Immunomodulatory Effect Of Host And Fungal Eicosanoids During Host-Pathogen Interactions With Candida Albicans

Candida albicans, an opportunistic fungal pathogen, poses a significant clinical threat to immunocompromised patients. Diseases associated with this fungus ranges from superficial mucosal infection to life-threatening systemic candidiasis. The mechanisms by which Candida persists at mucosal surfaces in the face of an adaptive response are unclear. Candida produces immunomodulatory oxylipins that cross-react functionally with host eicosanoids, which are considered to play important role in regulating innate and adaptive immune responses. Our objective was to characterize the role of prostaglandins produced by the host and this fungus during host pathogen interactions, both in vitro with dendritic cells (DCs) and macrophages, and in vivo during pathogenesis. At early time point, there was upregulation of Th2 cytokines IL-4, IL-10, and IL-13 by both plasmacytoid and myeloid DCs in the presence of hyphae and PGE2. At later time points, fungal or host PGE2 treatment resulted in decreased Th1 cytokine production (IL-12 and IL-6) and slightly increased Th2 cytokine production (IL-4). DC vaccination experiments demonstrated that yeast pulsed DCs imparted protection, which was abrogated with exposure to host or fungal PGE2. Non-protective responses were associated with Th2 cytokine production, and at later stages, exacerbated Th17 responses accompanied by uncontrolled fungal growth. Ours is the first study to report presence of Th17 cytokines in the mice kidneys during systemic candidiasis and its associated lack of protection. We also demonstrated that during the interaction of C. albicans with the macrophages, PGE2 and PGEx decreased phagocytosis and increased intracellular survival. We also investigated the effects of eicosanoid inhibitors during mucosal and systemic infection models. During experimental C. albicans vaginitis, treatment with inhibitors locally resulted in decreased fungal burden and PGE2 levels. Similar results were observed during systemic infection, which correlated with restoration of Th1 cytokines. These studies suggested that balanced manipulation with eicosanoid production can work without suppressing inflammatory response and inhibit fungal growth at same time. This could provide newer avenues for developing novel pharmacological intervention strategies to treat C. albicans infections

Signalling C-Type Lectins in Antimicrobial Immunity

Funding: This work was funded by the Wellcome Trust, Medical Research Council and the University of Aberdeen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Galectin-3. One molecule for an alphabet of diseases, from A to Z

Galectin-3 (Gal-3) regulates basic cellular functions such as cell–cell and cell–matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed

Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors

Peer reviewedPublisher PD

Isolates of Candida albicans that differ in virulence for mice elicit strain-specific antibody-mediated protective responses

Three distinct isolates of Candida albicans were used to establish systemic and oral infections in inbred mice that are genetically resistant or susceptible to tissue damage. Patterns of infection differed significantly between both yeasts and mouse strains. Systemic infection conferred significant protection against re-challenge with the homologous, but not the heterologous yeast; however, the protective effect was more evident in the tissue-susceptible CBA/CaH mice than in the resistant BALB/c strain. In contrast, oral infection induced protection against both homologous and heterologous oral challenge, although this was significant only in the CBA/CaH mice. CBA/CaH mice produced antibodies of both IgG1 and IgG2a subclasses, whereas BALB/c mice produced predominantly IgG1. Western blotting demonstrated considerable differences between epitopes recognised by serum antibodies from mice of both strains after immunisation with each of the three yeasts. Thus, different strains of yeast show considerable specificity in antibody responses elicited by either systemic or oral infection. (c) 2005 Elsevier SAS. All rights reserved

Vaccination against fungal diseases: lessons from Candida albicans

The advances in medicine have achieved great benefits by improving or even eliminating various debilitating diseases or malignancies, expanding life expectancy. However, it has also originated the development of a compromised population susceptible to opportunistic diseases. A global major concern is the emergence and spread of life-threatening invasive infections in immunocompromised patients, in which the opportunistic fungal infections have greatly increased in the last decades. The high mortality rates associated with these infections, which remain as high as 40%, are due to the limited therapeutic options and the emergence of drug-resistant fungi, but also due to the lack of efficient early diagnosis. Consequently, these facts led to the opinion that new approaches are needed to improve the outcome of these patients, such as immunopreventive strategies that could even be combined with standard antifungal treatment. In view of the proven effectiveness of various antibacterial and antiviral vaccines in preventing the respective diseases, several works have been developed to induce protective immunity against fungal infections as well. The better understanding of how the immune system works against fungal pathogens has made possible to explore immunomodulatory strategies that can protect both immunocompetent and immunocompromised hosts and generate memory. Recently, two fungal vaccines against Candida have advanced through clinical trials. However, there are still many challenges in the development of an efficient vaccine against invasive fungal infections. We will provide an update on the progress made in immunization against fungal infections, reviewing host-fungi interactions, antigens, and adjuvants exploited in vaccine strategies, and discuss concerns that need to be overcome to further advance in the area of fungal vaccines.(undefined)info:eu-repo/semantics/publishedVersio

B cells and autoantibodies in AIRE deficiency

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare but severe monogenetic autoimmune endocrine disease caused by failure of the Autoimmune Regulator (AIRE). AIRE regulates the negative selection of T cells in the thymus, and the main pathogenic mechanisms are believed to be T cell-mediated, but little is known about the role of B cells. Here, we give an overview of the role of B cells in thymic and peripheral tolerance in APS-1 patients and different AIRE-deficient mouse models. We also look closely into which autoantibodies have been described for this disorder, and their implications. Based on what is known about B cell therapy in other autoimmune disorders, we outline the potential of B cell therapies in APS-1 and highlight the unresolved research questions to be answered.publishedVersio

Identification of superficial Candida albicans germ tube antigens in a rabbit model of disseminated candidiasis. A proteomic approach

The diagnosis of invasive candidiasis remains a clinical challenge. The detection by indirect immunofluorescence of Candida albicans germ-tube-specific antibodies (CAGTA), directed against germ-tube surface antigens, is a useful diagnostic tool that discriminates between colonization and invasion. However, the standardization of this technique is complicated by its reliance on subjective interpretation. In this study, the antigenic recognition pattern of CAGTA throughout experimental invasive candidiasis in a rabbit animal model was determined by means of 2D-PAGE, Western blotting, and tandem mass spectrometry (MS/MS). Seven proteins detected by CAGTA were identified as methionine synthase, inositol-3-phosphate synthase, enolase 1, alcohol dehydrogenase 1,3-phosphoglycerate kinase, 14-3-3 (Bmh1), and Egd2. To our knowledge, this is the first report of antibodies reacting with Bmh1 and Egd2 proteins in an animal model of invasive candidiasis. Although all of the antigens were recognized by CAGTA in cell-wall dithiothreitol extracts of both germ tubes and blastospores of C. albicans, immunoelectron microscopy study revealed their differential location, as the antigens were exposed on the germ-tube cell-wall surface but hidden in the inner layers of the blastospore cell wall. These findings will contribute to developing more sensitive diagnostic methods that enable the earlier detection of invasive candidiasis. [Int Microbiol 2014; 17(1):21-29]Keywords: Candida albicans · germ tube antibodies · invasive candidiasis · rabbit mode

Immunotherapy for Fungal Infections

Opportunistic fungal infections are a major health problem being appointed by some studies as the fourth main cause of hospital-acquired infection in susceptible populations. The constantly growing incidences of these diseases are associated with the growing number of susceptible individuals, such as immunocompromised individuals (leukemia, AIDS, etc) and treatment-induced immunodeficiency (hematopoietic stem cell, solid organ transplant, anticancer therapy). Furthermore, other advances in medical care, patient’s long-term hospitalization and antimicrobial therapies have created several vulnerable populations to fungal infections. Currently, antifungal drug therapies are several times inefficient, and the poor outcomes are linked to difficulties in the early diagnosis of fungal infections and drug resistance among fungal pathogens. In this context, novel therapeutic approaches are welcome to stimulate efficiently the host immune response to eliminate the fungal pathogen. This chapter is intended to review advances in immunotherapy strategies for fungal infections

The hidden cost of modern medical interventions:how medical advances have shaped the prevalence of human fungal disease

Life expectancy in the West is the highest it has ever been, due to the introduction of better hygiene practices and sophisticated medical interventions for cancer, autoimmunity and infectious disease. With these modern advances, a rise in the prevalence of opportunistic infections has also been observed. These include several fungal infections, which present a particular clinical challenge due to the lack of fungal vaccines, limited diagnostics and increasing antifungal drug resistance. This mini-review outlines how modern-day clinical practices have shaped the recent increase in fungal diseases observed in the last few decades. We discuss new research that has implicated the use of immune-modulating drugs in the enhanced susceptibility of vulnerable patients to life-threatening fungal infections