Establishment of protective immunity against cerebral cryptococcosis by means of an avirulent, non melanogenic Cryptococcus neoformans strain

Barluzzi, Roberta; Brozzetti, Annalisa; Mariucci, Giuseppina; Tantucci, Michela; Neglia, Rachele Giovanna; Bistoni, Francesco; Blasi, Elisabetta

doi:10.1016/s0165-5728(00)00319-2

Cited by 32 publications

(29 citation statements)

References 41 publications

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“…These studies specifically redefine the role of laccase in virulence. Previous studies have compared cryptococcal strains with differences in the ability to melanize (2,15,31). The presumption that the mutations in these strains were specific to laccase may need to be reexamined.…”

Section: Discussionmentioning

confidence: 99%

“…Once in the bloodstream, urease appears to facilitate entry into the CNS (24a). The fact that CNLAC1-deficient cells can grow in the CNS but albino mutants cannot (2) suggests that unknown virulence factors (that are regulated along with CNLAC1) play a role in the neurotropism of C. neoformans. Thus, C. neofor- mans produces a number of factors that function in a stepwise fashion as site-specific virulence factors to promote the dissemination and virulence of this microbe after inhalation.…”

Section: Discussionmentioning

confidence: 99%

“…These studies used laccase high-and low-producing strains, limiting definitive conclusions on the role of CNLAC1 in vivo. In addition, other studies investigating the role of melanin and/or laccase in pathogenesis have used albino mutants that may contain mutations in regulatory genes that control melanization (2,15,31). To specifically investigate the role of CNLAC1, a set of congenic mutants of C. neoformans differing only in CNLAC1 production (2E-TU-4/2E-TUC-4) was used for the present study.…”

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CNLAC1Is Required for Extrapulmonary Dissemination ofCryptococcus neoformansbut Not Pulmonary Persistence

et al. 2004

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The pathogenic yeast Cryptococcus neoformans produces a laccase enzyme (CNLAC1), which catalyzes the synthesis of melanin in the presence of phenolic compounds. A number of genes have been implicated in the regulation of laccase and melanization, including IPC1, GPA1, MET3, and STE12. Albino mutants derived from random mutagenesis techniques may contain mutations in genes that regulate multiple virulence factors, including CNLAC1. The goal of our study is to investigate the role of CNLAC1 in virulence and evasion of pulmonary host defenses after infection via the respiratory tract. Using a set of congenic laccase-positive (2E-TUC-4) and laccase-deficient (2E-TU-4) strains, we found that both strains are avirulent at a lower dose (10 4 CFU/mouse) in mice. After the infectious dose was increased to 10 6 CFU/mouse, 70% mortality was observed in mice infected with 2E-TUC-4 compared to no mortality in mice infected with 2E-TU-4 at day 30 postinfection. This observation confirms the requirement for CNLAC1 in virulence. Interestingly, we observed no differences between the two strains in pulmonary growth or in elicitation of cellular immune responses in the lung. The only measurable defect of 2E-TU-4 was in dissemination to extrapulmonary sites. To examine the role of CNLAC1 in dissemination, mice were infected intravenously. By week 3 postinfection, equal numbers of strains 2E-TUC-4 and 2E-TU-4 were recovered from the brain and spleen. This observation indicates that CNLAC1 facilitates escape from the lung, but not growth in the lungs or brain, and suggests a novel role for CNLAC1 in virulence during an infection aquired via the respiratory tract.Cryptococcus neoformans is an opportunistic pathogenic yeast acquired via the respiratory tract. Clearance of a pulmonary infection requires the development of adaptive immunity. In immunocompromised hosts, C. neoformans can disseminate to extra-pulmonary sites, particularly the central nervous system (CNS), where infection can lead to fatal meningitis. C. neoformans produces a number of factors that are required for virulence, including growth at 37°C (13), the presence of polysaccharide capsule (5), urease (9), phospholipase B (7), and laccase (31,33,39).C. neoformans produces a phenoloxidase, or laccase (encoded by the CNLAC1 gene), that catalyzes melanin production from an exogenous diphenolic or indolic substrate (catecholamine, epinephrine, L-dopa, dopamine, and caffeic acid) (26). The resulting heterogeneous pigment is covalently linked to the cell wall (42). In addition to melanin, a variety of potentially toxic by-products are produced by laccase. Both melanin and laccase by-products have been detected in vivo (19,23). Therefore, multiple products of the laccase pathway likely play a role in virulence.In vitro studies have identified a number of possible molecular mechanisms for the role of laccase during pathogenesis. Melanin provides increased resistance to antifungal drugs (37), antibody-mediated phagocytosis (36), and defensins (10), and it is an antioxidant both...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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CNLAC1Is Required for Extrapulmonary Dissemination ofCryptococcus neoformansbut Not Pulmonary Persistence

et al. 2004

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“…For example, mannoprotein from acapsular strains and nonmelanogenic C. neoformans strains promotes Th1 responses that coincide with increased antifungal activity of effector cells (5,41,52). Experimental studies with different host genetic backgrounds showed that this also influences T helper cell differentiation (20,47).…”

Section: Discussionmentioning

confidence: 99%

Cytokine and Inducible Nitric Oxide Synthase mRNA Expression during Experimental Murine Cryptococcal Meningoencephalitis

et al. 2004

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The immune events that take place in the central nervous system (CNS) during cryptococcal infection are incompletely understood. We used competitive reverse transcription-PCR to delineate the time course of the local expression of mRNAs encoding a variety of cytokines and inducible nitric oxide synthase (iNOS) during progressive murine cryptococcal meningoencephalitis and assessed the CNS inflammatory response using immunohistochemistry. Interleukin 18 (IL-18), transforming growth factor ␤1, and IL-12p 40 mRNAs were constitutively expressed in the brains of infected and uninfected mice; IL-2 mRNA was not detected at any time. Increased levels of transcripts corresponding to IL-1␣, tumor necrosis factor alpha (TNF-␣), and iNOS were detected as early as day 1 postinfection, with TNF-␣ rising by ϳ30-fold and iNOS increasing by ϳ5-fold by day 7. Each remained at these levels thereafter. IL-4, IL-6, and gamma interferon transcripts were detected on day 5, and IL-1␤ and IL-10 transcripts were detected beginning on day 7. Once detected, each remained at a relatively constant level through 28 days of infection. This cytokine profile does not suggest a polarized Th1 or Th2 response. Immunohistochemistry did not reveal inflammatory infiltrates before day 7, despite the presence of cryptococci. Intraparenchymal abscesses with inflammatory cells in their peripheries were found beginning on day 10. The infiltrates were comprised primarily of cells expressing CD4, CD8, or CD11b; low numbers of cells expressing CD45R/B220 were also present. The persistence of Cryptococcus observed in the CNS may result from an ineffective immune response, perhaps owing to an insufficient anticryptococcal effector function of endogenous glial cells resulting from competing pro-and anti-inflammatory cytokines. These data detail the immune response in the brain and could be important for the future design of specific immunomodulatory therapies for this important opportunistic infection.

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“…The activation of caspase-1 is largely mediated by a cellular complex called inflammasome, which contains cytoplasmic PRRs such as NLRP3, NLRC4 or AIM2, adaptor protein ASC in most cases and pro-caspase-1 [4]. As IL-1β production via the NLRP3 inflammasome has been proved to be essential in host defense against pathogenic Candida albicans and Aspergillus fumigatus infections, and IL-1β production was detected from C. neoformansinfected mice [5][6][7], we hypothesized that C. neoformans can also activate the NLRP3 inflammasome and the latter is important for the control of C. neoformans infection. Indeed, in the present study, we found that biofilm from a clinical strain of C. neoformans induced robust IL-1β production from both human monocytes and murine dendritic cells in a NLRP3-dependent manner, and the NLRP3 inflammasome was essential for protection against C. neoformans infection.…”

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confidence: 99%

Biofilm from a clinical strain of Cryptococcus neoformans activates the NLRP3 inflammasome

Lei

Chen

et al. 2013

Cell Res

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Establishment of protective immunity against cerebral cryptococcosis by means of an avirulent, non melanogenic Cryptococcus neoformans strain

Cited by 32 publications

References 41 publications

CNLAC1Is Required for Extrapulmonary Dissemination ofCryptococcus neoformansbut Not Pulmonary Persistence

CNLAC1Is Required for Extrapulmonary Dissemination ofCryptococcus neoformansbut Not Pulmonary Persistence

Cytokine and Inducible Nitric Oxide Synthase mRNA Expression during Experimental Murine Cryptococcal Meningoencephalitis

Biofilm from a clinical strain of Cryptococcus neoformans activates the NLRP3 inflammasome

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