Fungal morphogenesis and virulence

Medical Mycolo gy 2000, 38, Supplement 1, 79– 86 Fungal morphogenesis and virulence Phenotypic variability in pathogenic fungi has long been correlated with virulence, but speciŽc genetic and molecular mechanisms are only recently being unraveled. Fungal morphogenesis, reecting the expression of several regulated genes, and the capacity of the rising forms or phases to cause disease has been focused on at the XIVth Congress of the International Society for Human and Animal Mycology. Three experimental models of pathogenic fungi have been discussed. In Cryptococcus neoformans, phenotypic variability or switching represents controlled and programmed changes rather than random mutations. Evaluated phenotypic traits were the capsular polysaccharide, cell and colony morphology and virulence. In the dimorphic Paracoccidioides brasiliensis, the serine-thiol proteinase from the yeast phase cleaves the main components of the basal membrane, thus being potentially relevant in fungal dissemination. In Candida albicans, relationships between adhesion proteins and those of lymphocytes and neutrophils are related to fungal pathogenicity. Regulation of the directional growth of hyphae and its tropic responses are correlated with the invasive potential of C. albicans. Keywords Candida albicans, Cryptococcus neoformans, Paracoccidioides brasiliensis, virulence Introduction Morphogenesis and phenotypic switching permit fungi to adapt to live in different microenvironments, and to survive in the infected host. Mechanisms have been established in several instances. The ability of Candida albicans to form hyphae is considered a virulence factor [1,2]. The properties of an apically growing hypha confer the ability Correspondence: G. San-Blas, Instituto Venezolano de Investigaciones Cientõ´Žcas (IVIC), Centro de Microbiologõ´a y Biologõ´a Celular, Apartado 21827, Caracas 1020A, Venezuela. Tel: » 58 2 5041496; fax: » 58 2 5041382; e-mail: © 2000 ISHAM to penetrate the host tissues and escape phagocytosis by macrophages [1– 3]. Dimorphic fungi elaborate a morphological phase more suitable for the progression of infection. The infective form produces adherence factors and exoenzymes for initial Žxation, growth and mobility in host tissues. Phenotypic switching in pathogens changes antigenic surface molecules [4], controls the expression of the capsule that determines the commensal or invasive nature of the pathogen [5], and allows host changes essential for their life cycles [6]. The present summary provides representative examples of morphogenesis and virulence, centering on the pathogenic fungi Cryptococcus neoformans, Paracoccidioides brasiliensis and C. albicans. G. SAN-BLAS*, L. R. TRAVASSOS² , B. C. FRIES³ , D. L. GOLDMAN³ , A. CASADEVALL³ , A. K. CARMONA§, T. F. BARROS² , R. PUCCIA² , M. K. HOSTETTER$, S. G. SHANKS¶, V. M. S. COPPING¶, Y. KNOX¶ & N. A. R. GOW¶ *Instituto V enezo lano de Investigaciones C ientṍŽcas, C entro de Microbiologiá y Biologṍá C elular , A partado 21827, C aracas 1020A , V enezuela; ² Universidade Federal de São Paulo , Disciplina de Biologia C elular , São Paulo , SP 04023 -062, Brazil; ³ A lbert Einstein C ollege of Medicine, Bronx, NY , USA ; §Departamento de Biofṍsica, São Paulo , SP 04023 -062, Brazil; $Yale University Scho ol of Medicine, New Haven, C T , USA ; ¶University of A berdeen , Department of Mo lecular and C ell Biology , A berdeen , UK 80 San Bias et al. Cryptococcus neoform ans T he SB4 and 24067A pheno typic switching system of C. neoformans Phenotypic switching has been described in strains J32 (serotype A), S134 (serotype A) and 24067A (serotype D). In the last two [12,13], phenotype instability was observed after prolonged in ×itro passage. SB4 undergoes reversible phenotypic switching from smooth (S) to serrated (C) or wrinkled (W) colony type. 24067A switches between smooth (SM), wrinkled (WR) or pseudohyphal (PH) colony types (Fig. 1). They arise spontaneously at a frequency of 1 in 10 ¼ 4 – 10 ¼ 5 and reversion to the parent S type occurs at a variable frequency (approximately 1 in 10 ¼ 3 – 10 ¼ 5 ). Alterations of the surface properties of the ‘switched’ colony types lead to increased adhesion to agar surface and occulence in liquid broth. W and WR cells have larger capsules than the smooth parent strain. PH cells have elongated cells with pseudohyphal protrusions and thin capsule. Contrary to other fungi, in C. neofor mans pseudohyphal cell morphology has been only occasionally observed in tissue and autopsy specimens [14] and more speciŽcally, in cocultivation with Acantha moeba polyphaga [15]. Differ ences in virulence In both SB4 and 24067A, phenotypic switching can augment virulence in animal models. In SB4, the W-colony is more virulent than the S- and C-colonies, presumably because it elicits a less organized inammatory response that fails to contain the infection [11]. The 24067A strain is usually unable to infect animal models [15]. Phenotypic switching to a WR-colony type, however, results in fungal persistence, and local inammatory responses possibly potentiated by an altered GXM. The PH- and C-colony type exhibit an intermediate virulence correlated with an intermediate tissue response. For SB4, the immune response to infection with each colony phenotype was associated with different antibody responses to cryptococcal proteins in rats. A nalysis of G XM structure GXM constitutes the main capsular polysaccharide and is composed of a (1 –4)-linked linear a-D -mannopyranan with xylose (at the 2-O and 4-O positions) and glucuronic acid residues (2-O position only) linked at various positions. Six different structure GXM reporter groups (structure reported group [SRG] M1-M6) (Fig. 2) correlate with differences in serotype (A– D) [16,17]. The GXMs of the WR and C colony type are composed of mixtures of SRGs involving linkage of a xylose residue at the 4-O position (M1:M5 for WR and M2:M3 for C). Reversion to a SM phenotype results in a GXM lacking these 4-O linked residues. The addition of a xylose group at the 4-O position in the C colony type of SB4 results in Fig. 1 (a) The colony types of C. neoformans strain SB4. S, smooth; C, serrated; W, wrinkled. (b) Colony types of C. neoformans strain 24067. SM, smooth; WR, wrinkled; PH, pseudohyphal; RSM, reverted smooth. © 2000 ISHAM, Medical Mycology, 38, Suppl. 1, 79–86 C. neoformans is an encapsulated pathogenic yeast that can cause disease in healthy and immunocompromised individuals, developing an often fatal meningoencephalitis [7]. It causes persistent infection, despite antifungal therapy, probably due to rapid changes (microevolution) undergone during chronic infection. Phenotypic variations are seen both in ×i×o and in ×itro. Differences in the glucuronoxylomannan (GXM) capsular structure [8], membrane sterol content [9], virulence ability [10] and karyotype [11] are some examples of changes that occur during chronic infection. a mix of M2 and (...truncated)