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Fulltext Multi-step pathogenesis and induction of local immune response by systemic Candida albicans infection in an intravenous challenge mouse model

Chin VK, Foong KJ, Maha A, Rusliza B, Norhafizah M, Chong PP

Int J Mol Sci, 2014;15(8):14848-67.
PMID: 25153636 DOI: 10.3390/ijms150814848

Different murine species differ in their susceptibility to systemic infection with Candida albicans, giving rise to varied host immune responses, and this is compounded by variations in virulence of the different yeast strains used. Hence, this study was aimed at elucidating the pathogenesis of a clinical C. albicans isolate (HVS6360) in a murine intravenous challenge model by examining the different parameters which included the counts of red blood cells and associated components as well as the organ-specific expression profiles of cytokines and chemokines. Kidneys and brains of infected mice have higher fungal recovery rates as compared to other organs and there were extensive yeast infiltration with moderate to severe inflammation seen in kidney and brain tissues. Red blood cells (RBCs) and haemoglobin (Hb) counts were reduced throughout the infection period. Pattern recognition receptors (PRRs), chemokines and cytokine transcription profiles were varied among the different organs (kidney, spleen and brain) over 72 h post infections. Transcription of most of the PRRs, cytokines and chemokines were suppressed at 72 h post infection in spleen while continuous expression of PRRs, cytokines and chemokines genes were seen in brain and kidney. Reduction in red blood cells and haemoglobin counts might be associated with the action of extracellular haemolysin enzyme and haeme oxygenase of C. albicans in conjunction with iron scavenging for the fungal growth. Renal cells responsible for erythropoietin production may be injured by the infection and hence the combined effect of haemolysis plus lack of erythropoietin-induced RBC replenishment leads to aggravated reduction in RBC numbers. The varied local host immune profiles among target organs during systemic C. albicans infection could be of importance for future work in designing targeted immunotherapy through immunomodulatory approaches.

Matched MeSH terms: Candidiasis/immunology*
Identification of immunogenic proteins of Candida parapsilosis by serological proteome analysis

Lee PY, Gam LH, Yong VC, Rosli R, Ng KP, Chong PP

J Appl Microbiol, 2014 Apr;116(4):999-1009.
PMID: 24299471 DOI: 10.1111/jam.12408

Systemic candidiasis is the leading fungal bloodstream infection, and its incidence has been on the rise. Recently, Candida parapsilosis has emerged as an increasingly prevalent fungal pathogen, but little is known about its antigenic profile. Hence, the current work was performed to discover immunogenic proteins of C. parapsilosis using serological proteome analysis.

Matched MeSH terms: Candidiasis/immunology
Emerging Complexity and the Need for Advanced Drug Delivery in Targeting Candida Species

Wadhwa R, Pandey P, Gupta G, Aggarwal T, Kumar N, Mehta M, et al.

Curr Top Med Chem, 2019;19(28):2593-2609.
PMID: 31746290 DOI: 10.2174/1568026619666191026105308

BACKGROUND: Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence system utilizes a wide array of the cells, proteins and chemical signals that are distributed in blood and tissues which further constitute the innate and adaptive immune system. The lack of antifungal agents and their limited therapeutic effects have led to high mortality and morbidity related to such infections.
METHODS: The necessary information collated on this review has been gathered from various literature published from 1995 to 2019.
RESULTS: This article sheds light on novel drug delivery approaches to target the immunological axis for several Candida species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. rugose, C. hemulonii, etc.).
CONCLUSION: It is clear that the novel drug delivery approaches include vaccines, adoptive transfer of primed immune cells, recombinant cytokines, therapeutic antibodies, and nanoparticles, which have immunomodulatory effects. Such advancements in targeting various underpinning mechanisms using the concept of novel drug delivery will provide a new dimension to the fungal infection clinic particularly due to Candida species with improved patient compliance and lesser side effects. This advancement in knowledge can also be extended to target various other similar microbial species and infections.

Matched MeSH terms: Candidiasis/immunology
Dissecting Candida albicans Infection from the Perspective of C. albicans Virulence and Omics Approaches on Host-Pathogen Interaction: A Review

Chin VK, Lee TY, Rusliza B, Chong PP

Int J Mol Sci, 2016 Oct 18;17(10).
PMID: 27763544

Candida bloodstream infections remain the most frequent life-threatening fungal disease, with Candida albicans accounting for 70% to 80% of the Candida isolates recovered from infected patients. In nature, Candida species are part of the normal commensal flora in mammalian hosts. However, they can transform into pathogens once the host immune system is weakened or breached. More recently, mortality attributed to Candida infections has continued to increase due to both inherent and acquired drug resistance in Candida, the inefficacy of the available antifungal drugs, tedious diagnostic procedures, and a rising number of immunocompromised patients. Adoption of animal models, viz. minihosts, mice, and zebrafish, has brought us closer to unraveling the pathogenesis and complexity of Candida infection in human hosts, leading towards the discovery of biomarkers and identification of potential therapeutic agents. In addition, the advancement of omics technologies offers a holistic view of the Candida-host interaction in a non-targeted and non-biased manner. Hence, in this review, we seek to summarize past and present milestone findings on C. albicans virulence, adoption of animal models in the study of C. albicans infection, and the application of omics technologies in the study of Candida-host interaction. A profound understanding of the interaction between host defense and pathogenesis is imperative for better design of novel immunotherapeutic strategies in future.

Matched MeSH terms: Candidiasis/immunology
Immunoproteomic analysis of antibody response to cell wall-associated proteins of Candida tropicalis

Lee PY, Gam LH, Yong VC, Rosli R, Ng KP, Chong PP

J Appl Microbiol, 2014 Sep;117(3):854-65.
PMID: 24909754 DOI: 10.1111/jam.12562

This study was conducted to identify antigenic proteins of Candida tropicalis that are targeted by the host immune system.

Matched MeSH terms: Candidiasis/immunology
Candida parapsilosis-specific monoclonal antibodies and their use for detection of Candida antigens in experimental systemic candidiasis

Wong SF, Mak JW

Hybridoma (Larchmt), 2010 Dec;29(6):539-46.
PMID: 21117988 DOI: 10.1089/hyb.2010.0049

Candida parapsilosis has emerged as one of the most common causes of bloodstream infection worldwide. The diagnosis of invasive candidiasis etiological agents to the species level remains a laboratory and clinical challenge. Thus, specific monoclonal antibodies to detect systemic candidiasis and to identify Candida virulence factors and associated pathogenesis through immunohistochemistry would be very useful. Inbred Balb/c mice were immunized with C. parapsilosis antigens, and blood was checked for the presence of reactive antibodies using ELISA. Fusion was performed using the harvested spleen cells and NS1 myeloma cells, and the clones were screened for the presence of antibody producing hybrid cells by dot-blot. The 1B11 clone secreted IgG2a monoclonal antibody that was reactive with the C. parapsilosis antigen at MW of 59 kDa and cross-reacted with C. tropicalis but not with other fungal and bacterial antigens tested. Another 3D1 clone secreted IgG1 monoclonal antibody that was reactive with C. parapsilosis antigen at MW of 30 kDa. The 3D1 monoclonal antibody was found to be species specific. Experimental systemic candidiasis in rats was induced through intravenous injection of C. parapsilosis, and all the vital organs were collected for immunohistochemistry study. These monoclonal antibodies were reactive against surface epitopes on the yeast cells, pseudohyphae, and immune complexes in tissue sections. Sandwich ELISAs using these antibodies were developed and were able to detect circulating antigens in experimental candidiasis in rats at 0.2 μg/μL. These monoclonal antibodies may have potential as primary capture antibodies for the development of rapid diagnostic test for human systemic fungal infection.

Matched MeSH terms: Candidiasis/immunology
Fulltext Successful treatment of Candida albicans endocarditis in a child with leukemia--a case report and review of the literature

Ariffin H, Ariffin W, Tharam S, Omar A, de Bruyne J, Lin HP

Singapore Med J, 1999 Aug;40(8):533-6.
PMID: 10572495

Candida species is now being increasingly recognised as an important cause of endocarditis especially in immunocompromised patients. A case of Candida albicans endocarditis in a child with acute lymphoblastic leukemia (ALL) is reported. The child did not have a central venous catheter at any time. Treatment consisted of intravenous amphotericin B and fluconazole for 3 weeks followed by oral fluconazole for 2 weeks. No surgical resection was necessary. We highlight here the importance of echocardiography in the management of prolonged febrile neutropenia and discuss the dilemma of continuing chemotherapy in such patients.

Matched MeSH terms: Candidiasis/immunology
Fulltext Glyoxylate cycle gene ICL1 is essential for the metabolic flexibility and virulence of Candida glabrata

Chew SY, Ho KL, Cheah YK, Ng TS, Sandai D, Brown AJP, et al.

Sci Rep, 2019 02 26;9(1):2843.
PMID: 30808979 DOI: 10.1038/s41598-019-39117-1

The human fungal pathogen Candida glabrata appears to utilise unique stealth, evasion and persistence strategies in subverting the onslaught of host immune response during systemic infection. However, macrophages actively deprive the intracellular fungal pathogen of glucose, and therefore alternative carbon sources probably support the growth and survival of engulfed C. glabrata. The present study aimed to investigate the role of the glyoxylate cycle gene ICL1 in alternative carbon utilisation and its importance for the virulence of C. glabrata. The data showed that disruption of ICL1 rendered C. glabrata unable to utilise acetate, ethanol or oleic acid. In addition, C. glabrata icl1∆ cells displayed significantly reduced biofilm growth in the presence of several alternative carbon sources. It was also found that ICL1 is crucial for the survival of C. glabrata in response to macrophage engulfment. Disruption of ICL1 also conferred a severe attenuation in the virulence of C. glabrata in the mouse model of invasive candidiasis. In conclusion, a functional glyoxylate cycle is essential for C. glabrata to utilise certain alternative carbon sources in vitro and to display full virulence in vivo. This reinforces the view that antifungal drugs that target fungal Icl1 have potential for future therapeutic intervention.

Matched MeSH terms: Candidiasis/immunology