Pathogenesis of invasive candidiasis

Veerdonk, Frank L. van de; Kullberg, Bart‐Jan; Netea, Mihai G.

doi:10.1097/mcc.0b013e32833e046e

Cited by 77 publications

(54 citation statements)

References 79 publications

(56 reference statements)

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“…Monocyte-dependent cytokines such as IL-1 and TNF-␣ are predominantly responsible for inflammation during disseminated candidiasis (28). Similarly, in vitro macrophage recognition and subsequent killing of C. albicans are mediated by proinflammatory cytokine production (29).…”

Section: Resultsmentioning

confidence: 99%

Distinct Roles of Candida albicans-Specific Genes in Host-Pathogen Interactions

et al. 2014

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Human fungal pathogens are distributed throughout their kingdom, suggesting that pathogenic potential evolved independently. Candida albicans is the most virulent member of the CUG clade of yeasts and a common cause of both superficial and invasive infections. We therefore hypothesized that C. albicans possesses distinct pathogenicity mechanisms. In silico genome subtraction and comparative transcriptional analysis identified a total of 65 C. albicans-specific genes (ASGs) expressed during infection. Phenotypic characterization of six ASG-null mutants demonstrated that these genes are dispensable for in vitro growth but play defined roles in host-pathogen interactions. Based on these analyses, we investigated two ASGs in greater detail. An orf19.6688⌬ mutant was found to be fully virulent in a mouse model of disseminated candidiasis and to induce higher levels of the proinflammatory cytokine interleukin-1␤ (IL-1␤) following incubation with murine macrophages. A pga16⌬ mutant, on the other hand, exhibited attenuated virulence. Moreover, we provide evidence that secondary filamentation events (multiple hyphae emerging from a mother cell and hyphal branching) contribute to pathogenicity: PGA16 deletion did not influence primary hypha formation or extension following contact with epithelial cells; however, multiple hyphae and hyphal branching were strongly reduced. Significantly, these hyphae failed to damage host cells as effectively as the multiple hypha structures formed by wild-type C. albicans cells. Together, our data show that species-specific genes of a eukaryotic pathogen can play important roles in pathogenicity.

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Section: Resultsmentioning

confidence: 99%

Distinct Roles of Candida albicans-Specific Genes in Host-Pathogen Interactions

et al. 2014

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“…New medical procedures, such as cancer chemotherapy or organ transplantation, that reduce host immunity allow C. albicans to escape normal physiological barriers and disseminate to deeper tissues. In addition, factors that permit the overgrowth of C. albicans, including the use of broad-spectrum antibacterial antibiotics or biofilm formation on catheters and indwelling medical devices, allow this fungus to infect immunocompetent individuals (5). Better antifungal therapies are needed to address this escalating problem (6).…”

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confidence: 99%

Protection from Systemic Candida albicans Infection by Inactivation of the Sts Phosphatases

et al. 2015

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The human fungal pathogen Candida albicans causes invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. The suppressor of TCR signaling 1 (Sts-1) and Sts-2 are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets. Functional inactivation of both Sts enzymes leads to profound resistance to systemic infection by C. albicans, such that greater than 80% of mice lacking Sts-1 and -2 survive a dose of C. albicans (2.5 ؋ 10 5 CFU/mouse) that is uniformly lethal to wild-type mice within 10 days. Restriction of fungal growth within the kidney occurs by 24 h postinfection in the mutant mice. This occurs without induction of a hyperinflammatory response, as evidenced by the decreased presence of leukocytes and inflammatory cytokines that normally accompany the antifungal immune response. Instead, the absence of the Sts phosphatases leads to the rapid induction of a unique immunological environment within the kidney, as indicated by the early induction of a proinflammatory cytokine (CXL10). Mice lacking either Sts enzyme individually display an intermediate lethality phenotype. These observations identify an opportunity to optimize host immune responses toward a deadly fungal pathogen.

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“…The transition from commensalism to parasitism requires a susceptible host, which includes individuals with humoral and/or cellular deficiencies as well as persons submitted to different immunosuppressive procedures. Candidiasis is the most common fungal infection diagnosed in humans [41][42][43] . Due to the emergence of pathogens resistant to conventional antifungals and the toxicity of some antimycotics, intense efforts have been made to develop more effective antifungal agents for clinical use [44][45][46][47][48] .…”

Section: Tripeptidyl Peptidases Dipeptidyl Peptidasesmentioning

confidence: 99%

Protease expression by microorganisms and its relevance to crucial physiological/pathological events

Santos¹

2011

WJBC

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The treatment of infections caused by fungi and trypanosomatids is difficult due to the eukaryotic nature of these microbial cells, which are similar in several biochemical and genetic aspects to host cells. Aggravating this scenario, very few antifungal and anti-trypanosomatidal agents are in clinical use and, therefore, therapy is limited by drug safety considerations and their narrow spectrum of activity, efficacy and resistance. The search for new bioactive agents against fungi and trypanosomatids has been expanded because progress in biochemistry and molecular biology has led to a better understanding of important and essential pathways in these microorganisms including nutrition, growth, proliferation, signaling, differentiation and death. In this context, proteolytic enzymes produced by these eukaryotic microorganisms are appointed and, in some cases, proven to be excellent targets for searching novel natural and/or synthetic pharmacological compounds, in order to cure or prevent invasive fungal/trypanosomatid diseases. With this task in mind, our research group and others have focused on aspartic-type proteases, since the activity of this class of hydrolytic enzymes is directly implicated in several facets of basic biological processes of both fungal and trypanosomatid cells as well as due to the participation in numerous events of interaction between these microorganisms and host structures. In the present paper, a concise revision of the beneficial effects of aspartic protease inhibitors, with emphasis on the aspartic protease inhibitors used in the anti-human immunodeficiency virus therapy, will be presented and discussed using our experience with the following microbial models: the yeast Candida albicans , the filamentous fungus Fonsecaea pedrosoi and the protozoan trypanosomatid Leishmania amazonensis .

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Pathogenesis of invasive candidiasis

Abstract: This knowledge provides the basis of exploring new treatment options in the fight against invasive candidiasis. Reports of beneficial effects of recombinant cytokine therapy in fungal infections, renders them prime candidates for adjuvant immunotherapy in Candida sepsis.

Cited by 77 publications

References 79 publications

Distinct Roles of Candida albicans-Specific Genes in Host-Pathogen Interactions

Distinct Roles of Candida albicans-Specific Genes in Host-Pathogen Interactions

Protection from Systemic Candida albicans Infection by Inactivation of the Sts Phosphatases

Protease expression by microorganisms and its relevance to crucial physiological/pathological events

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