In recent decades, Candida albicans (C. albicans) has been the leading cause of life-threatening invasive fungal infections, and despite the low treatment difficulty, invasive candidiasis ranges from mild symptomatic bacteremia to fulminant sepsis with an associated mortality rate of more than 70% (Pappas et al., 2018). According to recent reports, there are approximately 750,000 cases worldwide IC and over 50,000 deaths per year (Gonzalez-Lara and Ostrosky-Zeichner, 2020). C. albicans infection is the second most common cause of vaginal candidiasis (VVC). Among women of reproductive age, approximately 75% had at least one episode of VVC, and 40% had a second episode (Rolo et al., 2020). C. albicans, an important fungal pathogen in humans, exhibits different morphologies, such as yeast, pseudohyphae, and hyphae, which are recognized differently by the phagocytic cells of the innate immune response. Once C. albicans cells get into host tissues, immune cells like macrophages are drawn to the site of infection and activated to find, engulf, and kill the pathogen (Godoy et al., 2022). Understanding the virulence characteristics of C. albicans, the tissue-specific mechanisms of anti-Candida host defense, and its resistance mechanisms to existing antifungal agents should lead to better strategies to diagnose and treat affected individuals, which may help improve patient outcomes (Lopes and Lionakis, 2022). Cells of the innate immune system, including N eutrophils (N), macrophages (M), D endritic cells (DC), natural killer (NK) cells, and mast cells, play various roles in innate immune defense (Figure 1). Neutrophils can form neutrophil capture networks to kill pathogens (Jiang et al., 2019), but DC activates antigen-presenting cells and activates initial T cells to kill pathogens (de Albuquerque et al., 2018). Macrophages use surface pattern recognition receptor (PRRs) to recognize and phagocytose C. albicans by not only producing reactive oxygen species and reactive nitrogen species but also triggering the activation of signaling pathways such as MAPK and NF-kB, producing pro-inflammatory cytokines, and recruiting other immune cells to work together to eliminate pathogens (Gantner et al., 2005). A study found that C. albicans biofilm formation can destroy fine macrophages, and macrophages can also affect biofilm formation (Alonso et al., 2017; Arce Miranda et al., 2019). Candida-macrophage interactions are important immune defense responses associated with disseminated and deep-seated candidiasis in humans (Klotz et al., 2022). During C. albicans infection, macrophages can effectively detect, internalize, and kill invading pathogens, while C. albicans can escape macrophage killing by different pathways, and the interaction between the two leads to different diseases. And the mechanism by which C. albicans escapes lysosome digestion by macrophages remains to be investigated. In this paper, we describe how C. albicans identifies the cell wall components of C. albicans through the PRRs of macrophages, how macrophages engulf C. albicans, how they alter the phagocyte environment to induce hyphal formation, how C. albicans and macrophages interact, how C. albicans virulence factors, proteins, toxins and GPI proteins are responsible for its virulence on macrophages, etc. To provide a solid foundation for future research on C. albicans and macrophages. Understanding the mechanisms by which macrophages interact with C. albicans will facilitate more efficient killing of C. albicans by macrophages and reduced mortality from invasive C. albicans disease.

The cell wall of C. albicans is divided into an inner and an outer layer. The outer layer is mainly composed of mannose and proteins, with mainly O- and N-type mannose polymers (mannose) covalently linked to proteins to form glycoproteins. Among them, O-chain mannan, N-chain mannan and phosphorylated mannan are the main proinflammatory factors, and the inner layer is composed of skeletal polysaccharides, β-1,3-glucan, β-1,6-dextran and chitin, and its main components give shape and survival advantages to the cell (Silao et al., 2020). Compared with other pathogens, fungi can more easily activate the recognition mechanisms of the immune system, and almost all cell wall components belong to PAMP and interact with the corresponding PRRs to elicit an immune response in the host. Common PRRs where C. albicans interacts with macrophages mainly include type C lectin receptors (CLRs), Toll-like receptors (TLRs), and NOD -like receptors (NLRBs) (Figure 2).

There are four forms of C. albicans: yeast, hyphae, pseudomycelium, and chlamydial spores. The yeast is more resistant to macrophage killing and its virulence than the hyphal body. The ability of yeast to transform into hyphae is considered one of the most important pathogenic features of C. albicans. The transformation of yeast is often, but not always, influenced by environmental conditions such as pH, CO₂ levels, anaerobic conditions, and temperature. Among others, activation of the CAMP pathway plays an important role in the induction of certain genes. Expression during hyphal formation. Many previous studies have shown that environmental factors such as serum, CO2 concentration, glucosamine N-acetate (GlcNAc), and amino acids can activate the Ras- CAMP -signaling pathway under in vitro culture conditions (Salvatori et al., 2020). The CAMP -mediated signaling pathway is a protease. A (PKA) complex activates transcription factors that promote hyphal-specific gene expression and thus hyphal formation.

C. albicans is harmless as a commensal bacterium, but when the balance of normal flora is disturbed or immune defenses are compromised, these fungi can overgrow the mucosal flora and cause symptoms of disease. Two main types of infections have been observed after host immune status is compromised: superficial and invasive candidiasis. Superficial infection of the mucosal epithelium is common in immunocompromised patients, including chronic atrophic stomatitis, chronic cutaneous mucosal candidiasis, and vulvovaginal vaginitis. In more severe cases, C. albicans can enter the bloodstream and affect almost all organs of the body. Invasive candidiasis includes either acute or chronic hematogenous disseminated candidiasis and infection of a single or multiple deep organs, either by hematogenous seeding or by direct seeding. Although there is evidence that C. albicans can also disseminate in the lymphatic system, the major route of transmission is blood, and once Candida cells invade host tissues, the innate immune response is dominated by macrophages. Phagocytosis of these mononuclear phagocytes has been shown to slow the growth of C. albicans and leads to upregulation of genes involved in alternative carbon utilization and stress response. A study found that the importance of stress response pathways in drug resistance and tolerance is clear. These pathways directly affect the ability of the fungus to persist in its environment, and for fungal pathogens in humans, these signaling networks are critical factors in treatment failure (Henriques and Williams, 2020). In phagolysosomes, C. albicans is able to transform into a hyphal morphology that allows the pathogen to escape macrophages and thus continue to proliferate in the host. The hyphal-related aspartyl proteases Sap4, Sap5, and Sap6 have been shown to be required for macrophage survival. Proteases and phosphatomannose (PLM) on the surface of C. albicans can also promote macrophage survival by inducing apoptosis, for example by interacting with the ERK1/2 signal transduction pathway (Ibata-Ombetta et al., 2003). Some less pathogenic Candida species do not appear to respond in this way and are not viable (Mavor et al., 2005).

As the first line of defense of the innate immune response, macrophages mediate the clearance of invading C. albicans by intracellular killing. However, C. albicans has evolved sophisticated strategies for targeting macrophages to evade immune surveillance. The cytolytic peptide toxin, Candida lysine, promotes this fungal defense mechanism by disrupting immune cell membranes to escape the phagosomal environment. In the initial phase of interaction between C. albicans and macrophages, host cell lysis is mainly involved in mediating caspase-1-dependent cell pyroptosis through the activation of NOD -like receptor protein 3 (NLRP3) (Pietrella et al., 2013; Mao et al., 2020). The cytolytic peptide toxin Candida lysin contributes to macrophage lysis but also activates NLRP3, triggering secretion of pro-inflammatory cytokines that regulate macrophage defense against C. albicans. Candida bacteriolysin can be considered a microbial factor that has a dual function during its interaction with the host (König et al., 2020). It provides a mechanism for host cell lysis that contributes to escape from these immune cells. By activating NLRP3, it triggers a host proinflammatory protective response to eliminate C. albicans. This combination of beneficial and harmful effects on the host has also been proposed for the role of bacterial pore-forming toxin during its interaction with macrophages. The toxin causes host cell membrane damage associated with C. albicans invasion, translocation through the barrier, and escape from phagocytes. Macrophages are essential for the control of disseminated C. albicans. Elimination of C. albicans is mediated by a combination of antimicrobial activity during phagocytosis. C. albicans can counteract these attempts by producing hyphae that induce pyroptosis, mechanically stretching and eventually disrupting the phagosomal membrane, triggering immune cell death (Tucey et al., 2018; Li et al., 2022). However, Candida hemolysin also induces NLRP3 activation, leading to an enhanced host-protective proinflammatory response in mononuclear phagocytes (Kasper et al., 2018). Thus, Candida hemolysin promotes immune evasion by acting as a classical virulence factor but also contributes to the antifungal immune response (Case et al., 2021). Their differential effects in oral, vaginal and systemic infections highlight the dual function of this toxin in the interactions between C. albicans and macrophages as classical virulence factors and virulent toxic factors in mucosal and systemic infections (Patterson et al., 2013).

The morphological transition between yeast and hyphal forms of C. albicans, expression of cell surface adhesins and invasins, tropism, biofilm formation, phenotypic turnover, and secretion of hydrotolytic enzymes are considered virulence factors. The pathogenic yeast C. albicans was found to be coated with phospholimannose (PLM) consisting of a β-1,2-oligomannose site and phytoceramide. PLM-induced externalization of membrane phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation suggest that PLM promotes yeast survival by inducing macrophage death (Ibata-Ombetta et al., 2003).

Interaction of C. albicans with macrophages is an important immune system defense response to Candida disease associated with deep dissemination of Candida cells in humans. Despite the obvious efficiency of killing pathogens, macrophages fail to effectively control the disease process of candidiasis in severely damaged patients. The patients with low immunity, prolonged use of antibiotics and immunosuppressants may develop severe C. albicans infection. The development of drugs against the transformation of the C. albicans form and virulence-related target drugs has become an effective means for the accurate diagnosis and treatment of C. albicans. On the other hand, macrophage remodeling promotes macrophage redifferentiation from M2 to M1 phenotype, which promotes macrophage phagocytosis and lysosomal digestion of C. albicans. In conclusion, our study investigated the mechanism behind the escape of C. albicans hyphae from macrophages. Inhibition of hyphal escape can reduce the inflammatory response of macrophages to C. albicans infection and provides an accurate prevention, diagnosis, and treatment basis for C. albicans infection.

The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

SZ, AS, and XH designed the research study. MG, LS, and YH carried out the data analysis and processing. SZ prepared the original manuscript. AS and XH revised the manuscript and edited the final version. All authors read and approved the final manuscript.