions of the individual bacterial populations that constitute the consortia transferred in such studies remain mostly undefined. Colonization resistance — protection from exogenous pathogens by commensal bacteria — can be mediated by direct antagonism and by indirect effects on the host immune response. This Review outlines our current knowledge of immune-mediated colonization resistance against clinically relevant, antibiotic-resistant intestinal pathogens and how insights into commensal bacterial species and their mechanisms might be therapeutically used to restore resistance. Commensal bacteria inhabit mucosal and epidermal surfaces in mice and humans, and have effects on metabolic and immune pathways in their hosts. Recent studies indicate that the commensal microbiota can be manipulated to prevent and even to cure infections that are caused by pathogenic bacteria, particularly pathogens that are broadly resistant to antibiotics, such as vancomycin-resistant Enterococcus faecium , Gram-negative Enterobacteriaceae and Clostridium difficile . In this Review, we discuss how immune- mediated colonization resistance against antibiotic-resistant intestinal pathogens is influenced by the composition of the commensal microbiota. We also review recent advances characterizing the ability of different commensal bacterial families, genera and species to restore colonization resistance to intestinal pathogens in antibiotic-treated hosts.

Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus , thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection. During the influenza pandemic, a large number of deaths resulted from secondary bacterial pneumonia caused by common upper respiratory tract bacteria, such as Staphylococcus . Here, Moon et al, find that the interaction between airway epithelial CD47 and the pathogenic bacterial FnBP is critical in causing bacterial superinfection.

Blood transcriptomics analysis of tuberculosis has revealed an interferon-inducible gene signature that diminishes in expression after successful treatment; this promises improved diagnostics and treatment monitoring, which are essential for the eradication of tuberculosis. Sensitive radiography revealing lung abnormalities and blood transcriptomics have demonstrated heterogeneity in patients with active tuberculosis and exposed asymptomatic people with latent tuberculosis, suggestive of a continuum of infection and immune states. Here we describe the immune response to infection with Mycobacterium tuberculosis revealed through the use of transcriptomics, as well as differences among clinical phenotypes of infection that might provide information on temporal changes in host immunity associated with evolving infection. We also review the diverse blood transcriptional signatures, composed of small sets of genes, that have been proposed for the diagnosis of tuberculosis and the identification of at-risk asymptomatic people and suggest novel approaches for the development of such biomarkers for clinical use. O’Garra and colleagues describe the immune response to infection with Mycobacterium tuberculosis revealed through the use of transcriptomics and the value of blood transcriptional gene signatures for the diagnosis of tuberculosis.