Pathogen: Candida albicans

Disease: Candidiasis

Mouse study Li et al. (2022) reported that neutrophils upregulate the glucose uptake-associated transcript Slc2a1 (encoding glucose transporter Glut1) to meet increased metabolic requirements upon Candida albicans infection in the mouse kidney. Using dectin-1 deficient mice, the authors further showed that dectin-1-dependent recognition of fungal β-glucan regulates Glut1 transcription and phosphorylation in neutrophils. It is noteworthy that despite the only in vivo experiment was performed using the mouse kidney, the authors also assayed mouse neutrophils in vitro from a variety of origins including liver, bone marrow, blood, and spleen. The results are consistent. Finally, this study validated the role of Glut1 in neutrophil glucose uptake and fungicidal activity using the blood neutrophils from 10 healthy volunteers.

Human clinic study Candida albicans are responsible for more than 90% of cases of recurrent vulvovaginal candidiasis. The human clinic study I selected here focused on this disease in patients with mutated dectin-1. The authors showed that the binding of C. albicans β-glucan and human monocytes were markedly lower in dectin-1 deficient patients, accompanying with significantly reduced interleukin production than healthy control (Ferwerda et al., 2009). However, monocytes and neutrophils from the dectin-1 deficient patients were as effective at killing C. albicans as were cells from healthy controls (Ferwerda et al., 2009).

Type of infections between human clinic study and the mouse experimental model

Candida albicans is an opportunistic commensal that commonly found in human gut, mouth, throat, and vagina. It only causes problems when the growth is out of control. In human, the most common types of Candidiasis are mucosal and dermal infections that occurring at urinary tract, genitals, mouth, and skin (Nobile and Johnson, 2015). A more serious infection type occurs when C. albicans enters the blood stream, known as candidemia, from where they can infiltrate to internal organs, a condition known as disseminated candidiasis. In Li et al. (2022), with the aim of examining the importance of glucose metabolism of neutrophils in antifungal defense, they infected Glut1 knockout mice with C. albicans via two different ways: the lateral tail vein as the systemic infection or the OPC (oropharyngeal candidiasis) infection. In contrast, most of clinical studies regarding host defense to C. albicans isolated neutrophils from human blood. The mortality of intravenous/systemic infection is quite high as all mice died by day 7 post infection (Li et al., 2022). In contrast, the mice subjected to oral infection exhibited weight loss and defects in fungal clearance. In human, disseminated candida infection has a sizable mortality rates between 30% and 50% (Nobile and Johnson, 2015).

Neutrophils source between human and mouse study

Li et al. (2022) conducted most of in vitro experiments using neutrophils isolated from the mouse bone-marrow. In the human clinic study, Ferwerda et al. (2009) isolated mononuclear cells and neutrophils from dectin-1 deficient patients with recurrent vulvovaginal candidiasis (Ferwerda et al., 2009).

Recognition of C albicans β-glucans in the mouse and human neutrophils Mechanistically, a consensus has not been made regarding the neutrophil receptor of pathogenic β-glucans in human and mouse. The mouse study acknowledges many differences in neutrophils between human and mouse including absolute number and expression of antimicrobial peptides. Therefore, the authors isolated neutrophils from peripheral blood from 10 healthy volunteers and activated the cells with C. albicans or curdlan. As expected, human neutrophils exhibited increased Glut1-mediated glucose uptake whereas a Glut1-specific inhibitor blocked both glucose uptake and fungicidal activity in neutrophils (Li et al., 2022). However, this paper did not examine whether β-glucans recognition is also dependent on dectin-1 as shown in the mouse neutrophils. It is argued that human neutrophils use the lectin-binding integrin Complement receptor 3 (CR3) for Candida uptake and killing, in line with another study showing CR3 and not dectin-1 is the major receptor for β-glucan recognition by human neutrophils (Gazendam et al., 2014). The differences in β-glucan recognition in human and mouse neutrophils could be true because dectin-1-mutant patients showed normal killing of C. albicans by neutrophils. In the mouse study, in contrast, dectin-1 is essential for Glut1 transcription and phosphorylation in neutrophils to meet the metabolic needs for antifungal activities. Moreover, another study on the mouse showed that dectin-1 is required to activate CR3 for the cytotoxic response to C. albicans (Li et al., 2011). It is important to note that the human clinic study showed dectin-1 is required for β-glucan recognition in monocytes and macrophages. Deficiency in β-glucan recognition leads to defects in cytokine response. However, human neutrophils, serve as redundant innate immunity in phagocytosis, can probably use alternatively dectin-1-independent mechanism to protein against invasive fungal infection.

References

Ferwerda, B., Ferwerda, G., Plantinga, T.S., Willment, J.A., van Spriel, A.B., Venselaar, H., Elbers, C.C., Johnson, M.D., Cambi, A., Huysamen, C., et al. (2009). Human Dectin-1 Deficiency and Mucocutaneous Fungal Infections. New England Journal of Medicine 361, 1760–1767. https://doi.org/10.1056/NEJMoa0901053. Gazendam, R.P., van Hamme, J.L., Tool, AntonT.J., van Houdt, M., Verkuijlen, PaulJ.J.H., Herbst, M., Liese, J.G., van de Veerdonk, F.L., Roos, D., van den Berg, T.K., et al. (2014). Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects. Blood 124, 590–597. https://doi.org/10.1182/blood-2014-01-551473. Li, D.-D., Jawale, C.V., Zhou, C., Lin, L., Trevejo-Nunez, G.J., Rahman, S.A., Mullet, S.J., Das, J., Wendell, S.G., Delgoffe, G.M., et al. (2022). Fungal sensing enhances neutrophil metabolic fitness by regulating antifungal Glut1 activity. Cell Host & Microbe 30, 530-544.e6. https://doi.org/10.1016/j.chom.2022.02.017. Li, X., Utomo, A., Cullere, X., Choi, M.M., Milner, D.A., Venkatesh, D., Yun, S.-H., and Mayadas, T.N. (2011). The β-Glucan Receptor Dectin-1 Activates the Integrin Mac-1 in Neutrophils via Vav Protein Signaling to Promote Candida albicans Clearance. Cell Host & Microbe 10, 603–615. https://doi.org/10.1016/j.chom.2011.10.009. Nobile, C.J., and Johnson, A.D. (2015). Candida albicans Biofilms and Human Disease. Annu Rev Microbiol 69, 71–92. https://doi.org/10.1146/annurev-micro-091014-104330.