NLRX1和NLRP3在白色念珠菌感染中的角色

Abstract

NLRX1在全身性念珠菌病的老鼠模式中的負調控角色: 播散性念珠菌病是一種常見且具有高致死率的院內感染疾病，而主要造成此疾病的黴菌則是白色念珠菌。在對抗白色念珠菌的侵入過程中，身體免疫主要由嗜中性白血球以呼吸爆的方式殺死吞入的白色念珠菌。NLRX1是一個近年來發現的一個免疫負調控蛋白，它會抑制細胞面對細菌或病毒時的免疫反應，以避免過度嚴重的免疫作用產生。然而關於NLRX1在黴菌感染的角色是如何，至今仍沒有被闡明。故在此研究，我們探討NLRX1在老鼠模式的全身性念珠菌感染的功能。我們發現NLRX1缺失的老鼠，在念珠菌感染下，腎臟念珠菌的含量顯著地比正常老鼠還來得低；同時NLRX1缺失的老鼠腎臟中促進發炎的細胞激素以及趨化因子的表現比正常老鼠還來得低，但在發炎激素細胞介白素17表現量卻比正常老鼠還來得高；此外雖然NLRX1缺失的嗜中性白血球的呼吸爆表現沒有比正常嗜中性白血球高，但在體外實驗中，NLRX1缺失的嗜中性白血球有比正常嗜中性白血球殺死更多白色念珠菌的趨勢。總結來說，研究指出NLRX1是一種在面對黴菌感染時的免疫負調控蛋白。 NLRP3在胃腸念珠菌感染疾病的老鼠模式中的角色: 播散性念珠菌感染是一種常見且致命的院內感染疾病，近年來有報導指出此疾病常見的感染源，白色念珠菌，是來自於腸胃道。在黏膜免疫系統中，NLRP3發炎體被發現參與在對抗口咽念珠菌感染以及陰道念珠菌感染。然而NLRP3發炎體在胃腸念珠菌感染的角色仍沒有被發現。為了探討這個問題，我們利用了胃腸念珠菌感染的老鼠模式，去觀察NLRP3發炎體缺失的老鼠有甚麼不同的表徵。研究結果發現，不管是正常或是NLRP3發炎體缺失的老鼠，都對胃腸念珠菌感染表現相同的接受度，其中包括存活率、體重變化以及腸胃道的白色念珠菌移殖量。此外在正常和NLRP3發炎體缺失的老鼠中，白色念珠菌侵入老鼠器官中，如腎臟、肝或是腸道等，的數量也是相同。例外的是白色念珠菌在NLRP3發炎體缺失的老鼠胃部數量是顯著降低。而在腸道內介白素-1β的表現量上，正常和NLRP3發炎體缺失的老鼠也沒有差異。就以上觀察結果，NLRP3可能並不參與在對抗胃腸念珠菌感染疾病的免疫機制中。

The negative role of NLRX1 in animal model of systemic Candida albicans infection: Blood stream Candida infection is the most common and fatal nosocomial infection and C. albicans is the most dominant isolate. In the murine model of systemic candidiasis, kidney is the major target of disease due to the uncontrollable infection in this organ. Neutrophil is the dominant immune cell in defense against systemic candidiasis through ROS production and other mechanisms. NLRX1 is a negative regulator in viral and bacterial infections. It is also known to induce mitochondrial ROS during infection. However, although the function of NLRX1 in viral and bacterial infection has been reported, the role of NLRX1 in fungal infection has not been elucidated. Thus, we aimed to investigate whether NLRX1 is involved in the systemic candidiasis in mice. By using murine model of systemic candidiasis, we found that NLRX1 deficiency enhanced fungicidal ability in kidney of infected mice. Furthermore, NLRX1-/- mice had smaller inflammatory area and lower expression of proinflammatory cytokines, chemokines and chemokine receptors, but higher level of IL-17 than WT mice in infected kidney. In addition, NLRX1-/- neutrophils had higher ability to kill ingested C. albicans than WT neutrophils. However, ROS production by NLRX1-/- neutrophils was not higher than WT neutrophils in response to opsonized C. albicans yeasts. These results indicated that NLRX1 plays a negative role in systemic C. albicans infection. How NLRX1 regulated neutrophil anti-C. albicans still await to be investigated. The role of NLRP3 in animal model of gastrointestinal Candida albicans infection: Disseminated candidiasis is the common and fetal nonsocomial infection. Some reports have shown the origin of disseminated Candida species is originated from the gastrointestinal tract of human or mouse. In mucosal immunity, NLRP3 inflammasome has been shown to play a key role in oropharyngeal and vulvovaginal candidiasis. However, the role of NLRP3 inflammasome in gastrointestinal candidiasis remains unknown. To investigate this issue, we employ a murine model of gastrointestinal candidiasis and mice carrying NLRP3 deficiency. Our results indicate that both of NLRP3-/- and WT mice show similar susceptibility to gastrointestinal candidiasis with comparable survival ability, weight change and colonization of C. albicans in intestine. In addition, the fungal burden in different organs is similar, except the stomach which show significantly lower fungal burden in NLRP3-/- mice. Furthermore, the expression of pro-inflammatory cytokine, IL-1β, has no difference in small or large intestine of WT and NLRP3-/- mice. According these results, NLRP3 might not involve in the gastrointestinal immunity against Candida albicans infection.