School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, United States.
Front Cell Infect Microbiol. 2020 Feb 28;10:69. doi: 10.3389/fcimb.2020.00069. eCollection 2020.
Fungi are ubiquitous. Yet, despite our frequent exposure to commensal fungi of the normal mammalian microbiota and environmental fungi, serious, systemic fungal infections are rare in the general population. Few, if any, fungi are obligate pathogens that rely on infection of mammalian hosts to complete their lifecycle; however, many fungal species are able to cause disease under select conditions. The distinction between fungal saprophyte, commensal, and pathogen is artificial and heavily determined by the ability of an individual host's immune system to limit infection. Dramatic examples of commensal fungi acting as opportunistic pathogens are seen in hosts that are immune compromised due to congenital or acquired immune deficiency. Genetic variants that lead to immunological susceptibility to fungi have long been sought and recognized. Decreased myeloperoxidase activity in neutrophils was first reported as a mechanism for susceptibility to infection in 1969. The ability to detect genetic variants and mutations that lead to rare or subtle susceptibilities has improved with techniques such as single nucleotide polymorphism (SNP) microarrays, whole exome sequencing (WES), and whole genome sequencing (WGS). Still, these approaches have been limited by logistical considerations and cost, and they have been applied primarily to Mendelian impairments in anti-fungal responses. For example, loss-of-function mutations in were discovered by studying an extended family with a history of fungal infection. While discovery of such mutations furthers the understanding of human antifungal immunity, major Mendelian susceptibility loci are unlikely to explain genetic disparities in the rate or severity of fungal infection on the population level. Recent work using unbiased techniques has revealed, for example, polygenic mechanisms contributing to candidiasis. Understanding the genetic underpinnings of susceptibility to fungal infections will be a powerful tool in the age of personalized medicine. Future application of this knowledge may enable targeted health interventions for susceptible individuals, and guide clinical decision making based on a patient's individual susceptibility profile.
真菌无处不在。然而，尽管我们经常接触到正常哺乳动物微生物群中的共生真菌和环境真菌，但在普通人群中，严重的系统性真菌感染却很少见。如果有的话，很少有真菌是专性病原体，它们依赖于感染哺乳动物宿主来完成生命周期；然而，许多真菌物种在特定条件下能够引起疾病。真菌腐生物、共生菌和病原体之间的区别是人为的，很大程度上取决于个体宿主的免疫系统限制感染的能力。在由于先天性或获得性免疫缺陷而免疫功能受损的宿主中，可以看到共生真菌作为机会性病原体的显著例子。长期以来，人们一直在寻找并认识到导致对真菌产生免疫敏感性的遗传变异。1969 年，首次报道中性粒细胞髓过氧化物酶活性降低是易感染 感染的机制。随着单核苷酸多态性 (SNP) 微阵列、外显子组测序 (WES) 和全基因组测序 (WGS) 等技术的出现，检测导致罕见或微妙易感性的遗传变异和突变的能力得到了提高。尽管如此，这些方法受到了后勤考虑和成本的限制，并且主要应用于抗真菌反应的孟德尔缺陷。例如，通过研究一个有真菌感染史的大家庭，发现了 的功能丧失突变。虽然这些突变的发现有助于我们了解人类的抗真菌免疫，但主要的孟德尔易感性基因座不太可能解释人群中真菌感染的速度或严重程度的遗传差异。最近使用无偏技术的研究揭示了导致念珠菌病的多基因机制。了解对真菌感染易感性的遗传基础将是个性化医学时代的有力工具。未来对这方面知识的应用可能使易感个体能够进行有针对性的健康干预，并根据患者的个体易感性特征指导临床决策。
