[Show abstract][Hide abstract] ABSTRACT: Interleukin-22 (IL-22) is highly induced in response to infections with a variety of pathogens, and its main functions are considered to be tissue repair and host defense at mucosal surfaces. Here we showed that IL-22 has a unique role during infection in that its expression suppressed the intestinal microbiota and enhanced the colonization of a pathogen. IL-22 induced the expression of antimicrobial proteins, including lipocalin-2 and calprotectin, which sequester essential metal ions from microbes. Because Salmonella enterica ser. Typhimurium can overcome metal ion starvation mediated by lipocalin-2 and calprotectin via alternative pathways, IL-22 boosted its colonization of the inflamed intestine by suppressing commensal Enterobacteriaceae, which are susceptible to the antimicrobial proteins. Thus, IL-22 tipped the balance between pathogenic and commensal bacteria in favor of a pathogen. Taken together, IL-22 induction can be exploited by pathogens to suppress the growth of their closest competitors, thereby enhancing pathogen colonization of mucosal surfaces.
[Show abstract][Hide abstract] ABSTRACT: In this issue of Immunity, Zelante et al. (2013) and Qiu et al. (2013) provide mechanistic insights into functional interactions between commensal microbes and innate lymphoid cells via the aryl hydrocarbon receptor.
[Show abstract][Hide abstract] ABSTRACT: Probiotics are beneficial components of the microbiota that have been used for centuries because of the health benefits they confer to the host. Only recently, however, has the contribution of probiotics to modulation of immunological, respiratory, and gastrointestinal functions started to be fully appreciated and scientifically evaluated. Probiotics such as Escherichia coli Nissle 1917 and lactic acid bacteria are currently used to, or have been evaluated for use to, prevent or treat a range of intestinal maladies including inflammatory bowel disease, constipation, and colon cancer. Engineering these natural probiotics to produce immunomodulatory molecules may help to further increase the benefit to the host. In this article, we will discuss some of the mechanisms of action of probiotics as well as advances in the rational design of probiotics.
Cold Spring Harbor Perspectives in Medicine 01/2013; 3(3). · 7.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The saprophytic fungus Aspergillus fumigatus is a mold which is ubiquitously present in the environment. It produces large numbers of spores, called conidia that we constantly inhale with the breathing air. Healthy individuals normally do not suffer from true fungal infections with this pathogen. A normally robust resistance against Aspergillus is based on the presence of a very effective immunological defense system in the vertebrate body. Inhaled conidia are first encountered by lung-resident alveolar macrophages and then by neutrophil granulocytes. Both cell types are able to effectively ingest and destroy the fungus. Although some responses of the adaptive immune system develop, the key protection is mediated by innate immunity. The importance of phagocytes for defense against aspergillosis is also supported by large numbers of animal studies. Despite the production of aggressive chemicals that can extracellularly destroy fungal pathogens, the main effector mechanism of the innate immune system is phagocytosis. Very recently, the production of extracellular neutrophil extracellular traps (NETs) consisting of nuclear DNA has been added to the armamentarium that innate immune cells use against infection with Aspergillus. Phagocyte responses to Aspergillus are very broad, and a number of new observations have added to this complexity in recent years. To summarize established and newer findings, we will give an overview on current knowledge of the phagocyte system for the protection against Aspergillus.
International journal of medical microbiology: IJMM 06/2011; 301(5):436-44. · 4.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phagocytosis of conidia by macrophages and destruction of hyphae by neutrophils are key processes in the defense against infections caused by filamentous fungi. Impairment in phagocytic function leads to increased susceptibility for an infection with Aspergillus species. The fact that a Th1-based immune response to an infection with Aspergillus species results in an improved prognosis for survival underlines the importance of the phagocytic response. Recognition of conidia by macrophages occurs after shedding of the hydrophobic rodlet layer during swelling and germination. Whereas Aspergillus conidia are killed by various immune effector cells, hyphae are in particular targeted and killed by neutrophils. Moreover, both conidia and hyphae are trapped in neutrophil extracellular traps (NETs) that form a containment to localize the infection and to prevent systemic spreading of the fungus in the host. In addition, A. fumigatus interferes with the innate immunity, with both the complement system and defense mechanisms of phagocytes, thereby evading at least in part the innate immune system.
Current opinion in microbiology 08/2010; 13(4):409-15. · 7.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The opportunistic human pathogenic fungus Aspergillus fumigatus is a major cause of fungal infections in immunocompromised patients. Innate immunity plays an important role in the defense against infections. The complement system represents an essential part of the innate immune system. This cascade system is activated on the surface of A. fumigatus conidia and hyphae and enhances phagocytosis of conidia. A. fumigatus conidia but not hyphae bind to their surface host complement regulators factor H, FHL-1, and CFHR1, which control complement activation. Here, we show that A. fumigatus hyphae possess an additional endogenous activity to control complement activation. A. fumigatus culture supernatant efficiently cleaved complement components C3, C4, C5, and C1q as well as immunoglobulin G. Secretome analysis and protease inhibitor studies identified the secreted alkaline protease Alp1, which is present in large amounts in the culture supernatant, as the central molecule responsible for this cleavage. An alp1 deletion strain was generated, and the culture supernatant possessed minimal complement-degrading activity. Moreover, protein extract derived from an Escherichia coli strain overproducing Alp1 cleaved C3b, C4b, and C5. Thus, the protease Alp1 is responsible for the observed cleavage and degrades a broad range of different substrates. In summary, we identified a novel mechanism in A. fumigatus that contributes to evasion from the host complement attack.
Infection and immunity 05/2010; 78(8):3585-94. · 4.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinase-type plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.
Infection and immunity 03/2008; 76(2):820-7. · 4.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The fungal pathogens Aspergillus fumigatus and Candida albicans are major health threats for immune-compromised patients. Normally, macrophages and neutrophil granulocytes phagocytose inhaled Aspergillus conidia in the two-dimensional (2-D) environment of the alveolar lumen or Candida growing in tissue microabscesses, which are composed of a three-dimensional (3-D) extracellular matrix. However, neither the cellular dynamics, the per-cell efficiency, the outcome of this interaction, nor the environmental impact on this process are known. Live imaging shows that the interaction of phagocytes with Aspergillus or Candida in 2-D liquid cultures or 3-D collagen environments is a dynamic process that includes phagocytosis, dragging, or the mere touching of fungal elements. Neutrophils and alveolar macrophages efficiently phagocytosed or dragged Aspergillus conidia in 2-D, while in 3-D their function was severely impaired. The reverse was found for phagocytosis of Candida. The phagocytosis rate was very low in 2-D, while in 3-D most neutrophils internalized multiple yeasts. In competitive assays, neutrophils primarily incorporated Aspergillus conidia in 2-D and Candida yeasts in 3-D despite frequent touching of the other pathogen. Thus, phagocytes show activity best in the environment where a pathogen is naturally encountered. This could explain why "delocalized" Aspergillus infections such as hematogeneous spread are almost uncontrollable diseases, even in immunocompetent individuals.