Journal of Leukocyte Biology eBioscience full spectrum cell analysis
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Romani, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Romani, L.
(Journal of Leukocyte Biology. 2000;68:175-179.)
© 2000 by Society for Leukocyte Biology

Innate and adaptive immunity in Candida albicans infections and saprophytism

Luigina Romani

Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy

Correspondence: Luigina Romani, M.D., Ph.D., Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy. E-mail: lromani{at}unipg.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PROTECTIVE AND UNPROTECTIVE...
 REGULATION OF Th1- AND...
 CONCLUSIONS
 REFERENCES
 
Underlying acquired immunity to the fungus Candida albicans is usually present in adult immunocompetent individuals and is presumed to prevent mucosal colonization progressing to symptomatic infection. Exploration of immunological events leading to Candida resistance or susceptibility has indicated the central role of the innate and adaptive immune systems, the relative contribution of which may vary depending on the site of the primary infection. Nevertheless, acquired resistance to infection results from the development of Th1 responses. Cytokines produced by Th1 cells activate phagocytic cells to a candidacidal state. In contrast, cytokines produced by Th2 cells inhibit Th1 development and deactivate phagocytic effector cells. Because reciprocal influences have been recognized between innate and adaptive Th immunity, it appears that an integrated immune response determines the life-long commensalism of the fungus at the mucosal level, as well as the transition from mucosal saprophyte to pathogen.

Key Words: Th1/Th2 cells • cytokines • neutrophils • dendritic cells • fungi


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PROTECTIVE AND UNPROTECTIVE...
 REGULATION OF Th1- AND...
 CONCLUSIONS
 REFERENCES
 
Candida albicans is an opportunistic fungal pathogen commonly found in the human gastrointestinal and female lower genital tracts. It is a unique parasite capable of colonizing, infecting, and persisting on mucosal surfaces, and stimulating mucosal immune responses. Antigens that encounter the intestinal immune system can initiate two types of immune response, leading to the induction of immunity or tolerance [1 ]. In the case of C. albicans, underlying acquired immunity to the fungus, such as the expression of a positive delayed-type hypersensitivity, is usually present in adult immunocompetent individuals and is presumed to prevent mucosal colonization progressing to symptomatic infection [2 , 3 ]. However, if the ability of C. albicans to establish a disseminated infection involves neutropenia as a major predisposing factor, its ability to persist in infected tissues or to behave as a commensal may involve primarily downregulation of host cell-mediated adaptive immunity. These data argue for the importance of the innate and adaptive cell-mediated immune response in the control of C. albicans infections. Ultimately, the ability of the fungus to grow in different forms in vivo or to coevolute as a commensal might have resulted in an expanded repertoire of crossregulatory and overlapping antifungal host responses, whose proper integration allows generation of the optimal antifungal immunity.

As a commensal, C. albicans may be endowed with the ability to elude the host’s immunological surveillance, thus allowing its persistence on mucosal surfaces. One important virulence factor of C. albicans is believed to be its ability to switch reversibly from a unicellular yeast form into various filamentous forms, all of which can be found in tissues [4 , 5 ]. Although recent studies have clearly shown that the ability to switch from yeast to filamentous form is required for virulence [6 , 7 ], whether it is the yeast or the hyphal form that is responsible for pathogenicity is still an open question. Other pathogenic fungi appear to proliferate in the host exclusively as yeast-form cells [8 9 10 ]. One possibility is that the filamentous growth form is required to evade the cells of the immune system, whereas the yeast form may be the mode of proliferation in infected tissues. To make it likely, a cell should exist that finely discriminates between the two forms of the fungus in terms of class of immune response elicited.

This review summarizes recent studies on 1) the nature of protective and unprotective immune effector mechanisms in response to C. albicans, and 2) their regulation by cytokines and 3) by cells of the the innate immune system, such as neutrophils and dendritic cells (DC), capable of discriminating between virulent and nonvirulent forms of the fungus.


   PROTECTIVE AND UNPROTECTIVE IMMUNE-EFFECTOR MECHANISMS
TOP
 ABSTRACT
 INTRODUCTION
 PROTECTIVE AND UNPROTECTIVE...
REGULATION OF Th1- AND...
 CONCLUSIONS
 REFERENCES
 
The resistance of naive mice to acute systemic infection with virulent yeast reflects mostly the activity of natural immune mechanisms. However, in conditions in which mice were not overwhelmed by a high dose of the fungus, resistance to disseminated C. albicans infection varied among inbred strains of mice of different major histocompatibility complex (MHC) haplotypes [11 12 13 ]. This genetically determined resistance to primary and secondary infections correlated with the balance occurring between protective Th1 and unprotective Th2 CD4+ cells [reviewed in ref. 14 ]. The presence of an activated innate immunity, such as the ability of phagocytic cells to inhibit fungal growth, was required for the induction of CD4+ Th1 cells [12 ]. However, an activated innate immune system was not always sufficient, per se, to clear the infection. Thus, a proper integration between the innate and the adaptive immune systems is required for efficient control of C. albicans infections. The general conclusion from these studies is that resistance to C. albicans infection is determined by phagocytic mechanisms, the activity of which is augmented or reinforced by Th1 cytokines and impaired by Th2 cytokines. Cytokines produced by Th1 cells activate phagocytes to a fungicidal state, whereas those produced by Th2 cells exacerbate the disease because of their deactivating properties for fungicidal effector cells [15 ]. Thus, Th1 and Th2 cells, by critically providing cytokines with activating and deactivating signals to fungicidal phagocytes, may be instrumental in mobilizing and activating the proper anticandidal effector mechanism at the site of the infection.

Studies in humans have reinforced this concept, by showing that acquired immunity to C. albicans correlates with the expression of local or peripheral Th1 reactivity [16 , 17 ], whereas susceptibility to the infection seen in thermally injured patients [18 ], in patients with human immunodeficiency virus (HIV) infection [19 ], or in patients with chronic mucocutaneous [20 , 21 ] or hepatosplenic [22 ] candidiasis correlates with a biased Th2 response to the fungus. However, in attempting to accommodate the complexity of the spectrum of Candida diseases in humans with the deterministic and apparently reductionist approach provided by the Th1/Th2 paradigm in experimental animals, several points need to be considered. First, the highly polarized cytokine responses that are induced by injection of large yeast innocula into inbred mice with widely different degrees of susceptibility undoubtedly reflect the extreme conditions of testing. Yet, they may provide a unitary basis for explaining the yeast commensalistic relationship with humans and its ability to dynamically modulate the host’s response so as to favor its own persistence, and they may also clarify several aspects of fungal pathogenicity and immunopathology mechanisms. Second, human studies have identified several effector mechanisms that result in Candida killing. Yet, no convincing link has been established so far between a particular clinical condition and any specific effector mechanism [23 ], despite the long-recognized associations between systemic candidiasis and neutrophil deficiency and between chronic mucosal infections and abnormalities in the cell-mediated response [4 ].

The concept of a reciprocal regulation between the phagocyte system and the T-cell compartment may provide a unifying thread between the systemic immune response and events occurring on the mucosal surface. Therefore, despite recent evidence indicating some differences in cell and cytokine requirements for expression of resistance at mucosal or systemic levels [24 25 26 ], this regulation emphasizes the fact that the anticandidal responses that have been characterized in systemic and mucosal infections are not unique to either condition.


   REGULATION OF Th1- AND Th2-DEPENDENT IMMUNITY
TOP
 ABSTRACT
 INTRODUCTION
 PROTECTIVE AND UNPROTECTIVE...
 REGULATION OF Th1- AND...
CONCLUSIONS
 REFERENCES
 
The role of cytokines
Th1 and Th2 CD4+ T-cells develop from a common, naive CD4+ T-cell precursor, and several parameters have been shown to influence the pathway of differentiation of CD4+ T-cell precursors [27 ]. Among these, cytokines appear to play a major role, acting not only as modulators of antifungal effector functions but also as key regulators in the development of the different Th subsets from precursor Th cells. Studies in mice have shown that development of protective anticandidal Th1 responses requires the concerted actions of several cytokines, such as interferon (IFN)-{gamma} [28 , 29 ], transforming growth factor (TGF)-ß [30 ], interleukin (IL)-6 [31 ], tumor necrosis factor (TNF)-{alpha} [32 ], and IL-12 [33 , 34 ], in the relative absence of inhibitory Th2 cytokines, such as IL-4 and IL-10, which inhibit development of Th1 responses [35 ]. Early in infection, neutralization of Th1 cytokines (IFN-{gamma} and IL-12) leads to the onset of Th2 rather than Th1 responses, while neutralization of Th2 cytokines (IL-4 and IL-10) allows development of Th1- rather than Th2-cell responses [28 , 34 , 36 , 37 ]. However, in highly susceptible mice, exogenous IL-12 did not exert beneficial effects on the course and outcome of disseminated and mucosal infections [34 ]. Moreover, administration of IL-4 failed to convert an already established Th1 response into a Th2 response [35 , 38 ], and late IL-4 depletion exacerbated chronic infection [38 , 39 ]. These findings indicate the existence of complex immunoregulatory circuits underlying cytokine activity in mice with candidiasis. Studies performed in genetically modified mice, including cytokine-deficient mice, have furthered our understanding of cytokine-mediated regulation of Th-cell development and effector functions in candidiasis and have revealed complex levels of immunoregulation that were previously unappreciated [12 ]. TNF/lymphotoxin (LT)-{alpha} and IL-6 deficiencies render mice highly susceptible to C. albicans infections. In contrast, resistance to primary and secondary infections was not impaired in the absence of IL-1ß or IL-10, as occurs in IL-1-converting enzyme (ICE)- or IL-10-deficient mice, respectively [12 , 40 ]. Finally, IL-12, IL-4, or functional IFN-{gamma} deficiencies, although not affecting resistance to primary infections, render mice susceptible to reinfection. Resistance or susceptibility to infections correlates with the levels of Candida growth in target organs, as well as with the type of Th cytokine production by specific CD4+ T lymphocytes.

Reduced production of IL-4 and IL-10 and increased production of IFN-{gamma} and IL-2 were observed in mice that resisted primary and secondary infections, such as ICE- and IL-10-deficient mice. On the contrary, high-level production of IL-4 and IL-10 and low-level production of Th1 cytokines were observed in TNF/LT-{alpha}- and IL-6-deficient mice succumbing to primary infection, and in IL-12p40-, IFN-{gamma}R-, and IL-4-deficient mice succumbing to secondary infection [12 , 29 , 41 ]. Altogether these data demonstrate that susceptibility to primary and secondary C. albicans infections in cytokine-deficient mice correlates with the failure to develop anticandidal, protective Th1 responses and with the occurrence of unprotective IL-4- and IL-10-producing Th2 cells. Moreover, these studies revealed the existence of a hierarchical pattern of cytokine-mediated regulation of antifungal Th-cell development and effector function. Early in infection, production of some proinflammatory cytokines (TNF-{alpha} and IL-6) rather than others (IL-1ß) appears to be essential for the successful control of infection and the resulting protective Th1-dependent immunity. IL-12 production and IL-12 responsiveness are required for the development of Th1-cell responses that are maintained in the presence of physiological levels of IL-4 [39 ], IL-10 [41 ], and IL-18 (unpublished results). Thus, a finely regulated balance of directive cytokines, such as IL-4, IL-10, and IL-12, rather than the relative absence of opposing cytokines, appears to be required for optimal development and maintenance of Th1 reactivity in mice with candidiasis.

The role of neutrophils
In candidiasis, the initial handling of fungal pathogen by cells of the innate immune system plays a major role in determining CD4+ Th development. Indeed, qualitative or quantitative defects of antifungal effector and immunoregulatory functions of phagocytic cells result in the development of anticandidal Th2, rather than Th1, cell responses [15 ]. The instructive role of the innate immune system in the adaptive immune response to the fungus is operative at different levels. Regulation of the early fungal burden [38 ], cytokine production [42 , 43 ], and expression of costimulatory molecules [32 , 41 ] are possible pathways through which the innate immune system may control CD4+ Th development. Professional mononuclear phagocytes [44 ] and unprofessional phagocytes such as epithelial cells [45 ] have been found to have an important role in primary and acquired Th1 reactivity to C. albicans.

However, an important immunoregulatory role has been attributed to neutrophils recently. Neutrophils, more than macrophages, were endowed with the ability to produce directive cytokines such as IL-10 and IL-12. Most importantly, IL-12 appeared to be released in response to a low-virulence Candida strain that initiates Th1 development in vivo, but IL-10 was released in response to a virulent strain [42 , 43 ]. Human neutrophils also produced bioactive IL-12 in response to a mannoprotein fraction of C. albicans, capable of inducing Th1 cytokine expression in peripheral blood mononuclear cells [46 ]. By producing directive cytokines such as IL-10 and IL-12, neutrophils influenced antifungal Th-cell development, as evidenced by the inability of neutropenic mice to mount protective anticandidal Th1 responses. Production of IL-12 by neutrophils occurred independently of TNF-{alpha} [32 ] and IFN-{gamma} [29 ]. It was impaired upon iron overload [47 ] but increased upon in vitro priming with IL-4 [39 ] through upregulation of IL-4 receptor expression. Thus, the IL-12-promoting activity of IL-4 may account for its requirement in sustaining memory Th1-cell responses to the fungus [39 ]. Cytokine production by neutrophils also occurred in vivo in infected mice to such an extent that Th1-mediated resistance was increased upon IL-12 administration in neutropenic mice or IL-10 neutralization in nonneutropenic mice. Because of the large number of neutrophils present in the blood or inflammatory tissues in infection [15 ], it is likely that neutrophil production of cytokines may influence the development and maintenance of the Th cell repertoire in response to C. albicans. Ultimately, this would be a likely expectation, shared with other cells of the innate immune system that although devoid of highly specific receptors, may nevertheless influence the final outcome of T-cell differentiation by responding to more general patterns of microbial molecules. Interestingly, it has been shown recently that neutrophils quickly release Candida antigens upon phagocytosis [48 ]. In addition, neutrophils expressed costimulatory molecules upon interaction with C. albicans (unpublished results). Thus, it is likely that the immunoregulatory role of neutrophils in candidiasis may go beyond its cytokine production, to include signaling through antigen presentation and costimulation.

Human studies confirm the multiple and complex role neutrophils have in candidiasis. First, risk factors for invasive fungal infections are not the same in all neutropenic patients [49 ]. Secondly, chronic systemic candidiasis initiated by neutropenia may persist in spite of normal neutrophil counts and adequate antifungal therapy [50 ]. Third, some patients, particularly transplant recipients who have adequate or even normal neutrophil counts, may be at high risk for invasive mycoses [51 , 52 ].

The role of dendritic cells
The recognition that DC are uniquely able to initiate responses in naive T-cells and that they also participate in Th-cell education [53 , 54 ] prompted us to investigate whether DC interact with C. albicans, in its different forms, and to elucidate possible mechanisms and consequences of this interaction. This issue appeared to be particularly relevant in candidiasis, considering the fungus behaves as a commensal and true pathogen of skin and mucosal surfaces [13 ], which are known to be highly enriched with DC. For adaptive immune responses to be mounted against fungi, it would seem necessary that DC should be phagocytic at some stage in their life cycle. We have, therefore, taken advantage of an immature myeloid DC cell line established from fetal mouse skin [55 ] capable of efficiently stimulating T-cells in vitro and in vivo upon cytokine treatment [56 ]. In a system devoid of contaminating cells, we found that DC ingested yeasts and hyphae of the fungus, apparently through different phagocytic mechanisms. Engulfment of yeasts occurred via coiling or overlapping phagocytosis, eventually leading to phagolysosome formation, where different stages of progressive yeast degradation were seen. In contrast, internalization of hyphae appeared to occur through a more conventional zipper-type phagocytosis. Once inside the cells, hyphae appeared to promote rupture of the phagosomal membrane and escaped into the cytoplasm. Thus, not only are yeasts and hyphae ingested through different forms of phagocytosis, but once inside the cells, they reside in distinct cellular compartments.

After phagocytosis of yeasts or hyphae, the downstream cellular events are clearly different. Ingestion of yeasts, but not hyphae, activated DC for IL-12 and nitric oxide production. In vivo, generation of antifungal protective immunity was observed upon injection of DC ex vivo-pulsed with C. albicans yeasts but not hyphae [57]. These results indicate that dendritic cells fulfill the requirement of a cell uniquely capable of sensing the two forms of C. albicans in terms of the type of immune response elicited.

Accumulating evidence points to the unique role of DC in infections, because they are regarded as a sentinel for innate recognition and an initiator of Th-cell differentiation and functional commitment [58 ]. In candidiasis, this behavior requires that DC be exquisitely sensitive to the different forms of the fungus, a finding in-line with increasing awareness of the importance of pattern-recognition receptors in host defense [59 , 60 ]. Considering that human DC also phagocytosed C. albicans [61 ] and activated T-cell responses to the fungus [62 ], our findings provide important and novel insights into the general mechanisms of immunoregulation in fungal infections. Moreover, as the morphogenesis of C. albicans is activated in vivo by a wide range of signals [63 ], DC may also act as key regulators of Th reactivity in saprophytism.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PROTECTIVE AND UNPROTECTIVE...
 REGULATION OF Th1- AND...
 CONCLUSIONS
REFERENCES
 
A large body of evidence, in preclinical settings and in humans, support the model of specific immunity to opportunistic fungal infections as being highly susceptible to cytokine influences and reciprocally regulated by cells of the innate immune system [64 , 65 ]. Therefore, finding cells and cytokines that are essential to control fungal infectivity or oppose fungus-associated immunopathology represents an intense area of research, the results of which may have important implications in the development of vaccines, and immunodiagnosis of and therapy for human fungal infections.


   ACKNOWLEDGEMENTS
 
This study was supported by the National Research Project on AIDS, contract 50B.33, "Opportunistic Infections and Tuberculosis," Italy. I thank Jo-Anne Rowe for editorial assistance.

Received October 28, 1999; revised January 14, 2000; accepted January 18, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PROTECTIVE AND UNPROTECTIVE...
 REGULATION OF Th1- AND...
 CONCLUSIONS
 REFERENCES
 

  1. Duchmann, R., Neurath, M. F., Meyer zum Büschenfelde, K. H. (1998) Responses to self and non-self intestinal microflora in health and inflammatory bowel disease Res. Immunol. 148,589-594
  2. Fidel, P. L., Jr, Sobel, J. D. (1994) The role of cell-mediated immunity in candidiasis Trends Microbiol 6,202-206
  3. Puccetti, P., Romani, L., Bistoni, F. (1995) A TH1-TH2-like switch in candidiasis: new perspectives for therapy Trends Microbiol 3,237-240[Medline]
  4. Odds, F. C. (1988) Candida and Candidosis 2nd ed ,68-92 Baillière-Tindall London.
  5. Kobayashi, S. D., Cutler, J. E. (1998) Candida albicans hyphal formation and virulence: is there a clearly defined role? Trends Microbiol 6,2-4
  6. Lo, H-J., Kohler, J. R., DiDomenico, B., Loebenberg, D., Cacciapuoti, A., Fink, G. R. (1997) Nonfilamentous C. albicans mutants are avirulent Cell 90,939-949[Medline]
  7. Gale, C. A., Bendel, C. M., McClellan, M., Hauser, M., Becker, J. M., Berman, J., Hostetter, M. K. (1998) Linkage of adhesion, filamentous growth, and virulence in Candida albicans to a single gene, INT1 Science 279,1355-1358[Abstract/Free Full Text]
  8. Bullock, W. E. (1990) Histoplasma capsulatum Mandell, G. L. Douglas, R. G. Bennett, J. E. eds. Principles and Practice of Infectious Diseases ,2340-2353 Churchill Livingstone New York.
  9. Chapman, S. W. (1990) Blastomyces dermatitidis Mandell, G. L. Douglas, R. G. Bennett, J. E. eds. Principles and Practice of Infectious Diseases ,2353-2365 Churchill Livingstone New York.
  10. Diamond, R. D. (1990) Cryptococcus neoformans Mandell, G. L. Douglas, R. G. Bennett, J. E. eds. Principles and Practice of Infectious Diseases ,2331-2340 Churchill Livingstone New York.
  11. Romani, L. (1999) Immunity to Candida albicans: Th1, Th2 cells and beyond Curr. Opin. Microbiol. 2,363-367[Medline]
  12. Mencacci, A., Cenci, E., Bistoni, F., Del Sero, G., Bacci, A., Montagnoli, C., Fè d’Ostiani, C., Romani, L. (1998) Specific and non-specific immunity to Candida albicans: a lesson from genetically modified animals Res. Immunol. 149,352-336[Medline]
  13. Romani, L. (1997) The T cell response to fungi Curr. Opin. Immunol. 9,484-490[Medline]
  14. Romani, L., Puccetti, P., Bistoni, F. (1996) Biological role of helper T-cell subsets in candidiasis Chem. Immunol. 63,113-137
  15. Romani, L., Bistoni, F., Puccetti, P. (1997) Initiation of T helper cell immunity to Candida albicans by IL-12: the role of neutrophils Chem. Immunol. 68,110-135[Medline]
  16. Fidel, P. L., Ginsburg, K. A., Cutright, J. L., Wolf, N. A., Leaman, D., Dunlap, K., Sobel, J. D. (1997) Vaginal-associated immunity in women with recurrent vulvovaginal candidiasis: evidence for vaginal Th1-type responses following intravaginal challenge with Candida antigen J. Infect. Dis. 176,728-739[Medline]
  17. La Sala, A., Urbani, F., Torosantucci, A., Cassone, A., Ausiello, C. (1996) Mannoproteins from Candida albicans elicit a Th1-type-1 cytokine profile in human Candida specific long-term T cell cultures J. Biol. Regul. Homeost. Agents 10,8-12[Medline]
  18. Kobayashi, M., Kobayashi, H., Herndon, D. N., Pollard, R. B., Suzuki, F. (1998) Burn-associated Candida albicans infection caused by CD30+ type 2 T cells J. Leukoc. Biol. 63,723-731[Abstract]
  19. Leigh, J. E., Steele, C., Wormerly, F. L., Jr, Luo, W., Gallaher, W., Fidel, P. L., Jr (1998) Th1/Th2 cytokine expression in saliva of HIV-positive and HIV-negative individuals: a pilot study in HIV-positive individuals with oropharyngeal candidiasis J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 19,373-380[Medline]
  20. Lilic, D., Cant, A. J., Abinun, M., Calvert, J. E., Spickett, G. P. (1996) Chronic mucocutaneous candidiasis. I. Altered antigen-stimulated IL-2, IL-4, IL-6 and interferon-gamma (IFN-{gamma}) production Clin. Exp. Immunol. 105,205-212[Medline]
  21. Kobrynski, L. J., Tanimune, L., Kilpatrick, L., Campbell, D. E., Douglas, S. D. (1996) Production of T-helper cell subsets and cytokines by lymphocytes from patients with chronic mucocutaneous candidiasis Clin. Diagn. Lab. Immunol. 3,740-745[Abstract]
  22. Roilides, E., Sein, T., Schaufele, R., Chanock, S. J., Walsh, T. J. (1998) Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis J. Infect. Dis. 178,589-592[Medline]
  23. Ashman, R. B., Papadimitriou, J. M. (1995) Production and function of cytokines in natural and acquired immunity to Candida albicans infection Microbiol. Rev. 59,646-672[Abstract/Free Full Text]
  24. Wagner, R. D., Vasquez-Torres, A., Jones-Carson, J., Wagner, T., Balish, E. (1996) B-cell knockout mice are resistant to mucosal and systemic candidiasis of endogenous origin but susceptible to experimental candidiasis J. Infect. Dis. 174,589-597[Medline]
  25. Balish, E., Vasquez-Torres, A., Jones-Carson, J., Wagner, R. D., Warner, T. (1996) Importance of b2-microglobulin in murine resistance to mucosal and systemic candidiasis Infect. Immun. 64,5092-5097[Abstract]
  26. Schuman, P., Sobel, J. D., Ohmit, E., Mayer, K. H., Carpenter, C. J., Rompalo, A., Duerr, A., Smith, D. K., Warren, D., Klein, R. S. (1998) Mucosal candidal colonization and candidiasis in women with or at risk for immunodeficiency virus infection J. Infect. Dis. 27,1161-1167
  27. O’Garra, A. (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets Immunity 8,275-283[Medline]
  28. Romani, L., Cenci, E., Mencacci, A., Spaccapelo, R., Grohmann, U., Puccetti, P., Bistoni, F. (1992) Gamma interferon modifies CD4+ subset expression in murine candidiasis Infect. Immun. 60,4950-4952[Abstract/Free Full Text]
  29. Cenci, E., Mencacci, A., Del Sero, G., Fè d’Ostiani, C., Mosci, P., Kopf, M., Romani, L. (1998) IFN-{gamma} is required for IL-12 responsiveness in mice with Candida albicans infection J. Immunol. 161,3543-3550[Abstract/Free Full Text]
  30. Spaccapelo, R., Romani, L., Tonnetti, L., Cenci, E., Mencacci, A., Tognellini, R., Reed, S. G., Puccetti, P., Bistoni, F. (1995) TGF-ß is important in determining the in vivo susceptibility or resistance in mice infected with Candida albicans J. Immunol. 155,1349-1360[Abstract]
  31. Romani, L., Mencacci, A., Cenci, E., Spaccapelo, R., Toniatti, C., Puccetti, P., Bistoni, F., Poli, V. (1996) Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin-6-deficient mice infected with Candida albicans J. Exp. Med. 183,1-11[Free Full Text]
  32. Mencacci, A., Cenci, E., Del Sero, G., Fè d’Ostiani, C., Mosci, P., Bistoni, F., Montagnoli, C., Bacci, A., Bistoni, F., Quesneaux, V. F. J., Ryffel, B., Romani, L. (1998) Defective co-stimulation and impaired Th1 development in tumor necrosis factor/lymphotoxin-{alpha} double-deficient mice infected with Candida albicans Int. Immunol. 10,37-48[Abstract/Free Full Text]
  33. Romani, L., Mencacci, A., Tonnetti, L., Spaccapelo, R., Cenci, E., Wolf, S., Puccetti, P., Bistoni, F. (1994) Interleukin-12 but not interferon-{gamma} production correlates with induction of T helper type-1 phenotype in murine candidiasis Eur. J. Immunol. 24,909-915[Medline]
  34. Romani, L., Mencacci, A., Tonnetti, L., Spaccapelo, R., Cenci, E., Puccetti, P., Wolf, S. F., Bistoni, F. (1994) Interleukin-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candidiasis J. Immunol. 53,5157-5175
  35. Tonnetti, L., Spaccapelo, R., Cenci, E., Mencacci, A., Puccetti, P., Coffman, R. L., Bistoni, F., Romani, L. (1995) Interleukin-4 and -10 exacerbate candidiasis in mice Eur. J. Immunol. 25,1559-1565[Medline]
  36. Romani, L., Mencacci, A., Grohmann, U., Mocci, S., Mosci, P., Puccetti, P., Bistoni, F. (1992) Neutralizing antibody to interleukin 4 induces systemic protection and T helper type 1-associated immunity in murine candidiasis J. Exp. Med. 176,19-25[Abstract/Free Full Text]
  37. Romani, L., Puccetti, P, Mencacci, A., Cenci, E., Spaccapelo, R., Tonnetti, L., Grohmann, U., Bistoni, F. (1993) Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans J. Immunol. 152,3514-3521[Abstract]
  38. Mencacci, A., Spaccapelo, R., Del Sero, G., Enssle, K-H., Cassone, A., Bistoni, F., Romani, L. (1996) CD4+ T-helper-cell responses in mice with low-level Candida albicans infection Infect. Immun. 64,4907-4914[Abstract]
  39. Mencacci, A., Del Sero, G., Cenci, E., Fè d’Ostiani, C., Bacci, A., Montagnoli, C., Kopf, M., Romani, L. (1998) IL-4 is required for development of protective CD4+ T helper type 1 cell responses to Candida albicans J. Exp. Med. 187,307-317[Abstract/Free Full Text]
  40. Del Sero, G., Mencacci, A., Cenci, E., Fè d’Ostiani, C., Montagnoli, C., Bacci, A., Mosci, P., Kopf, M., Romani, L. (1999) Antifungal T helper type 1 responses are upregulated in IL-10-deficient mice Microbes Infect 1,1169-1180[Medline]
  41. Mencacci, A., Cenci, E., Del Sero, G., Fè d’Ostiani, C., Mosci, P., Bistoni, F., Trinchieri, G., Adorini, L., Romani, L. (1998) IL-10 is required for development of protective CD4+ T helper type 1 cell responses to Candida albicans J. Immunol. 161,6228-6237[Abstract/Free Full Text]
  42. Romani, L., Mencacci, A., Cenci, E., Del Sero, G., Bistoni, F., Puccetti, P. (1997) An immunoregulatory role for neutrophils in CD4+ T helper subset selection in mice with candidiasis J. Immunol. 158,2356-2362[Abstract]
  43. Romani, L., Mencacci, A., Cenci, E., Spaccapelo, R., Del Sero, G., Nicoletti, I., Trinchieri, G., Bistoni, F., Puccetti, P. (1997) Neutrophils production of IL-12 and IL-10 in candidiasis and efficacy of IL-12 therapy in neutropenic mice J. Immunol. 158,5349-5356[Abstract]
  44. Vasquez-Torres, A., Balish, E. (1997) Macrophages in resistance to candidiasis Microbiol. Mol. Rev. 61,170-192[Abstract]
  45. Fidel, P. L., Sobel, J. D. (1998) Protective immunity in experimental Candida vaginitis Res. Immunol. 149,361-373[Medline]
  46. Cassone, A., Chiani, P., Quinti, I., Torosantucci, A. (1997) A possible participation of polymorphonuclear cells stimulated by microbial immunomodulators in cytokine dysregulated patterns of AIDS patients J. Leuk. Biol. 62,60-66[Abstract]
  47. Mencacci, A., Cenci, E., Boelaert, J. R., Bucci, P., Mosci, P., Fè d’Ostiani, C., Bistoni, F., Romani, L. (1997) Iron overload alters innate and T helper cell responses to Candida albicans in mice J. Infect. Dis. 175,1467-1476[Medline]
  48. Ashley, C., Morhart, M., Rennie, R., Ziola, B. (1997) Release of Candida albicans yeast antigens upon interaction with human neutrophils in vitro J. Med. Microbiol. 46,747-755[Abstract]
  49. Walsh, T. J., Hiemenz, J., Pizzo, P. A. (1994) Evolving risk factors for invasive fungal infections: all neutropenic patients are not the same Clin. Infect. Dis. 18,793-798[Medline]
  50. Bodey, G. P., Anaissie, E. J. (1989) Chronic systemic candidiasis Eur. J. Clin. Microbiol. Infect. Dis. 8,855-857[Medline]
  51. Bow, E. J., Loewen, R., Cheang, M. S., Schacter, B. (1995) Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileukemic regimen Clin. Infect. Dis. 21,361-369[Medline]
  52. La Rocco, M., Burgert, S. J. (1997) Fungal infections in the transplant recipient and laboratory methods for diagnosis Rev. Iberoam. Micol. 14,143-146[Medline]
  53. Steinman, R. M. (1991) The dendritic cell system and its role in immunogenicity Annu. Rev. Immunol. 9,271-296[Medline]
  54. Banchereau, J., Steinman, R. M. (1998) Dendritic cells and the control of immunity Nature 392,245-252[Medline]
  55. Girolomoni, G., Manfred, B. L., Pastore, S., Assmann, C. A., Cavani, A., Ricciardi-Castagnoli, P. (1995) Establishment of a cell line with features of early dendritic cell precursors from fetal mouse skin Eur. J. Immunol. 25,2163-2169[Medline]
  56. Lutz, M. B., Assmann, C. A., Girolomoni, G., Ricciardi-Castagnoli, P. (1996) Different cytokines regulate antigen uptake and presentation of a precursor dendritic cell line Eur. J. Immunol. 26,586-594[Medline]
  57. Fè d’Ostiani, C., Del Sero, G., Bacci, A., Montagnoli, C., Spreca, A., Mencacci, A., Ricciardi-Castagnoli, P., Romani, L. (2000) Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans: Implications for initiation of Th immunity in vitro and in vivo J. Exp. Med. 15,1661-1674
  58. Reis e Sousa, G., Sher, A., Kaye, P. (1999) The role of dendritic cells in the induction and regulation of immunity to microbial infection Curr. Opin. Immunol. 11,392-399[Medline]
  59. Kopp, E. B., Medzhitov, R. (1999) The Toll-receptor family and control of innate immunity Curr. Opin. Immunol. 11,13-18[Medline]
  60. Stahl, P. D., Ezekowitz, R. A. (1998) The mannose receptor is a pattern recognition receptor involved in host defense Curr. Opin. Immunol. 10,50-55[Medline]
  61. Chen, B-G., Shi, Y., Smith, J. D., Choi, D., Geiger, J. D., Mulé, J. J. (1998) The role of tumor necrosis factor {alpha} in modulating the quantity of peripheral blood-derived, cytokine-driven human dendritic cells and its role in enhancing the quality of dendritic cell function in presenting soluble antigens to CD4+ T cells in vitro Blood 91,4652-4661[Abstract/Free Full Text]
  62. Newman, S. L., Holly, A. (1999) Phagocytosis and killing of Candida albicans (Ca) by human dendritic cells. Society for Leukocyte Biology, 15th International Congress, Cambridge, UK, Sept. 22–26, 1999, 18.
  63. Brown, A. J. P., Gow, N. A. R. (1999) Regulatory networks controlling Candida albicans morphogenesis Trends Microbiol 7,333-338[Medline]
  64. Poynton, H. C. (1997) Immune modulation by cytokines in the treatment of opportunistic infections Curr. Opin. Infect. Dis. 10,275-280
  65. Polonelli, L., Cassone, A. (1999) Novel strategies for treating candidiasis Curr. Opin. Infect. Dis. 12,61-66



This article has been cited by other articles:


Home page
 J. Immunol.Home page
A. Coste, C. Lagane, C. Filipe, H. Authier, A. Gales, J. Bernad, V. Douin-Echinard, J.-C. Lepert, P. Balard, M.-D. Linas, et al.
IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2-/- Mice via Peroxisome Proliferator-Activated Receptor-{gamma} Activation
J. Immunol., April 1, 2008; 180(7): 4939 - 4947.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
S. P. Saville, A. L. Lazzell, A. K. Chaturvedi, C. Monteagudo, and J. L. Lopez-Ribot
Use of a Genetically Engineered Strain To Evaluate the Pathogenic Potential of Yeast Cell and Filamentous Forms during Candida albicans Systemic Infection in Immunodeficient Mice
Infect. Immun., January 1, 2008; 76(1): 97 - 102.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
R. Nisini, A. Torosantucci, G. Romagnoli, P. Chiani, S. Donati, M. C. Gagliardi, R. Teloni, V. Sargentini, S. Mariotti, E. Iorio, et al.
{beta}-Glucan of Candida albicans cell wall causes the subversion of human monocyte differentiation into dendritic cells
J. Leukoc. Biol., November 1, 2007; 82(5): 1136 - 1142.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
J. Chandra, T. S. McCormick, Y. Imamura, P. K. Mukherjee, and M. A. Ghannoum
Interaction of Candida albicans with Adherent Human Peripheral Blood Mononuclear Cells Increases C. albicans Biofilm Formation and Results in Differential Expression of Pro- and Anti-Inflammatory Cytokines
Infect. Immun., May 1, 2007; 75(5): 2612 - 2620.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
M. S. Renna, S. G. Correa, C. Porporatto, C. M. Figueredo, M. P. Aoki, M. G. Paraje, and C. E. Sotomayor
Hepatocellular apoptosis during Candida albicans colonization: involvement of TNF-{alpha} and infiltrating Fas-L positive lymphocytes
Int. Immunol., December 1, 2006; 18(12): 1719 - 1728.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
E Obi, A Roy, V Bates, and C Sandy
Bilateral chronic fungal dacryocystitis caused by Candida dubliniensis in a neutropenic patient.
J. Clin. Pathol., November 1, 2006; 59(11): 1194 - 1195.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
S. G. Correa, M. C. Rodriguez-Galan, B. Salido-Renteria, R. Cano, H. Cejas, and C. E. Sotomayor
High dissemination and hepatotoxicity in rats infected with Candida albicans after stress exposure: potential sensitization to liver damage
Int. Immunol., December 1, 2004; 16(12): 1761 - 1768.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
A. Torosantucci, G. Romagnoli, P. Chiani, A. Stringaro, P. Crateri, S. Mariotti, R. Teloni, G. Arancia, A. Cassone, and R. Nisini
Candida albicans Yeast and Germ Tube Forms Interfere Differently with Human Monocyte Differentiation into Dendritic Cells: a Novel Dimorphism-Dependent Mechanism To Escape the Host's Immune Response
Infect. Immun., February 1, 2004; 72(2): 833 - 843.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
G. Romagnoli, R. Nisini, P. Chiani, S. Mariotti, R. Teloni, A. Cassone, and A. Torosantucci
The interaction of human dendritic cells with yeast and germ-tube forms of Candida albicans leads to efficient fungal processing, dendritic cell maturation, and acquisition of a Th1 response-promoting function
J. Leukoc. Biol., January 1, 2004; 75(1): 117 - 126.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
B. Spellberg, D. Johnston, Q. T. Phan, J. E. Edwards Jr., S. W. French, A. S. Ibrahim, and S. G. Filler
Parenchymal Organ, and Not Splenic, Immunity Correlates with Host Survival during Disseminated Candidiasis
Infect. Immun., October 1, 2003; 71(10): 5756 - 5764.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M. C. Rodriguez-Galan, C. Sotomayor, M. E. Costamagna, A. M. Cabanillas, B. S. Renteria, A. M. Masini-Repiso, and S. Correa
Immunocompetence of macrophages in rats exposed to Candida albicans infection and stress
Am J Physiol Cell Physiol, January 1, 2003; 284(1): C111 - C118.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
D. Pietrella, R. Mazzolla, P. Lupo, L. Pitzurra, M. J. Gomez, R. Cherniak, and A. Vecchiarelli
Mannoprotein from Cryptococcus neoformans Promotes T-Helper Type 1 Anticandidal Responses in Mice
Infect. Immun., December 1, 2002; 70(12): 6621 - 6627.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
G. J. Wanten, M. G. Netea, T. H. Naber, J. H. Curfs, L. E. Jacobs, T. J. Verver-Jansen, and B.-J. Kullberg
Parenteral Administration of Medium- but Not Long-Chain Lipid Emulsions May Increase the Risk for Infections by Candida albicans
Infect. Immun., November 1, 2002; 70(11): 6471 - 6474.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
C. Bromuro, A. Torosantucci, P. Chiani, S. Conti, L. Polonelli, and A. Cassone
Interplay between Protective and Inhibitory Antibodies Dictates the Outcome of Experimentally Disseminated Candidiasis in Recipients of a Candida albicans Vaccine
Infect. Immun., October 1, 2002; 70(10): 5462 - 5470.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
G. Santoni, M. Boccanera, D. Adriani, R. Lucciarini, C. Amantini, S. Morrone, A. Cassone, and F. De Bernardis
Immune Cell-Mediated Protection against Vaginal Candidiasis: Evidence for a Major Role of Vaginal CD4+ T Cells and Possible Participation of Other Local Lymphocyte Effectors
Infect. Immun., September 1, 2002; 70(9): 4791 - 4797.
[Abstract] [Full Text] [PDF]

Home page
 J Med MicrobiolHome page
M. SCHALLER, R. MAILHAMMER, and HANS.C. KORTING
Cytokine expression induced by Candida albicans in a model of cutaneous candidosis based on reconstituted human epidermis
J. Med. Microbiol., August 1, 2002; 51(8): 672 - 676.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Bozza, R. Gaziano, A. Spreca, A. Bacci, C. Montagnoli, P. di Francesco, and L. Romani
Dendritic Cells Transport Conidia and Hyphae of Aspergillus fumigatus from the Airways to the Draining Lymph Nodes and Initiate Disparate Th Responses to the Fungus
J. Immunol., February 1, 2002; 168(3): 1362 - 1371.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
J. Brieland, D. Essig, C. Jackson, D. Frank, D. Loebenberg, F. Menzel, B. Arnold, B. DiDomenico, and R. Hare
Comparison of Pathogenesis and Host Immune Responses to Candida glabrata and Candida albicans in Systemically Infected Immunocompetent Mice
Infect. Immun., August 1, 2001; 69(8): 5046 - 5055.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
R. Nisini, G. Romagnoli, M. J. Gomez, R. La Valle, A. Torosantucci, S. Mariotti, R. Teloni, and A. Cassone
Antigenic Properties and Processing Requirements of 65-Kilodalton Mannoprotein, a Major Antigen Target of Anti-Candida Human T-Cell Response, as Disclosed by Specific Human T-Cell Clones
Infect. Immun., June 1, 2001; 69(6): 3728 - 3736.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Romani, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Romani, L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS