The glycobiology of uropathogenic E. coli infection: the sweet and bitter role of sugars in urinary tract immunity

Urinary tract infections (UTI) are among the most prevalent infectious diseases and the most common cause of nosocomial infections, worldwide. Uropathogenic E. coli (UPEC) are responsible for approximately 80% of all UTI, which most commonly affect the bladder. UPEC colonise the urinary tract by ascension of the urethra, followed by cell invasion, and proliferation inside and outside urothelial cells, thereby causing symptomatic infections and quiescent intracellular reservoirs that may lead to recurrence. Sugars or glycans are key molecules for host‐pathogen interactions, and UTI are no exception. Surface glycans regulate many of the events associated with UPEC adhesion and infection, as well as induction of the host immune response. Whilst the bacterial protein FimH binds mannose‐containing host glycoproteins to initiate infection and UPEC‐secreted polysaccharides block immune mechanisms to favour intracellular replication, host glycans on the urothelial surface and on secreted glycoproteins prevent or limit infection by inhibiting UPEC adhesion. Given the importance of glycans during UTI, here we review the glycobiology of UPEC infection to highlight fundamental sugar‐mediated processes of immunological interest for their potential clinical applications. Interdisciplinary approaches incorporating glycomics and infection biology may help to develop novel non‐antibiotic based therapeutic strategies for bacterial infections as the spread of antimicrobial resistant uropathogens is currently threatening modern health care systems

Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder

International audienceResident macrophages are abundant in the bladder, playing key roles in immunity to uropathogens. Yet, whether they are heterogeneous, where they come from, and how they respond to infection remain largely unknown. We identified two macrophage subsets in mouse bladders, MacM in muscle and MacL in the lamina propria, each with distinct protein expression and transcriptomes. Using a urinary tract infection model, we validated our transcriptomic analyses, finding that MacM macrophages phagocytosed more bacteria and polarized to an anti-inflammatory profile, whereas MacL macrophages died rapidly during infection. During resolution, monocyte-derived cells contributed to tissue-resident macrophage pools and both subsets acquired transcriptional profiles distinct from naïve macrophages. Macrophage depletion resulted in the induction of a type 1-biased immune response to a second urinary tract infection, improving bacterial clearance. Our study uncovers the biology of resident macrophages and their responses to an exceedingly common infection in a largely overlooked organ, the bladder

Limited Macrophage Positional Dynamics in Progressing or Regressing Murine Atherosclerotic PlaquesBrief Report

Objective Macrophages play important roles in the pathogenesis of atherosclerosis, but their dynamics within plaques remain obscure. We aimed to quantify macrophage positional dynamics within progressing and regressing atherosclerotic plaques. Approach and Results In a stable intravital preparation, large asymmetrical foamy macrophages in the intima of carotid artery plaques were sessile, but smaller rounded cells nearer plaque margins, possibly newly recruited monocytes, mobilized laterally along plaque borders. Thus, to test macrophage dynamics in plaques over a longer period of time in progressing and regressing disease, we quantified displacement of nondegradable phagocytic particles within macrophages for up to 6 weeks. In progressing plaques, macrophage-associated particles appeared to mobilize to deeper layers in plaque, whereas in regressing plaques, the label was persistently located near the lumen. By measuring the distance of the particles from the floor of the plaque, we discovered that particles remained at the same distance from the floor regardless of plaque progression or regression. The apparent deeper penetration of labeled cells in progressing conditions could be attributed to monocyte recruitment that generated new superficial layers of macrophages over the labeled phagocytes. Conclusion: s Although there may be individual exceptions, as a population, newly differentiated macrophages fail to penetrate significantly deeper than the limited depth they reside on initial entry, regardless of plaque progression, or regression. These limited dynamics may prevent macrophages from escaping areas with unfavorable conditions (such as hypoxia) and pose a challenge for newly recruited macrophages to clear debris through efferocytosis deep within plaque

CD11b+, Ly6G+ Cells Produce Type I Interferon and Exhibit Tissue Protective Properties Following Peripheral Virus Infection

The goal of the innate immune system is containment of a pathogen at the site of infection prior to the initiation of an effective adaptive immune response. However, effector mechanisms must be kept in check to combat the pathogen while simultaneously limiting undesirable destruction of tissue resulting from these actions. Here we demonstrate that innate immune effector cells contain a peripheral poxvirus infection, preventing systemic spread of the virus. These innate immune effector cells are comprised primarily of CD11b+Ly6C+Ly6G- monocytes that accumulate initially at the site of infection, and are then supplemented and eventually replaced by CD11b+Ly6C+Ly6G+ cells. The phenotype of the CD11b+Ly6C+Ly6G+ cells resembles neutrophils, but the infiltration of neutrophils typically occurs prior to, rather than following, accumulation of monocytes. Indeed, it appears that the CD11b+Ly6C+Ly6G+ cells that infiltrated the site of VACV infection in the ear are phenotypically distinct from the classical description of both neutrophils and monocyte/macrophages. We found that CD11b+Ly6C+Ly6G+ cells produce Type I interferons and large quantities of reactive oxygen species. We also observed that depletion of Ly6G+ cells results in a dramatic increase in tissue damage at the site of infection. Tissue damage is also increased in the absence of reactive oxygen species, although reactive oxygen species are typically thought to be damaging to tissue rather than protective. These data indicate the existence of a specialized population of CD11b+Ly6C+Ly6G+ cells that infiltrates a site of virus infection late and protects the infected tissue from immune-mediated damage via production of reactive oxygen species. Regulation of the action of this population of cells may provide an intervention to prevent innate immune-mediated tissue destruction

Sex differences shape the response to infectious diseases

International audienceHistorically, we have overlooked sex as a variable in infectious disease research

Biology of nonmuscle-invasive bladder cancer

International audiencePURPOSE OF REVIEW:Despite that nearly 75% of bladder cancer patients are diagnosed with nonmuscle-invasive disease, our understanding of the biological landscape in bladder cancer is primarily within the context of muscle-invasive bladder cancer. More recent studies addressing the genomic changes and immunology of nonmuscle-invasive bladder cancer (NMIBC) have helped to extend our understanding of this prevalent disease.RECENT FINDINGS:Genomic studies reveal that NMIBC possesses complexity that can be defined by specific gene expression signatures and has helped to define subsets within this disease. These subsets possess different risk profiles that may impact treatment decisions. In addition, the baseline or posttreatment immunological response to the growing tumor may help to inform whether a specific NMIBC subset is likely to progress.SUMMARY:Findings from studies addressing the molecular landscape of NMIBC may help to establish parameters for stratifying patient risk within this disease as well as establish novel or targeted treatment strategies. Inclusion of information about the immune response within tumors will likely contribute to defining the relative risk and treatment strategy for these patients

Mechanisms of BCG immunotherapy and its outlook for bladder cancer

International audienceBCG immunotherapy is the gold-standard treatment for non-muscle-invasive bladder cancer at high risk of recurrence or progression. Preclinical and clinical studies have revealed that a robust inflammatory response to BCG involves several steps: attachment of BCG; internalization of BCG into resident immune cells, normal cells, and tumour urothelial cells; BCG-mediated induction of innate immunity, which is orchestrated by a cellular and cytokine milieu; and BCG-mediated initiation of tumour-specific immunity. As an added layer of complexity, variation between clinical BCG strains might influence development of tumour immunity. However, more than 40 years after the first use of BCG for bladder cancer, many questions regarding its mechanism of action remain unanswered. Clearly, a better understanding of the mechanisms underlying BCG-mediated tumour immunity could lead to improved efficacy, increased tolerance of treatment, and identification of novel immune-based therapies. Indeed, enthusiasm for bladder cancer immunotherapy, and the possibility of combining BCG with other therapies, is increasing owing to the availability of targeted immunotherapies, including checkpoint inhibitors. Understanding of the mechanism of action of BCG immunotherapy has advanced greatly, but many questions remain, and further basic and clinical research efforts are needed to develop new treatment strategies for patients with bladder cancer

ShiA Abrogates the Innate T-Cell Response to Shigella flexneri Infection

Shigella spp. are the causative agent of bacillary dysentery. Infection results in acute colonic injury due to the host inflammatory response. The mediators of the damage, infiltrating polymorphonuclear leukocytes (PMN), also resolve the infection. Shigella flexneri's virulence effectors are encoded on its large virulence plasmid and on pathogenicity islands in the chromosome. The SHI-2 pathogenicity island encodes the virulence factor ShiA, which down-regulates Shigella-induced inflammation. In the rabbit ileal loop model, infection with a shiA null strain (ΔshiA) induces a more severe inflammation than wild-type infection. Conversely, a Shigella strain that overexpresses ShiA (ShiA(+)) is less inflammatory than the wild-type strain. To determine the host responses modulated by ShiA, we performed infection studies using the mouse lung model, which recapitulates the phenotypes observed in the rabbit ileal loop model. Significantly, ShiA(+) strain-infected mice cleared the bacteria and survived infection, while wild-type- and ΔshiA strain-infected mice could not clear the bacteria and ultimately died. Surprisingly, microarray analysis of infected lungs revealed the regulation of genes involved in innate T-cell responses to infection. Immunohistochemistry showed that wild-type- and ΔshiA strain-infected animals have greater numbers of PMN and T cells in their lungs over the course of infection than ShiA(+) strain-infected animals. These results suggest that the T-cell innate response is suppressed by ShiA in Shigella infections

Interleukin‐22 in urinary tract disease – new experimental directions

International audienceInterleukin (IL)-22 is expressed by immune cells in the urinary tract and IL-22 receptor is expressed in urothelium and renal tubule cells. IL-22 can be specifically targeted in the urinary tract or conditionally depleted in mice and targeted therapeutically in humans

Is bacterial prostatitis a urinary tract infection?

International audienceDiagnosis of urinary tract infection (UTI) includes anatomical distinctions because the severity of infection and treatment decisions depend on the infected organ; however, bacterial prostatitis is usually absent from discussions regarding UTI. By considering bacterial prostatitis a UTI, we can increase understanding of the pathogenesis and immune response in the prostate to develop improved therapeutics [...