scholarly journals The Case for an Expanded Concept of Trained Immunity

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Antonio Cassone
Keyword(s):  
Innate Immunity ◽  
Candida Albicans ◽  
Epithelial Cells ◽  
Nk Cells ◽  
Inflammatory Diseases ◽  
Living Cells ◽  
Content Type ◽  
Trained Immunity ◽  
Innate Immunity Cells ◽  
Expanded Concept

ABSTRACTTrained immunity was originally proposed as a program of innate immunity memory by innate immunity cells of hematopoietic origin such as the monocytes/macrophages and the NK cells. Here I discuss some old and new data justifying this program and some specific, still unanswered, questions it raises regarding the model fungusCandida albicansand the chronic, inflammatory vulvovaginal disease it causes. Building upon this well-established program, the recent reports that epithelial cells of mammals can also acquire memory from previous stimulations, and the apparent intrinsic ability of many living cells from bacteria to mammals to learn from experience, I suggest an expansion of the concept of trained immunity to include all cells of different lineages with the potential of memorizing previous microbial encounters. This expansion would better fit the complexity of innate immunity and the role it plays in infectious and inflammatory diseases.

scholarly journals Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis

2015 ◽  
Vol 83 (7) ◽  
pp. 2614-2626 ◽  
Author(s):  
Rohitashw Kumar ◽  
Darpan Saraswat ◽  
Swetha Tati ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Oral Candidiasis ◽  
Oral Microbiome ◽  
Proteinase Activity ◽  
Adhesion Properties ◽  
Content Type ◽  
Oral Epithelial Cells ◽  
Oral Epithelial ◽  
Cell Cell

Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually withC. albicanscells overexpressing Sap6 (SAP6OE and a Δsap8strain) had thicker fungal plaques and more severe oral infection, while infection with the Δsap6strain was attenuated. These hypervirulent strains had highly aggregative colony structurein vitroand higher secreted proteinase activity; however, the levels of proteinase activity ofC. albicansSaps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6OE and Δsap8cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increasedC. albicansadhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.

scholarly journals Candida albicans Adhesion to and Invasion and Damage of Vaginal Epithelial Cells: Stage-Specific Inhibition by Clotrimazole and Bifonazole

2011 ◽  
Vol 55 (9) ◽  
pp. 4436-4439 ◽  
Author(s):  
Betty Wächtler ◽  
Duncan Wilson ◽  
Bernhard Hube
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Antifungal Agents ◽  
Vaginal Epithelium ◽  
Specific Inhibition ◽  
Content Type ◽  
Vaginal Epithelial Cells ◽  
Specific Activities ◽  
Low Levels ◽  
Adhesion And Invasion

ABSTRACTClotrimazole and bifonazole are highly effective antifungal agents against mucosalCandida albicansinfections. Here we examined the effects of low levels of clotrimazole and bifonazole on the ability ofC. albicansto adhere, invade, and damage vaginal epithelial cells. Although adhesion and invasion were not affected, damage was greatly reduced upon azole treatment. This clearly indicates that low levels of azoles influence specific activities ofC. albicansduring distinct stages of vaginal epithelium infections.

scholarly journals The Human Gut Microbial Metabolome Modulates Fungal Growth via the TOR Signaling Pathway

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Carlos García ◽  
Faiza Tebbji ◽  
Michelle Daigneault ◽  
Ning-Ning Liu ◽  
Julia R. Köhler ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inflammatory Diseases ◽  
Opportunistic Pathogen ◽  
Convincing Evidence ◽  
Commensal Bacteria ◽  
Bioactive Molecules ◽  
Mucosal Barrier ◽  
Content Type ◽  
Bowel Diseases ◽  
The One

ABSTRACT Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of C. albicans, from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of C. albicans and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between C. albicans and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti-Candida activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases. Candida albicans is well known as a major human fungal pathogen, but it is also a permanent resident of healthy gastrointestinal tracts. Recent studies have shown that the human gut microbial metabolome represents an interesting source of bioactive molecules with a significant degree of chemical diversity. Some of these bioactive molecules may have useful antivirulence activities. For instance, intestinal bacterial species belonging to the Lachnospiraceae family were found to secrete molecules that attenuate Salmonella pathogenicity and repress the expression of virulence genes. Here, we have investigated whether the microbial gut metabolome (GM) contains molecules that might promote the commensal lifestyle and/or inhibit the expression of virulence of C. albicans in the intestine. We found that metabolites from human feces inhibited the growth of C. albicans and other opportunistic yeasts. A genetic screen in C. albicans suggested that TOR is the molecular target of the antifungal molecule(s) of the GM. In addition, we found that the GM metabolites inhibit both C. albicans hyphal growth and the invasion of human enterocytes. The antigrowth and antivirulence activities were partially recapitulated by secretions from Roseburia spp. and Bacteroides ovatus strains, respectively. This study demonstrates that the antimicrobial activity of the GM can be extended to a eukaryotic pathogen, C. albicans, illuminating the antagonistic interkingdom interactions between a fungus and intestinal commensal bacteria. IMPORTANCE Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of C. albicans, from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of C. albicans and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between C. albicans and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti-Candida activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases.

scholarly journals Trained Innate Immunity Induced by Vaccination with Low-Virulence Candida Species Mediates Protection against Several Forms of Fungal Sepsis via Ly6G + Gr-1 + Leukocytes

mBio ◽  
2021 ◽  
Author(s):  
Elizabeth A. Lilly ◽  
Breah E. Bender ◽  
Shannon Esher Righi ◽  
Paul L. Fidel ◽  
Mairi C. Noverr
Keyword(s):  
Innate Immunity ◽  
Candida Albicans ◽  
Bloodstream Infection ◽  
Candida Species ◽  
Content Type ◽  
Cytokine Responses ◽  
Fungal Sepsis ◽  
Intravenous Inoculation

Trained innate immunity (TII) is induced following immunization with live attenuated microbes and represents a clinically important strategy to enhance innate defenses. TII was initially demonstrated following intravenous inoculation with low-virulence Candida albicans , with protection against a subsequent lethal C. albicans intravenous bloodstream infection (BSI) mediated by monocytes with enhanced cytokine responses.

scholarly journals Gut-Evolved Candida albicans Induces Metabolic Changes in Neutrophils

2021 ◽  
Vol 11 ◽  
Author(s):  
Jose Antonio Reales-Calderon ◽  
Gloria H. W. Tso ◽  
Alrina S. M. Tan ◽  
Pei Xiang Hor ◽  
Julia Böhme ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Nk Cells ◽  
Bone Marrow Cells ◽  
Metabolic Changes ◽  
Immune Memory ◽  
Cellular Mechanisms ◽  
Fungal Cell ◽  
Mouse Splenocytes ◽  
Trained Immunity ◽  
Wide Range

Serial passaging of the human fungal pathogen Candida albicans in the gastrointestinal tract of antibiotics-treated mice selects for virulence-attenuated strains. These gut-evolved strains protect the host from infection by a wide range of pathogens via trained immunity. Here, we further investigated the molecular and cellular mechanisms underlying this innate immune memory. Both Dectin-1 (the main receptor for β-glucan; a well-described immune training molecule in the fungal cell wall) and Nod2 (a receptor described to mediate BCG-induced trained immunity), were redundant for the protection induced by gut-evolved C. albicans against a virulent C. albicans strain, suggesting that gut-evolved C. albicans strains induce trained immunity via other pathways. Cytometry by time of flight (CyTOF) analysis of mouse splenocytes revealed that immunization with gut-evolved C. albicans resulted in an expansion of neutrophils and a reduction in natural killer (NK) cells, but no significant numeric changes in monocytes, macrophages or dendritic cell populations. Systemic depletion of phagocytes or neutrophils, but not of macrophages or NK cells, reduced protection mediated by gut-evolved C. albicans. Splenocytes and bone marrow cells of mice immunized with gut-evolved C. albicans demonstrated metabolic changes. In particular, splenic neutrophils displayed significantly elevated glycolytic and respiratory activity in comparison to those from mock-immunized mice. Although further investigation is required for fully deciphering the trained immunity mechanism induced by gut-evolved C. albicans strains, this data is consistent with the existence of several mechanisms of trained immunity, triggered by different training stimuli and involving different immune molecules and cell types.

scholarly journals Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in Mice

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Eva Pericolini ◽  
Elena Gabrielli ◽  
Mario Amacker ◽  
Lydia Kasper ◽  
Elena Roselletti ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Common Disease ◽  
Content Type ◽  
Neutrophil Influx ◽  
Caspase 1 ◽  
Vaginal Epithelial Cells ◽  
Pepstatin A ◽  
Aspartyl Proteinases

ABSTRACTVaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungusCandida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits ofC. albicansthat have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candidavaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome-dependent interleukin-1β (IL-1β) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated byC. albicansintravaginal injection, and a mutant strain lackingSAP1,SAP2, andSAP3was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1β and IL-18 production by vaginal epithelial cells, and blockade of the IL-1β receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteinsin vivoand can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells toC. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis.IMPORTANCECandidal vaginitis is an acute inflammatory disease that affects many women of fertile age, with no definitive cure and, in its recurrent forms, causing true devastation of quality of life. Unraveling the fungal factors causing inflammation is important to be able to devise novel tools to fight the disease. In an experimental murine model, we have discovered that aspartyl proteinases, particularly Sap2, may cause the same inflammatory signs of vaginitis caused by the fungus and that anti-Sap antibodies and the protease inhibitor Pepstatin A almost equally inhibit Sap- andC. albicans-induced inflammation. Sap-induced vaginitis is an early event during vaginal infection, is uncoupled from fungal growth, and requires Sap and caspase-1 enzymatic activities to occur, suggesting that Sap or products of Sap activity activate an inflammasome sensor of epithelial cells. Our data support the notion that anti-Sap antibodies could help control the essence of candidal vaginitis, i.e., the inflammatory response.

scholarly journals Trained Immunity as an Adaptive Branch of Innate Immunity

2021 ◽  
Vol 22 (19) ◽  
pp. 10684
Author(s):  
Vaclav Vetvicka ◽  
Petr Sima ◽  
Luca Vannucci
Keyword(s):  
Innate Immunity ◽  
Life Span ◽  
Nk Cells ◽  
Natural Killer ◽  
Adaptive Immunity ◽  
Epigenetic Reprogramming ◽  
Immunocompetent Cells ◽  
Infectious Agents ◽  
Immune Reactions ◽  
Trained Immunity

The concept of trained immunity has become one of the most interesting and potentially commercially and clinically relevant ideas of current immunology. Trained immunity is realized by the epigenetic reprogramming of non-immunocompetent cells, primarily monocytes/macrophages and natural killer (NK) cells, and is less specific than adaptive immunity; therefore, it may cross-protect against other infectious agents. It remains possible, however, that some of the observed changes are simply caused by increased levels of immune reactions resulting from supplementation with immunomodulators, such as glucan. In addition, the question of whether we can talk about trained immunity in cells with a life span of only few days is still unresolved.

scholarly journals Vaginal Epithelial Cell-Derived S100 Alarmins Induced by Candida albicans via Pattern Recognition Receptor Interactions Are Sufficient but Not Necessary for the Acute Neutrophil Response during Experimental Vaginal Candidiasis

2013 ◽  
Vol 82 (2) ◽  
pp. 783-792 ◽  
Author(s):  
Junko Yano ◽  
Glen E. Palmer ◽  
Karen E. Eberle ◽  
Brian M. Peters ◽  
Thomas Vogl ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Candida Albicans ◽  
Epithelial Cells ◽  
Biologically Active ◽  
Polymorphonuclear Neutrophil ◽  
Vaginal Candidiasis ◽  
Content Type ◽  
Vaginal Epithelial Cells

ABSTRACTVulvovaginal candidiasis (VVC), caused byCandida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response toC. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previousin vitrodata and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluatedin vitroorin vivoin the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression andC. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reportedin vitrodata, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxisin vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9−/−mice, had no effect on the PMN responsein vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction inC. albicans-induced S100A8/S100A9 mRNAsin vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response toC. albicansinvolves PRRs in addition to SIGNR1 and TLR4, or other induction pathways.

scholarly journals A Fungal Transcription Regulator of Vacuolar Function Modulates Candida albicans Interactions with Host Epithelial Cells

mBio ◽  
2021 ◽  
Author(s):  
Philipp Reuter-Weissenberger ◽  
Juliane Meir ◽  
J. Christian Pérez
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Aids Patients ◽  
Content Type ◽  
Immune Systems ◽  
Transcription Regulator ◽  
Mucosal Disease ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
Oral Thrush

Candida albicans is a fungus that resides on various human mucosal surfaces. Individuals with debilitated immune systems are prone to develop C. albicans infections, which can range in severity from mucosal disease (e.g., oral thrush in AIDS patients) to life-threatening conditions (e.g., deep-seated, disseminated infections in patients undergoing organ transplants).

scholarly journals Interplay between Candida albicans and the Mammalian Innate Host Defense

2012 ◽  
Vol 80 (4) ◽  
pp. 1304-1313 ◽  
Author(s):  
Shih-Chin Cheng ◽  
Leo A. B. Joosten ◽  
Bart-Jan Kullberg ◽  
Mihai G. Netea
Keyword(s):  
Innate Immunity ◽  
Candida Albicans ◽  
Host Defense ◽  
High Mortality ◽  
Fungal Pathogen ◽  
Immunocompromised Patients ◽  
Healthy Individuals ◽  
Content Type ◽  
At Risk Populations ◽  
Host Innate Immunity

ABSTRACTCandida albicansis both the most common fungal commensal microorganism in healthy individuals and the major fungal pathogen causing high mortality in at-risk populations, especially immunocompromised patients. In this review, we summarize the interplay between the host innate system andC. albicans, ranging from how the host recognizes, responds, and clearsC. albicansinfection to howC. albicansevades, dampens, and escapes from host innate immunity.

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