Innate Immunity to Fungal Pathogens
In the last years, the increased of invasive fungal infections in humans, emerged associated with the lack of early diagnosis, effective antifungal therapies and vaccine development. Disturbances in immune homeostasis are well known as risk factors for acquiring these fungal infections. Our investigations are aimed to determine the pathogenic mechanisms and the molecular interactions between the opportunistic fungus Candida albicans, virulence factors and the host immune system. Due to its characteristics, Candida can infect different mucosal surfaces and in the invasive form of mycosis can invade several organs. In each biological niche, this pathogen can adapt and display a particular virulence factor profile and activate different mechanisms of response in the host. We employ different strategy of work such as: In Vivo models of infection using normal or genetically modified animals (Knock ut mice); In Vitro studies with murine and human cell lines and with C. albicans strains collection, clinical isolates from patients and strains of the fungus with spontaneous or induced mutations. In our laboratory we carry out different research lines that allow it study:
. Vulvovaginal Candidiasis (VVC). C. albicans is the major causative agent of VVC, the incidence of this pathology is high and affects about 75% of women at least once in their life. There is another group of women, 5-10% who have a recurrent VVC (RVVC) defined by a frequency of at least 3 episodes a year. In our laboratory we have developed an animal model of VVC which reproduces the features of human pathology. Currently two topic are object of our investigations. For last years we have been studying the antimicrobial peptides of the β-defensin family and their contribution to the pathogenesis of Candida vaginal infection. Recently, we have begun to explore the role of classically molecules involved in the antiviral response, such as Type I Interferons, during the development and progression of VVC.
. Candidiasis of the Central Nervous System. C. albicans is a common component of oral, gastrointestinal and genital tracts of man, and from these primary niches can spread and invade different organs, including Central Nervous System (CNS). More than 40% of patients who die from systemic candidiasis, present C. albicans invasion in CNS. In addition to the lesions characteristic of Neurocandidiasis, this fungus is considered responsible for various neurological manifestations, mental retardation and psychomotor difficulties in the neonates. Little is known about the role of innate immunity receptors, their activation and the contribution of glial cells (astrocytes and microglia) during the course of Candida brain infection. Our research includes the study of the role of Dectin-1, NLRP3 inflammasome receptors and the activation of Caspase-1 dependent pathway in the early stages of infection in CNS.
. Antifungal agents. The therapeutic targets of classic antifungal agents are different molecules or metabolic pathways required for the survival of the pathogen. They have high toxicity and some of them induce resistance. Our studies explore the ability of antifungal agents to interact with innate immunity cells and modulate their functions.
TRANSLATIONAL RESEARCH LINES
. Acute and Recurrent Vulvovaginal Candidiasis (VVCR). While the acute form of VVC is easily resolved with antifungal therapy, RVVC is difficult to treat and several aspects of its pathogenesis remain unclear. This line of work includes the study of risk factors, predisposing causes, clinical features, types of treatment, time of evolution of the pathology and production of different immune mediators such as cytokines and antimicrobial peptides levels in the female genital tract of patients. In clinical isolates of the fungus we evaluate the production of virulence factors such as lipases, proteinases and biofilm forming capacity.
. Invasive Candidiasis. Candidemia is the most frequent invasive fungal infection in hospitalized patients worldwide. The term of invasive candidiasis includes candidemia and deep organ candidiasis. Our group aims to establish the clinical and epidemiological behaviour of candidemia in our environment, in order to give bases in recommendations to reduce the impact of this disease of a high mortality of 40%. This study also explores the fungus resistance patterns and one of its virulence factors most important such as the biofilm forming ability.
- Rodriguez-Galán MC, SG Correa , P Iribarren and C E Sotomayor. Phenotypic and functional changes on phagocytic cells recruited at the site of Candida albicans infection after chronic varied stress exposure. Medical Mycology 40: 485-492. 2002. ISSN 1369-3786. Francis and Taylor Group (*JRK: 0,90).
- Rodriguez-Galán MC , CE Sotomayor, ME Costamagna, AM Cabanillas, B Salido-Rentería, AM Masini-Repiso, and S Correa. Immunocompetence of macrophages in rats exposed to Candida albicans infection and stress. American Journal of Cell Physiol- Cell Physiol 284: 111-118. 2003. ISSN:0363-6143. High Wire Press. (*JRK: 0,91)
- Correa SG, Sotomayor CE, Aoki MP, Maldonado CA, and Rabinovich GA. Opposite effects of galectin-1 on alternative metabolic pathways of L-arginine in resident, inflammatory or activated macrophages. Glicobiology 13:1-10. 2003. ISSN: 0959-6658. Oxford University Press. (*JRK: 0,86).
- Correa SG, Rodriguez-Galán MC, Salido-Rentería B, Cano R, Cejas H and CE Sotomayor. High dissemination and hepatotoxicity in animals infected with Candida albicans : potential sensitization to liver damage after stress exposure. International Immunology. 16: 1761-8. 2004. ISSN 0953-8178 Oxford Journals (*JRK: 0,90).
- Assis MA, Collino C, Figuerola ML, Sotomayor CE and LM Cancela. Amphetamina triggers an increase in Met-enkephalin simultaneously in Brain and Immune Cells. Jounal of Neuroimmunology 178: 62-75. 2006. ISSN: 0165-5728. (*JRK: 0,80)
- Meragelman TL, Silva GL, Salido-Rentaría B, CE Sotomayor and R Gil. Modified Secoiridoid from Acicarpha tribuliodes and Inhibition of Nitric Oxide production in LPS-Activated Macrophages. Phytochemistry, 20: 1363-1369. 2006. ISSN: 0031-9422 (*JRK: 0,80).
- Renna MS, Correa SG, Porporatto C, Figueredo CM, Paraje MG, Aoki MP, and CE Sotomayor. Hepatocellular Apoptosis during C. albicans colonization: involvement of TNF-alpha and infiltrating Fas-L positive lymphocytes. International Immunology 18: 1719-1728. 2006. ISSN 0953-8178 Oxford Journals (*JRK: 0,90).
- Correa S G, Maccioni M, Rivero V, Iribarren P, Sotomayor CE and CM Riera. Cytokines and the immune –neuroendocrine network: what did we learn from infection and autoimmunity?. In Cytokines coming of age in South America, Cytokine and Growth Factor Reviews. 18: 125-134. 2007. ISSN: 1359-6101 ELSEVIER (*JRK: 0,92).
- Assis MA, AM Pacchioni, C Collino, MC Paz , Sotomayor CE, AM Basso and LM Cancela . A dopamine mechanism is implied in the acquisition and expression of amphetamine and stress-induced effects observed in the lymphocyte subpopulations. Eur J Pharmacol. 584: 405-414. 2008. ISSN: 0014-2999 ELSEVIER (**JRK: 0,95).
- Paraje MG, Correa SG, Renna MS, Theumer M and CE Sotomayor. Candida albicans-secreted lipase induces injury and steatosis in immune and parenchymal cells. Can J Microbiol. 54:647-59. 2008. ISSN: 0008-4166. (**JRK: 0,60).
- Paraje MG, Correa SG, Albesa I and Sotomayor CE. Lipase of Candida albicans induces activation of NADPH oxidase and L-arginine pathways on resting and activated macrophages. Bichemical and Biophysical Research Comunications ISSN: 0006-291X 2009. 390: 263-268. Elsevier (#JRK: 0,47).
- Rodriguez-Galán MC, C Porporatto, CE Sotomayor, R Cano, H Cejas and SG Correa. Immune-metabolic balance in stressed rats during Candida albicans infection. Stress 3: 373-83. 2010. ISSN 10253890. Informa Healthcare USA, Inc. (#JRK: 0,71)
- Rodríguez Galán MC, Sotomayor CE, Cano R, Porporatto C, Cejas H, Renna MS, Paraje MG and CS Correa. Immune Neuroendocrine Interactions during fungal infection in Immuno competentent or Immunosuppressed Hosts. Neuroimmunomodulation. 2010. 17:188-191.. ISSN: 1021-7401. Karger. (#JRK: 0,29)
- Arce Miranda JE, Sotomayor CE, Albesa I, Paraje MG Oxidative and nitrosative stress in Staphylococcus aureus biofilm. FEMS Microbiol Lett. 2011. 315: 23-27 ISSN: 1574-6968 (#JRK: 0,40)
- Assis MA, Valdomero A, García-Keller C, Sotomayor C, Cancela LM. Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels. Brain Behav Immun. 2011. 25: 647-567. ISSN: 0889-1591. ELSEVIER (#JRK: 0,86).
- Renna MS, Figueredo CM, Rodríguez-Galán MC, Icely PA, Peralta Ramos JM, Correa SG, Sotomayor CE. Abrogation of spontaneous liver tolerance during immune response to Candida albicans: contribution of NKT and hepatic mononuclear cells. Int Immunol. 2012. 24: 315-325. ISSN 0953-8178 Oxford Journals (#JRK: 0,65).
- Gonzaga de Freitas Araújo MG, Hilário F, Vilegas W, Dos Santos LC, Brunetti IL, Sotomayor CE, Bauab TM. Correlation among Antioxidant, Antimicrobial, Hemolytic, and Antiproliferative Properties of Leiothrix spiralis Leaves Extract. Int J Mol Sci 2012. 13: 9260-9277. doi: 10.3390/ ijms13079260. (#JRK: 0,69)
- Gonzaga de Freitas Araújo M; Pacífico M; Vilegas W; Campaner dos Santos L; Icely PA; Miró MS; Costa Scarpa MV, Bauab TM and CE Sotomayor. Evaluation of Syngonanthus nitens (Bong.) Ruhl. extract as antifungal and in treatment of vulvovaginal candidiasis. Medical Mycology 2013. 7: 673-682. ISSN 1460-2709. Oxford Journals. (#JRK: 0,90).
- García LN, Leimgruber C, Uribe Echevarría EM, Acosta PL, Brahamian JM, Polack FP, Miró MS, Quintar AA, Sotomayor CE, Maldonado CA. Protective phenotypes of club cells and alveolar macrophages are favored as part of endotoxin-mediated prevention of asthma. Exp Biol Med 2014 doi:10.1177/1535370214562338 (#JRK: 0,62)
- Renna MS, Figueredo CM, Rodriguez-Galán MC, Icely PA, Cejas H, Cano R, Correa SG and CE Sotomayor. Candida albicans up-regulates the Fas-L expression in liver Natural Killer and Natural Killer T cells. Immunobiology 2015 doi: 10.1016/j.imbio.2015.06.014 . (#JRK: 0,85)