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Cryptococcus neoformans (CN) cells survive within the acidic phagolysosome of macrophages for extended times, then escape without impacting the viability of the host cell via a phenomenon that has been coined ‘vomocytosis’. Through this mechanism, CN disseminate throughout the body, sometimes resulting in a potentially fatal condition - Cryptococcal Meningitis (CM). Justifiably, vomocytosis studies have focused primarily on macrophages, as alveolar macrophages within the lung act as first responders that ultimately expel this fungal pathogen. Herein, we hypothesize that dendritic cells (DCs), an innate immune cell with attributes that include phagocytosis and antigen presentation, can also act as ‘vomocytes’. Presciently, this report shows that vomocytosis of CN indeed occurs from DCs. Primarily through time-lapse microscopy imaging, we show that rates of vomocytosis events from DCs are comparable to those seen from macrophages and further, are independent of the presence of the CN capsule and infection ratios. Moreover, phagosome-altering drugs such as chloroquine and bafilomycin A, as well as the actin-modifying drug, cytochalasin B inhibit this phenomenon from DCs. Although DC immunophenotype does not affect the total number of vomocytic events, we observed differences in the numbers of CN per phagosome and expulsion times. Interestingly, these observations were similar in primary, murine macrophages. Understanding the vomocytic behavior of different phagocytes and their phenotypic subtypes is needed to help elucidate the full picture of the dynamic interplay between CN and the immune system. Critically, deeper insight into vomocytosis could reveal novel approaches to treat CM, as well as other immune-related conditions.
Cryptococcus neoformans (CN) cells survive within the acidic phagolysosome of macrophages for extended times, then escape without impacting the viability of the host cell via a phenomenon that has been coined ‘vomocytosis’. Through this mechanism, CN disseminate throughout the body, sometimes resulting in a potentially fatal condition - Cryptococcal Meningitis (CM). Justifiably, vomocytosis studies have focused primarily on macrophages, as alveolar macrophages within the lung act as first responders that ultimately expel this fungal pathogen. Herein, we hypothesize that dendritic cells (DCs), an innate immune cell with attributes that include phagocytosis and antigen presentation, can also act as ‘vomocytes’. Presciently, this report shows that vomocytosis of CN indeed occurs from DCs. Primarily through time-lapse microscopy imaging, we show that rates of vomocytosis events from DCs are comparable to those seen from macrophages and further, are independent of the presence of the CN capsule and infection ratios. Moreover, phagosome-altering drugs such as chloroquine and bafilomycin A, as well as the actin-modifying drug, cytochalasin B inhibit this phenomenon from DCs. Although DC immunophenotype does not affect the total number of vomocytic events, we observed differences in the numbers of CN per phagosome and expulsion times. Interestingly, these observations were similar in primary, murine macrophages. Understanding the vomocytic behavior of different phagocytes and their phenotypic subtypes is needed to help elucidate the full picture of the dynamic interplay between CN and the immune system. Critically, deeper insight into vomocytosis could reveal novel approaches to treat CM, as well as other immune-related conditions.
A criptococose é uma micose sistêmica provocada por leveduras do gênero Cryptococcus, majoritariamente pelas espécies Cryptococcus neoformans e Cryptococcus gattii. As alternativas terapêuticas disponíveis atualmente para o tratamento da doença são escassas, possuem elevada toxicidade, alto custo e dificuldades de acesso. O reposicionamento de fármacos (RF), estratégia que consiste na pesquisa de novas aplicações terapêuticas para fármacos ou candidatos a fármacos, constitui uma abordagem promissora para a descoberta de novas alternativas para o tratamento da criptococose. Nesse sentido, o objetivo do presente trabalho consistiu na avaliação do potencial antifúngico de fármacos com estruturas privilegiadas (EP), subestruturas moleculares que possuem propriedades versáteis de interações com diferentes alvos biológicos, para o reposicionamento no tratamento da criptococose. Para tanto, foi criada uma biblioteca com 28 fármacos com EP que foi avaliada frente a linhagens de C. neoformans e C. gattii. Os fármacos albendazol (ALB), duloxetina (DUL), fembendazol (FEM), flubendazol (FLU), mebendazol (MEB) e paroxetina (PAR), apresentaram atividade anticriptocócica promissora, com concentração inibitória mínima (CIM) e concentração fungicida mínima (CFM) entre 0,047 µM e 100 µM. Quando avaliados em combinação com o fluconazol (FLZ) frente C. neoformans ATCC H99, nenhum dos fármacos da biblioteca apresentou índice da concentração inibitória fracionária (ICIF) ≤ 0,5, não sendo, portanto, observado sinergismo. No entanto, foram observados efeitos aditivos para as combinações de FLZ com finasterida (FIN), hidroxizina (HID) e PAR com ICIF igual a 1 para os três fármacos. As combinações e FLZ+FIN, FLZ+HID E FLZ+PAR foram analisadas pelos modelos de referência de Bliss, Loewe, HSA e ZIP, que sugerem efeitos aditivos para as combinações. Foi observado efeito pós-antifúngico (EPAF) para a CIM dos fármacos ALB, DUL, FEM, FLU, MEB e PAR entre 3,5 e 10,5 horas, bem como para as combinações aditivas FLZ+FIN, FLZ+HID e FLZ+PAR com EPAF entre 12 e 22,5 horas. Além disso, para todos os fármacos avaliados foi possível observar impactos morfológicos significativos com redução do diâmetro celular e do tamanho da cápsula em C. neoformans ATCC H99 após tratamento com concentrações subinibitórias.
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