The F₁F_o-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism

ABSTRACT

Sepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F₁F_o-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F₁F_o-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F₁F_o-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1β, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F₁F_o-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F₁F_o-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F₁F_o-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F₁F_o-ATP synthase α subunit activity to control the induction of host inflammatory responses.

KEYWORDS:

• Candida albicans
• F1fo-ATP synthase
• α subunit
• inflammatory response
• amino acid catabolism

Acknowledgements

We are grateful to the Central Laboratory of the First Affiliated Clinical Hospital of Jinan University for providing the necessary laboratory equipment and venue for the acquisition of experimental data.

Data availability statement

All data are available from the authors upon reasonable request.

Disclosure statement

As stated by the authors, this study does not contain any underlying conflicts of interest related to personal or financial matters.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2023.2190645

Additional information

Funding

This work was supported by the National Key R&D Program of China (2021YFC2300400), National Natural Science Foundation of China (82272357/81971913/81903675), Natural Science Foundation of Guangdong Province (2018A030313595), Innovation Team Project of Guangdong University (2022KCXTD002) and Science and Technology Projects in Guangzhou (2023A03J1027).