Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.
Department of Pediatrics, Carver College of Medicine, University of Iowagrid.412584.egrid.214572.7, Iowa City, Iowa, USA.
mBio. 2022 Feb 22;13(1):e0344721. doi: 10.1128/mbio.03447-21. Epub 2022 Jan 11.
Oropharyngeal candidiasis (OPC) is a common infection that complicates a wide range of medical conditions and can cause either mild or severe disease depending on the patient. The pathobiology of OPC shares many features with candidal biofilms of abiotic surfaces. The transcriptional regulation of C. albicans biofilm formation on abiotic surfaces has been extensively characterized and involves six key transcription factors (Efg1, Ndt80, Rob1, Bcr1, Brg1, and Tec1). To determine if the biofilm transcriptional regulatory network also plays a role in OPC, we carried out a systematic genetic interaction analysis in a mouse model of C. albicans OPC. Whereas each of the six transcription factors are required for biofilm formation, only three homozygous deletion mutants (ΔΔ, ΔΔ, and ΔΔ) and one heterozygous mutant (Δ/) have reduced infectivity in the mouse model of OPC. Although single mutants (heterozygous or homozygous) of and have no effect on fungal burden, double heterozygous and homozygous mutants have dramatically reduced infectivity, indicating a critical genetic interaction between these two transcription factors during OPC. Using epistasis analysis, we have formulated a genetic circuit, [+]→→, that is required for OPC infectivity and oral epithelial cell endocytosis. Surprisingly, we also found transcription factor mutants with defects in filamentation, such as ΔΔ, ΔΔ, and ΔΔ filament, during oral infection and that reduced filamentation does not correlate with infectivity. Taken together, these data indicate that key biofilm transcription factors are involved in OPC but that the network characteristics and functional connections during infection are distinct from those observed . The pathology of oral candidiasis has features of biofilm formation, a well-studied process . Based on that analogy, we hypothesized that the network of transcription factors that regulates biofilm formation has similarities and differences during oral infection. To test this, we employed the first systematic genetic interaction analysis of C. albicans in a mouse model of oropharyngeal infection. This revealed that the six regulators involved in biofilm formation played roles but that the functional connections between factors were quite distinct. Surprisingly, we also found that while many of the factors are required for filamentation , none of the transcription factor deletion mutants was deficient for this key virulence trait . These observations clearly demonstrate that C. albicans regulates key aspects of its biology differently and .
口咽念珠菌病（OPC）是一种常见的感染，它会使许多医学疾病复杂化，并且根据患者的不同，疾病的严重程度也不同。OPC 的病理生物学与无生命表面的念珠菌生物膜有许多共同特征。无生命表面上 C. albicans 生物膜形成的转录调控已得到广泛描述，涉及六个关键转录因子（Efg1、Ndt80、Rob1、Bcr1、Brg1 和 Tec1）。为了确定生物膜转录调控网络是否也在 OPC 中发挥作用，我们在 C. albicans OPC 的小鼠模型中进行了系统的遗传相互作用分析。虽然这六个转录因子都需要生物膜形成，但只有三个纯合缺失突变体（ΔΔ、ΔΔ 和 ΔΔ）和一个杂合突变体（Δ/）在 OPC 的小鼠模型中感染性降低。虽然 和 的单个突变体（杂合或纯合）对真菌负荷没有影响，但双杂合和纯合突变体的感染性显著降低，表明这两个转录因子在 OPC 期间存在关键的遗传相互作用。通过上位性分析，我们制定了一个遗传电路，[+]→→，它是 OPC 感染和口腔上皮细胞内吞所必需的。令人惊讶的是，我们还发现了在口腔感染期间具有菌丝缺陷的转录因子突变体，例如 ΔΔ、ΔΔ 和 ΔΔ 菌丝，并且菌丝缺陷与感染性无关。总之，这些数据表明，关键的 生物膜转录因子参与了 OPC，但在感染过程中网络特征和功能连接与观察到的明显不同。口腔念珠菌病的病理学具有生物膜形成的特征，这是一个研究得很好的过程。基于这种类比，我们假设调节 生物膜形成的转录因子网络在口腔感染期间具有相似性和差异。为了验证这一点，我们在小鼠模型中对 C. albicans 进行了首次系统的遗传相互作用分析。这表明，参与 生物膜形成的六个调节因子在感染中发挥了作用，但因子之间的功能连接却大不相同。令人惊讶的是，我们还发现，尽管许多因子都需要菌丝形成，但没有一个转录因子缺失突变体在这个关键的毒力特性上存在缺陷。这些观察结果清楚地表明，C. albicans 以不同的方式调节其生物学的关键方面。
