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Infection and Immunity, June 2006, p. 3079-3084, Vol. 74, No. 6
0019-9567/06/$08.00+0 doi:10.1128/IAI.00431-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
| GUEST COMMENTARY |
Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461
THE MICROBE AS AN ENCAPSULATED PATHOGEN
Cryptococcus neoformans, like most other pathogenic fungi, enjoys a wide host range and does not require a mammalian host for survival. However, this pathogenic yeast is also unique among fungi because it has a polysaccharide capsule, which serves as its central virulence factor and is essential for pathogenicity in normal hosts. In this regard, C. neoformans shares important virulence mechanisms with encapsulated bacteria, such as typeable Haemophilus influenzae, Streptococcus pneumoniae (pneumococcus), and Neisseria meningitidis (meningococcus). Like these encapsulated microbes, C. neoformans is acquired by the respiratory route early in life (24) and causes disease syndromes dominated by pulmonary and central nervous system damage. However, while most encapsulated bacterial pathogens either are eliminated or cause disease after a period of nasopharyngeal colonization, C. neoformans can establish a state of latency. C. neoformans infections can represent reactivation disease, but primary infection also occurs (discussed in reference 9).
The major risk factor for the disease syndromes caused by encapsulated bacteria is impaired antibody-mediated immunity (50). As such, infants and young children, who suffer from a physiological delay in the ability to mount antibody responses to capsular polysaccharides, and patients with underlying antibody and B-cell defects are at the highest risk for disease (50). In contrast, the major risk factor for cryptococcosis is impaired CD4+-T-cell-mediated immunity (discussed in reference 9). The link between T-cell deficiency and the risk for cryptococcosis was first appreciated in patients receiving immunosuppressive therapies but was not fully revealed until the onset of the human immunodeficiency virus (HIV)/AIDS pandemic. The prevalence of HIV-associated cryptococcosis at the height of the HIV epidemic in New York City was a staggering 6 to 8% of those at risk (11). Although the prevalence of cryptococcosis has fallen dramatically in the United States and other nations where antiretroviral therapy is in use, the incidence of HIV-associated cryptococcosis is as high as 30 to 60% in individuals with AIDS in developing regions, such as Africa (2). In addition, cryptococcosis has emerged as an important manifestation of highly active antiretroviral therapy- and solid organ transplant-associated immune reconstitution (59, 60) and is an emerging problem in solid organ transplant recipients (26).
Despite the incontrovertible association between cryptococcosis and CD4+-T-cell deficiency in humans and animal models, CD4+-T-cell deficiency alone is insufficient to discriminate those who will develop disease from those who will not. Hence, additional factors must contribute to the risk for disease. Evidence that C. neoformans is acquired early in life (24), that it assumes a latent state (25), and that it has worldwide environmental niches (39) suggests that most humans should be continuously at risk for reactivation or reinfection. However, the prevalence of disease in normal individuals is extremely low (7), and factors that render most people, including many with T-cell deficiency, resistant to cryptococcosis remain largely unknown.
At present, the contribution of defects in humoral immunity to the pathogenesis of human cryptococcosis remains undefined. Nonetheless, ample clinical observations reveal an increased prevalence of cryptococcosis in certain patient populations with humoral and T-cell deficiency, including HIV-infected individuals. HIV infection is associated with profound B-cell defects (37) that include deficiency of the predominant gene family used in antibodies to the C. neoformans capsular polysaccharide component glucuronoxylomannan (GXM), VH3 (discussed in references 49 and 61). Deficiency of VH3 was observed among HIV-infected individuals who developed cryptococcosis but not in those who did not develop cryptococcosis, with this deficiency being evident at CD4+-T-cell levels significantly higher than the level at which disease occurs (20). This observation suggested that certain individuals could have underlying humoral defects that predispose them to cryptococcosis in the setting of T-cell deficiency. Consistent with this hypothesis, underlying B-cell defects are common in patients with hypogammaglobulinemia and hyper-immunoglobulin M (IgM) syndromes, immunoglobulin disorders that have been linked to an increased risk for cryptococcosis (discussed in reference 61). Lower levels of GXM-reactive IgM have been found among HIV-infected individuals than among HIV-uninfected individuals (61). IgM, like complement, is an important serum opsonin. Notably, IgM deficiency impaired the ability of mice to activate the classical complement pathway during the innate immune response to pneumococcus (5), and mice with complement component 5a (C5a) or C3 deficiency are more susceptible to experimental cryptococcosis than complement-sufficient mice (51, 57). Complement deficiency has not been implicated as a risk factor for human cryptococcosis, but one study demonstrated depletion of complement components during human and experimental cryptococcal fungemia in guinea pigs (42).
This issue of Infection and Immunity features an article by Gates and Kozel that reports an intriguing and innovative finding concerning the interaction between complement and the C. neoformans capsule (23a). In that report, the authors used a variety of different approaches to demonstrate that the location of C3 deposition on the C. neoformans capsule is species specific. While human serum deposited C3 at the outermost edge of the capsule, mouse serum deposited C3 beneath the capsular edge and rat and guinea pig serum produced intermediate patterns of deposition. This finding underscores the need to consider species differences in animal models of microbial pathogenesis. The significance of the species difference in capsular C3 localization discovered by Gates and Kozel lies in the intriguing parallel between capsular C3 localization and the relative susceptibilities of different species to cryptococcosis; humans are the most resistant, mice are the most susceptible, and rats have intermediate susceptibility (9). However, it should be noted that it is difficult to compare the susceptibilities of rodents, which are infected experimentally with large inocula, and humans, who are infected asymptomatically early in life (24). Furthermore mice without an intact complement system are highly susceptible to C. neoformans (51, 57). The potential relationship between C3 localization on the cryptococcal capsule and host defense against C. neoformans calls for a closer look at the structure of the cryptococcal capsule and a review of our current understanding of interactions between the cryptococcal capsule and the complement system.
THE LANDSCAPE: THE CRYPTOCOCCAL CAPSULE
The C. neoformans polysaccharide capsule is composed of mannoproteins, GXM, and galactomannan (GalXM), with GXM comprising over 80% of the capsular polysaccharide by mass (45). GXM consists of repeating units of a linear 
-(1-3)-mannan-trisaccharide backbone that is modified by acetyl groups and glucopyranosyluronic acid and xylopyranosyl side groups (45). Recent work has shown that far from being a static, homogenous, predictable collection of carbohydrate residues, the C. neoformans capsule is highly complex, heterogenous (6), and dynamic, with the ability to undergo remodeling during growth (73). Critical aspects of capsular complexity are that the structure and density of GXM are variable and dynamic, rather than conserved and constant, and that the concentration of GXM increases as a function of the distance away from the cell wall but decreases at the capsular edge, where new residues are found (6, 23). In addition to the demonstration that GXM structure varies in cultured cells, there is also ample evidence that C. neoformans undergoes antigenic variation in vivo (21, 52). Hence, available data suggest that the antigenic complexity of GXM presents an enormous challenge to the immune system.
Many important insights into the complexity and antigenicity of GXM were gained through studies with monoclonal antibodies (MAbs) (discussed in reference 8). MAbs with defined GXM specificity prolong the survival of mice with experimental cryptococcosis and mediate other beneficial effects by a multitude of mechanisms, including by functioning as immunoregulators (8). In addition to protective MAbs, nonprotective MAbs have also been identified in defined, inbred mouse models (8). Nonprotective MAbs and MAbs that do not promote macrophage phagocytosis in vitro have unique GXM specificity, which is manifested as a punctuate capsular binding pattern by immunofluorescence (discussed in reference 8) or a puffy binding pattern by differential interference contrast microscopy (47). The ability to promote macrophage phagocytosis in vitro appears to be a surrogate for MAbs that are protective in mice. On the other hand, intracellular replication in macrophages is an important virulence mechanism for C. neoformans (19, 64). Hence, deciphering the effect of serum opsonin-mediated phagocytosis on host defense will be critically important to advancing our understanding of species differences in susceptibility and resistance to C. neoformans.
The C. neoformans capsule contributes to virulence by a multiplicity of mechanisms principally mediated by GXM. GXM exerts a variety of deleterious effects on host immunity, including inhibition of leukocyte migration, reduced costimulatory molecule expression, altered cytokine expression, and reduced antibody responsiveness (17, 46, 66). Perhaps of the greatest relevance to virulence, the cryptococcal capsule inhibits phagocytosis (32, 72). For C. neoformans (72), as for encapsulated bacteria (4, 43, 68), capsular polysaccharide-mediated inhibition of phagocytosis has been linked to cell wall or subcapsular deposition of complement component 3 (C3). As such, polysaccharide capsules are generally considered to be antiphagocytic.
HOST-LANDSCAPE INTERACTION: COMPLEMENT ACTIVATION BY THE CRYPTOCOCCAL CAPSULE
Studies from the Kozel laboratory have provided a wealth of information on the interaction of complement with the cryptococcal capsule (33, 34, 70). A seminal finding that emerged from previous studies in the Kozel laboratory was that the C. neoformans capsule initiates complement activation by the alternative complement pathway and blocks complement activation by the cell wall (33). Initiation of the alternative complement pathway in human serum by encapsulated C. neoformans results in the deposition of >107 C3 molecules per cell on the capsular surface, albeit after a delay of several minutes (33, 34). In contrast, zymosan or unencapsulated cells activate both the classical and alternative complement pathways in human serum and deposit 3 x 106 to 4 x 106 C3 molecules at the cell wall (33). Hence, the cryptococcal capsule is a powerful activator of the alternative complement pathway in human serum. Other encapsulated microbes, such as type III group B streptococcus (43) and encapsulated strains of Staphylococcus aureus, also activate the alternative complement pathway in human serum (48).
The article by Gates and Kozel in this issue of Infection and Immunity presents compelling and fascinating new data on C. neoformans-initiated complement activation that reveal striking species-specific differences in the dominant complement activation pathway and the location of C3 deposition on the capsule (23a). Incubation of C. neoformans in mouse serum resulted in activation of the classical complement pathway and nearly immediate C3 deposition distal to the capsular surface rather than at the edge. Since this result was in marked contrast to the results with human serum, which activates the alternative complement pathway exclusively, resulting in C3 deposition at the outer capsular edge, the authors sought to identify a classical pathway initiator in mouse serum. Such a factor was not discovered, leaving open the question of why C. neoformans preferentially activates the classical complement pathway in mouse serum. Nonimmune (natural) mouse IgM can serve as an initiator of the classical complement pathway by the encapsulated microbe pneumococcus (5); nonspecific human IgM can initiate classical complement activation by Mycobacterium leprae (55); and human IgM expressing VH3, the gene family used in antibodies to GXM, can activate the classical complement pathway upon superantigen binding (35). These observations raise the question of whether nonimmune IgM can activate the classical pathway in mouse serum upon binding to an unknown C. neoformans determinant.
A second major finding in the Gates and Kozel study is that the location of C3 deposition is also species specific. Human C3 was deposited at the outer capsular surface or edge, whereas mouse C3 was deposited beneath the capsular surface away from the edge. Treatment of mouse serum with EGTA to block the classical complement pathway altered the kinetics of C3 deposition, resulting in a delay similar to that observed with human serum, but the location of C3 deposition was unaltered. Hence, activation of either the alternative or the classical complement pathway in mouse serum resulted in the same pattern of C3 localization. Remarkably, the addition of human C3 to mouse serum altered the location of C3 deposition to a position closer to the capsular edge. Using different C. neoformans strains and commercially obtained mouse serum, Zaragoza et al. also found that mouse C3 was deposited away from the capsular edge (72). These studies provide strong support for the conclusion that the C3 localization on the cryptococcal capsule is species specific. In their article, Gates and Kozel (23a) provide a detailed analysis of possible mechanisms to explain species differences in C3 deposition and conclude that there must be a fundamental difference between mouse and human C3 which results in unique GXM specificity or a difference in C3 stability.
In view of evidence that GXM structure is highly variable and that the GXM concentration decreases toward the capsular edge (6, 23, 73), GXM could feature a staggering number of unique binding sites for C3. Although species-specific C3 binding motifs have not been described, variants of guinea pig C3 with different functional activities have been described (36). Evolutionary divergence and differential function of C4 from different species (13, 15) and mouse strain differences in the rate of degradation of C3 (41) have also been reported. Given that C3 is a multifunctional, multimeric protein that evolved from smaller protein domains (27), it is reasonable to hypothesize that human and mouse C3 could have evolved with divergent structures. Structural differences in C3 could alter either its specificity for a microbial ligand, the rate at which it is degraded, or both.
Despite the ability of other encapsulated microbes to activate the alternative complement pathway in human serum, C3 deposition on these microbes is beneath the capsular surface (48, 68) or inversely proportional to the amount of encapsulation (43). Hence, C. neoformans appears to be unique in its ability to promote human C3 binding at the outermost edge of the capsule. The mechanism driving differential deposition of mouse and human C3 is unknown. The C. neoformans capsular polysaccharide (30), like that of other encapsulated bacteria (18, 40), expresses O-acetylated surface moieties, albeit in different positions on different residues. De-O-acetylation of C. neoformans decreases capsule size (71) and increases alternative complement pathway activation in human serum while increasing capsular C3 deposition by 25 to 47% (71). A similar phenomenon was reported for Cryptococcus gattii, another cryptococcal species (67). Although the ability of de-O-acetylated cells to activate the alternative complement pathway in mouse serum has not been studied, O-acetylated surface residues inhibited mouse erythrocyte activation of the human alternative complement pathway (65). In addition, mouse erythrocytes had the highest (60%) while human erythrocytes had the lowest (5%) level of O acetylation (58), making it intriguing to wonder whether mouse C3 fails to interact with O-acetyl moieties, such as those on GXM, and whether this could have evolved as a mechanism to preserve erythrocyte survival.
THE SIGNIFICANCE OF COMPLEMENT OPSONIN BINDING TO THE CRYPTOCOCCAL CAPSULE
Current thought centers on the paradigm that surface deposition of opsonins enhances, whereas opsonin deposition distal to the capsular surface inhibits, phagocytosis of encapsulated microbes, including C. neoformans (72). This question has been addressed experimentally almost exclusively with primary or macrophage-like cell lines in vitro, principally in studies of antibody-mediated phagocytosis, although some studies have examined complement-mediated phagocytosis (29, 62, 72). The Kozel laboratory demonstrated that encapsulated C. neoformans opsonized with mouse serum was phagocytosed by mouse macrophages but that the uptake of cells opsonized with C3 from human serum by neutrophils was more robust (29). This early paper suggested the existence of additional layers of complexity in complement-mediated phagocytosis, since species differences in the serum source or effector cells or differences in the type of effector cell could have contributed to differences in the efficiency of phagocytosis. Using mouse serum, Zaragoza et al. showed that the ability of mouse macrophage-like cells to promote uptake of C. neoformans was a function of the volume of the yeast cell, with smaller yeasts being more readily phagocytosed (72). The Zaragoza et al. study also demonstrated that mouse C3 was deposited beneath the capsular surface as a function of the radius of the yeast cell: the smaller the volume of the cell, the closer to the capsular edge C3 was deposited, and the larger the volume of the cell, the further from the capsular edge C3 was deposited (72). In their article, Gates and Kozel found that mouse C3 deposition on large-capsule cryptococcal cells obtained from mouse tissue was closer to the capsular edge than that observed for large-capsule cells grown in culture (23a). The authors suggest that this difference could be due to the fact that the concentration of GXM is higher at the periphery of tissue-derived than in vitro grown cells. Interestingly, the tissue-derived cells used in the study were obtained from brain, a tissue in which C. neoformans cells were found to manifest less diversity than other tissues (22). These observations raise the possibility that the GXM specificity of mouse C3 could be tissue specific in vivo, perhaps for an epitope that emerges during growth in brain tissue. Enhanced or preferential phagocytosis of cryptococcus in brain could explain why complement is required for resistance of naïve, untreated mice to cryptococcosis (57).
THE SIGNIFICANCE OF ANTIBODY OPSONIN BINDING TO THE CRYPTOCOCCAL CAPSULE
Studies with defined MAbs that react with different GXM determinants have provided a wealth of information on the interaction of antibodies to GXM with the cryptococcal surface (8). In studies with human serum, the Kozel laboratory previously reported that complement activation led to differential localization of IgG and C3, with IgG deposition beneath and C3 deposition at the capsular surface, whereas immune rabbit serum promoted IgG deposition at the capsular surface (29). In this instance, the IgG was a naturally occurring antibody that is reactive with the cell wall. Later studies with MAbs demonstrated that GXM-specific antibodies bind to the outer surface of the cryptococcal capsule (see references 8 and 47). Another important study from the Kozel laboratory found that certain group II (mouse) MAbs to GXM suppressed the alternative complement pathway in human serum while promoting early activation of the classical complement pathway and leading to C3 deposition on the capsular surface (28). Group II MAbs include protective and nonprotective MAbs derived from the same gene elements. Hence, like the Gates and Kozel study in this issue (23a), that study showed that the location of C3 deposition is not a function of the complement pathway that is activated. Interestingly, group II IgG1s inhibited C3 binding to the capsular surface since isotype affects the specificity of MAbs to GXM (see references 8 and 63). The ability of certain MAbs to inhibit capsular surface C3 binding suggests that they could bind the same GXM determinant as C3. This raises a further question concerning whether the apparently dichotomous relationship between capsular activation of the alternative complement pathway in nonimmune human serum and activation of the classical complement pathway by specific antibody could modulate surface availability of C3 when specific antibody is present. Of relevance to this hypothesis, the Kozel laboratory has shown that complement-mediated phagocytosis and antibody-mediated phagocytosis are functionally redundant for Candida albicans (31). The interplay between different constituents of the humoral immune system could be an important factor in host defense against C. neoformans.
THE SIGNIFICANCE OF CAPSULAR C3 LOCALIZATION FOR CRYPTOCOCCAL RESISTANCE
It has long been held that surface availability of opsonins promotes host defense against encapsulated pathogens by overcoming the inhibition of phagocytosis attributable to the polysaccharide capsule. The efficiency of phagocytosis by mouse macrophage-like cells in vitro was increased for cryptococcal cells when C3 was localized closer to the capsular edge and was decreased when C3 was localized further away from the capsular edge (72). However, the relationship between C3 availability on the capsular surface and host defense in vivo remains unknown for mice and humans. The discovery by Gates and Kozel that mouse and human serum promote different C3 localization patterns on the cryptococcal capsule suggests a compelling association with susceptibility to cryptococcosis, since mice are considered to be more susceptible than humans (9). Nonetheless, complement-deficient mice are more susceptible to cryptococcosis than complement-sufficient mice (51, 57), raising the question of how complement enhances resistance to cryptococcosis in mice if the mechanism does not involve promoting complement-dependent phagocytosis. One clue could be the aforementioned discovery by Gates and Kozel that C3 deposition on brain-derived cryptococcus was closer to the outer edge of the capsule, suggesting such cells could be phagocytosed more efficiently. Nonetheless, since a multitude of factors, including characteristics of the infecting cryptococcal strain, the cytokine environment, the presence of cellular immune subsets, and the mouse genetic strain, influence mouse susceptibility to C. neoformans (see references 8 and 9), multivariate analysis (44) will almost certainly be required to determine the effect of C3 capsular localization on cryptococcal pathogenesis in vivo.
The importance of opsonin-induced phagocytosis for reducing the fungal burden and host defense against C. neoformans in vivo remains to be directly established. While the ability of complement and antibody opsonins to induce phagocyte uptake of C. neoformans is well established in vitro, the downstream events and host consequences in vivo, from antifungal activity to the nature, degree, and regulation of any accompanying inflammation, are largely unknown. The enhanced susceptibility to pulmonary cryptococcosis of mice compared to rats was associated with superior phagocytic function of rat alveolar macrophages, which was accompanied by a more favorable cytokine milieu (56). In theory, excessive surface opsonins could induce an overly exuberant inflammatory phagocytic response. Certain phenotypic variants (21) and cytokine milieus (53) induce excessive inflammatory responses to C. neoformans. Such responses could also be responsible for highly active antiretroviral therapy- or post-organ transplantation-associated immune reconstitution cryptococcosis (59, 60) or that which can occur after antifungal treatment itself (16), underscoring that cryptococcosis can occur in the setting of strong as well as weak immune responses (12). Strong inflammatory responses could occur if complement and antibody deposition on the cryptococcal surface promote phagocytosis by activating both complement and Fc receptors. Fc receptor-mediated inflammation is a well-established consequence of phagocytosis (10), while nonspecific immunoglobulin, such as that derived from normal serum, has recognized anti-inflammatory effects that are mediated by inhibitory Fc receptors (54). Tissue- or cell type-specific differences in complement and/or activating and inhibitory Fc receptor expression (3, 29) underscore the necessity for using research approaches that can address complexity in determining the outcome of opsonin-mediated phagocytosis of C. neoformans in vivo.
In addition to serving as a phagocytosis-inducing ligand, C3 is the precursor of anaphylatoxins, such as C3a and C5a, which could also affect the inflammatory response to cryptococcus. C5a has been implicated in C. neoformans-induced chemotaxis and neutrophil migration (38, 51). There is emerging evidence that C5a serves as an immunoregulator of allergic responses in the lung (14, 69). In light of these observations and strong evidence linking the pathogenesis of asthma to the immune response to fungi, including cryptococcus (1), it is intriguing to wonder if the generation of C5a following C3 deposition on the cryptococcal surface can enhance resistance to cryptococcosis through immunomodulation.
IMPLICATIONS FOR FUTURE STUDIES OF HOST RESISTANCE TO CRYPTOCOCCOSIS
The Gates and Kozel study in this issue of Infection and Immunity issues a compelling yet sobering challenge to the current dominance of mouse models in studies of cryptococcal pathogenesis while endorsing and underscoring the importance of further development and studies in rat models (23a, 56). This article firmly installs another variable, namely, the location of capsular C3 deposition, as a factor that could contribute to species-specific differences in the success or failure of host immune responses to C. neoformans. Moreover, the article also provides a powerful impetus for further study of the interactions between constituents of the humoral immune system, including complement, antibody, and other serum proteins, and the cryptococcal capsule at its interface with host receptors.
ACKNOWLEDGMENTS
I acknowledge support from grants RO1 AI35370, AI44374, and AI45459 from the National Institutes of Health.
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FOOTNOTES |
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FOOTNOTES
The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.
Editor: A. Casadevall
REFERENCES
| 1. | Arora, S., and G. B. Huffnagle. 2005. Immune regulation during allergic bronchopulmonary mycosis: lessons taught by two fungi. Immunol. Res. 33:53-68.[CrossRef][Medline] |
| 2. | Banerjee, U., K. Datta, T. Majumdar, and K. Gupta. 2001. Cryptococcosis in India: the awakening of a giant? Med. Mycol. 39:51-67.[Medline] |
| 3. | Berger, M., T. M. Norvell, M. F. Tosi, S. N. Emancipator, M. W. Konstan, and J. R. Schreiber. 1994. Tissue-specific Fc gamma and complement receptor expression by alveolar macrophages determines relative importance of IgG and complement in promoting phagocytosis of Pseudomonas aeruginosa. Pediatr. Res. 35:68-77.[Medline] |
| 4. | Brown, E. J., K. A. Joiner, R. M. Cole, and M. Berger. 1983. Localization of complement component 3 on Streptococcus pneumoniae: anti-capsular antibody causes complement deposition on the pneumococcal capsule. Infect. Immun. 39:403-409. |
| 5. | Brown, J. S., T. Hussell, S. M. Gilliland, D. W. Holden, J. C. Paton, M. R. Ehrenstein, M. J. Walport, and M. Botto. 2002. The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice. Proc. Natl. Acad. Sci. USA 99:16969-16974. |
| 6. | Bryan, R. A., O. Zaragoza, T. Zhang, G. Ortiz, A. Casadevall, and E. Dadachova. 2005. Radiological studies reveal radial differences in the architecture of the polysaccharide capsule of Cryptococcus neoformans. Eukaryot. Cell 4:465-475. |
| 7. | Casadevall, A., and J. R. Perfect (ed.). 1998. Cryptococcus neoformans, p. 407-457. American Society for Microbiology, Washington, D.C. |
| 8. | Casadevall, A., and L. Pirofski. 2005. Insights into mechanisms of antibody-mediated immunity from studies with Cryptococcus neoformans. Curr. Mol. Med. 5:421-433.[CrossRef][Medline] |
| 9. | Casadevall, A., and L. A. Pirofski. 2005. Feasibility and prospects for a vaccine to prevent cryptococcosis. Med. Mycol. 43:667-680.[CrossRef][Medline] |
| 10. | Clynes, R., J. S. Maizes, R. Guinamard, M. Ono, T. Takai, and J. V. Ravetch. 1999. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J. Exp. Med. 189:179-185. |
| 11. | Currie, B. P., and A. Casadevall. 1994. Estimation of the prevalence of cryptococcal infection among patients infected with the human immunodeficiency virus in New York City. Clin. Infect. Dis. 19:1029-1033.[Medline] |
| 12. | Datta, K., and L. Pirofski. 2006. Towards a vaccine for Cryptococcus neoformans: principles and caveats. FEMS Yeast Res. [Online.] doi 10.1111/j.1567-1364.2006.00073.x. |
| 13. | Dodds, A. W., and S. K. Law. 1990. The complement component C4 of mammals. Biochem. J. 265:495-502.[Medline] |
| 14. | Drouin, S. M., M. Sinha, G. Sfyroera, J. D. Lambris, and R. A. Wetsel. 26 January 2006. A protective role for the fifth complement component (C5) in allergic airway disease. Am. J. Respir. Crit. Care Med. [Epub ahead of print.] |
| 15. | Ebanks, R. O., and D. E. Isenman. 1996. Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity. Mol. Immunol. 33:297-309.[CrossRef][Medline] |
| 16. | Einsiedel, L., D. L. Gordon, and J. R. Dyer. 2004. Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman. Clin. Infect. Dis. 39:e78-e82.[CrossRef][Medline] |
| 17. | Ellerbroek, P. M., A. M. Walenkamp, A. I. Hoepelman, and F. E. Coenjaerts. 2004. Effects of the capsular polysaccharides of Cryptococcus neoformans on phagocyte migration and inflammatory mediators. Curr. Med. Chem. 11:253-266.[CrossRef][Medline] |
| 18. | Fattom, A. I., J. Sarwar, L. Basham, S. Ennifar, and R. Naso. 1998. Antigenic determinants of Staphylococcus aureus type 5 and type 8 capsular polysaccharide vaccines. Infect. Immun. 66:4588-4592. |
| 19. | Feldmesser, M., Y. Kress, P. Novikoff, and A. Casadevall. 2000. Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection. Infect. Immun. 68:4225-4237. |
| 20. | Fleuridor, R., R. H. Lyles, and L. Pirofski. 1999. Quantitative and qualitative differences in the serum antibody profiles of HIV-infected persons with and without Cryptococcus neoformans meningitis. J. Infect. Dis. 180:1526-1536.[CrossRef][Medline] |
| 21. | Fries, B. C., C. P. Taborda, E. Serfass, and A. Casadevall. 2001. Phenotypic switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection. J. Clin. Investig. 108:1639-1648.[CrossRef][Medline] |
| 22. | Garcia-Hermoso, D., F. Dromer, and G. Janbon. 2004. Cryptococcus neoformans capsule structure evolution in vitro and during murine infection. Infect. Immun. 72:3359-3365. |
| 23. | Gates, M. A., P. Thorkildson, and T. R. Kozel. 2004. Molecular architecture of the Cryptococcus neoformans capsule. Mol. Microbiol. 52:13-24.[CrossRef][Medline] |
| 23a. | Gates, M. A., and T. R. Kozel. 2006. Differential localization of complement component 3 within the capsular matrix of Cryptococcus neoformans. Infect. Immun. 74:3096-3106. |
| 24. | Goldman, D. L., H. Khine, J. Abadi, D. L. Lindenberg, L. Pirofski, R. Niang, and A. Casadevall. 2001. Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 107:e66. |
| 25. | Goldman, D. L., S. C. Lee, A. J. Mednick, L. Montella, and A. Casadevall. 2000. Persistent Cryptococcus neoformans pulmonary infection in the rat is associated with intracellular parasitism, decreased inducible nitric oxide synthase expression, and altered antibody responsiveness to cryptococcal polysaccharide. Infect. Immun. 68:832-838. |
| 26. | Husain, S., M. M. Wagener, and N. Singh. 2001. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg. Infect. Dis. 7:375-381.[Medline] |
| 27. | Janssen, B. J., E. G. Huizinga, H. C. Raaijmakers, A. Roos, M. R. Daha, K. Nilsson-Ekdahl, B. Nilsson, and P. Gros. 2005. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437:505-511.[CrossRef][Medline] |
| 28. | Kozel, T. R., B. C. deJong, M. M. Grinsell, R. S. MacGill, and K. K. Wall. 1998. Characterization of anticapsular monoclonal antibodies that regulate activation of the complement system by the Cryptococcus neoformans capsule. Infect. Immun. 66:1538-1546. |
| 29. | Kozel, T. R., B. A. Highison, and C. J. Stratton. 1984. Localization on encapsulated Cryptococcus neoformans of serum components opsonic for phagocytosis by macrophages and neutrophils. Infect. Immun. 43:574-579. |
| 30. | Kozel, T. R., S. M. Levitz, F. Dromer, M. A. Gates, P. Thorkildson, and G. Janbon. 2003. Antigenic and biological characteristics of mutant strains of Cryptococcus neoformans lacking capsular O acetylation or xylosyl side chains. Infect. Immun. 71:2868-2875. |
| 31. | Kozel, T. R., R. S. MacGill, A. Percival, and Q. Zhou. 2004. Biological activities of naturally occurring antibodies reactive with Candida albicans mannan. Infect. Immun. 72:209-218. |
| 32. | Kozel, T. R., G. S. Pfrommer, A. S. Guerlain, B. A. Highison, and G. J. Highison. 1988. Strain variation in phagocytosis of Cryptococcus neoformans: dissociation of susceptibility to phagocytosis from activation and binding of opsonic fragments of C3. Infect. Immun. 56:2794-2800. |
| 33. | Kozel, T. R., M. A. Wilson, and J. W. Murphy. 1991. Early events in initiation of alternative complement pathway activation by the capsule of Cryptococcus neoformans. Infect. Immun. 59:3101-3110. |
| 34. | Kozel, T. R., M. A. Wilson, G. S. Pfrommer, and A. M. Schlageter. 1989. Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins. Infect. Immun. 57:1922-1927. |
| 35. | Kozlowski, L. M., A. M. Soulika, G. J. Silverman, J. D. Lambris, and A. I. Levinson. 1996. Complement activation by a B cell superantigen. J. Immunol. 157:1200-1206.[Abstract] |
| 36. | Lamping, N., R. R. Schumann, and R. Burger. 2000. Detection of two variants of complement component C3 in C3-deficient guinea pigs distinguished by the absence and presence of a thiolester. Mol. Immunol. 37:333-341.[CrossRef][Medline] |
| 37. | Lane, C. H., H. Masur, L. C. Edgar, G. Whalen, A. H. Rook, and A. S. Fauci. 1983. Abnormalities of B cell activation and immunoregulation in patients with AIDS. N. Engl. J. Med. 309:453-458.[Abstract] |
| 38. | Laxalt, K. A., and T. R. Kozel. 1979. Chemotaxigenesis and activation of the alternative complement pathway by encapsulated and non-encapsulated Cryptococcus neoformans. Infect. Immun. 26:435-440. |
| 39. | Levitz, S. M. 1991. The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. Rev. Infect. Dis. 13:1163-1169.[Medline] |
| 40. | Lewis, A. L., V. Nizet, and A. Varki. 2004. Discovery and characterization of sialic acid O-acetylation in group B Streptococcus. Proc. Natl. Acad. Sci. USA 101:11123-11128. |
| 41. | Lynch, D. M., P. H. Kay, J. M. Papadimitriou, and M. D. Grounds. 1993. Studies on the structure of complement C3 and the stability of C3 derived phagocytic ligands C3b/iC3b in SJL/J and BALB/c mice. Eur. J. Immunogenet. 20:1-9.[Medline] |
| 42. | Macher, A. M., J. E. Bennett, J. D. Gadek, and M. M. Frank. 1978. Complement depletion in cryptococcal sepsis. J. Immunol. 120:1686-1690. |
| 43. | Marques, M. B., D. L. Kasper, M. K. Pangburn, and M. R. Wessels. 1992. Prevention of C3 deposition by capsular polysaccharide is a virulence mechanism of type III group B streptococci. Infect. Immun. 60:3986-3993. |
| 44. | McClelland, E. E., P. Bernhardt, and A. Casadevall. 2006. Estimating the relative contributions of virulence factors for pathogenic microbes. Infect. Immun. 74:1500-1504. |
| 45. | McFadden, D. C., M. De Jesus, and A. Casadevall. 2006. The physical properties of the capsular polysaccharides from Cryptococcus neoformans suggest features for capsule construction. J. Biol. Chem. 281:1868-1875. |
| 46. | Murphy, J. W. 1999. Immunological down-regulation of host defenses in fungal infections. Mycoses 42(Suppl. 2):37-43.[CrossRef][Medline] |
| 47. | Netski, D., and T. R. Kozel. 2002. Fc-dependent and Fc-independent opsonization of Cryptococcus neoformans by anticapsular monoclonal antibodies: importance of epitope specificity. Infect. Immun. 70:2812-2819. |
| 48. | Peterson, P. K., Y. Kim, B. J. Wilkinson, D. Schmeling, A. F. Michael, and P. G. Quie. 1978. Dichotomy between opsonization and serum complement activation by encapsulated staphylococci. Infect. Immun. 20:770-775. |
| 49. | Pirofski, L. 2001. Polysaccharides, mimotopes and vaccines for encapsulated pathogens. Trends Microbiol. 9:445-452.[CrossRef][Medline] |
| 50. | Pirofski, L.-A., and A. Casadevall. 1998. Use of licensed vaccines for active immunization of the immunocompromised host. Clin. Microbiol. Rev. 11:1-26. |
| 51. | Rhodes, J. C. 1985. Contribution of complement component C5 to the pathogenesis of experimental murine cryptococcosis. Sabouraudia 23:225-234.[Medline] |
| 52. | Rivera, J., M. Feldmesser, M. Cammer, and A. Casadevall. 1998. Organ-dependent variation of capsule thickness in Cryptococcus neoformans during experimental murine infection. Infect. Immun. 66:5027-5030. |
| 53. | Rivera, J., J. Mukherjee, L. M. Weiss, and A. Casadevall. 2002. Antibody efficacy in murine pulmonary Cryptococcus neoformans infection: a role for nitric oxide. J. Immunol. 168:3419-3427. |
| 54. | Samuelsson, A., T. L. Towers, and J. V. Ravetch. 2001. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484-486. |
| 55. | Schlesinger, L. S., and M. A. Horwitz. 1994. A role for natural antibody in the pathogenesis of leprosy: antibody in nonimmune serum mediates C3 fixation to the Mycobacterium leprae surface and hence phagocytosis by human mononuclear phagocytes. Infect. Immun. 62:280-289. |
| 56. | Shao, X., A. Mednick, M. Alvarez, N. van Rooijen, A. Casadevall, and D. L. Goldman. 2005. An innate immune system cell is a major determinant of species-related susceptibility differences to fungal pneumonia. J. Immunol. 175:3244-3251. |
| 57. | Shapiro, S., D. O. Beenhouwer, M. Feldmesser, C. Taborda, M. C. Carroll, A. Casadevall, and M. D. Scharff. 2002. Immunoglobulin G monoclonal antibodies to Cryptococcus neoformans protect mice deficient in complement component C3. Infect. Immun. 70:2598-2604. |
| 58. | Sharma, V., M. Chatterjee, G. Sen, C. A. Kumar, and C. Mandal. 2000. Role of linkage specific 9-O-acetylated sialoglycoconjugates in activation of the alternate complement pathway in mammalian erythrocytes. Glycoconj. J. 17:887-893.[CrossRef][Medline] |
| 59. | Shelburne, S. A., F. Visnegarwala, J. Darcourt, E. A. Graviss, T. P. Giordano, A. C. White, Jr., and R. J. Hamill. 2005. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19:399-406.[Medline] |
| 60. | Singh, N., O. Lortholary, B. D. Alexander, K. L. Gupta, G. T. John, K. Pursell, P. Munoz, G. B. Klintmalm, V. Stosor, R. del Busto, A. P. Limaye, J. Somani, M. Lyon, S. Houston, A. A. House, T. L. Pruett, S. Orloff, A. Humar, L. Dowdy, J. Garcia-Diaz, A. C. Kalil, R. A. Fisher, and S. Husain. 2005. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin. Infect. Dis. 40:1756-1761.[CrossRef][Medline] |
| 61. | Subramaniam, K., N. French, and L.-A. Pirofski. 2005. Cryptococcus neoformans-reactive and total immunoglobulin profiles of human immunodeficiency virus-infected and uninfected Ugandans. Clin. Diagn. Lab. Immunol. 12:1168-1176. |
| 62. | Taborda, C. P., and A. Casadevall. 2002. CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are involved in complement-independent antibody-mediated phagocytosis of Cryptococcus neoformans. Immunity 16:791-802.[CrossRef][Medline] |
| 63. | Torres, M., R. May, M. D. Scharff, and A. Casadevall. 2005. Variable-region-identical antibodies differing in isotype demonstrate differences in fine specificity and idiotype. J. Immunol. 174:2132-2142. |
| 64. | Tucker, S. C., and A. Casadevall. 2002. Replication of Cryptococcus neoformans in macrophages is accompanied by phagosomal permeabilization and accumulation of vesicles containing polysaccharide in the cytoplasm. Proc. Natl. Acad. Sci. USA 99:3165-3170. |
| 65. | Varki, A., and S. Kornfeld. 1980. An autosomal dominant gene regulates the extent of 9-O-acetylation of murine erythrocyte sialic acids. A probable explanation for the variation in capacity to activate the human alternate complement pathway. J. Exp. Med. 152:532-544. |
| 66. | Vecchiarelli, A. 2005. The cellular responses induced by the capsular polysaccharide of Cryptococcus neoformans differ depending on the presence or absence of specific protective antibodies. Curr. Mol. Med. 5:413-420.[CrossRef][Medline] |
| 67. | Washburn, R. G., B. J. Bryant-Varela, N. C. Julian, and J. E. Bennett. 1991. Differences in Cryptococcus neoformans capsular polysaccharide structure influence assembly of alternative complement pathway C3 convertase on fungal surfaces. Mol. Immunol. 28:465-470.[CrossRef][Medline] |
| 68. | Wilkinson, B. J., S. P. Sisson, Y. Kim, and P. K. Peterson. 1979. Localization of the third component of complement on the cell wall of encapsulated Staphylococcus aureus M: implications for the mechanism of resistance to phagocytosis. Infect. Immun. 26:1159-1163. |
| 69. | Wills-Karp, M., and J. Koehl. 2005. New insights into the role of the complement pathway in allergy and asthma. Curr. Allergy Asthma Rep. 5:362-369.[Medline] |
| 70. | Wilson, M. A., and T. R. Kozel. 1992. Contribution of antibody in normal human serum to early deposition of C3 onto encapsulated and nonencapsulated Cryptococcus neoformans. Infect. Immun. 60:754-761. |
| 71. | Young, B. J., and T. R. Kozel. 1993. Effects of strain variation, serotype, and structural modification on kinetics for activation and binding of C3 to Cryptococcus neoformans. Infect. Immun. 61:2966-2972. |
| 72. | Zaragoza, O., C. P. Taborda, and A. Casadevall. 2003. The efficacy of complement-mediated phagocytosis of Cryptococcus neoformans is dependent on the location of C3 in the polysaccharide capsule and involves both direct and indirect C3-mediated interactions. Eur. J. Immunol. 33:1957-1967.[CrossRef][Medline] |
| 73. | Zaragoza, O., A. Telzak, R. A. Bryan, E. Dadachova, and A. Casadevall. 2006. The polysaccharide capsule of the pathogenic fungus Cryptococcus neoformans enlarges by distal growth and is rearranged during budding. Mol. Microbiol. 59:67-83.[CrossRef][Medline] |
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