Introduction
C. albicans is a yeast (microscopic fungus) that lives in our mouth, skin, gut, and genital tract, often without causing harm. It is a diploid, single-celled eukaryotic microfungus that is usually commensal and co-exists with us. However, when we are sick and our immune system is weakened, this tiny yeast turns pathogenic and may cause infections. Figure 1 shows the structure of a C. albicans cell.
Figure 1: Yeast cell structure. Image from: https://www.bbc.co.uk/bitesize/guides/ztmktv4/revision/3
Conditions such as HIV/AIDS, cancer treatments, invasive surgery, use of antibiotics or immunosuppressive drugs can disrupt the normal microbiota and diminish our immune responses. This causes a decrease in the competition from other good microbiota, which allows C. albicans to proliferate freely and invade tissues. This can result in mild mucosal to severe systemic infections. Examples of mild infections are oral thrush, impacting approximately 41% of healthy adults at least once in their life; and vaginal thrush (vulvovaginitis) which affects around 75% of females. One of the serious systemic infections caused by this fungal pathogen is candidaemia, a bloodstream infection linked with a high mortality rate in the range of 30%-40%. This indicates that under suitable conditions and opportunities in our body, C. albicans can act as an opportunistic pathogen. The commensal sites and diseases by C. albicans on the human body are depicted in Figure 2.
Upon C. albicans infection, our immune system responds by recruiting innate immune cells to the infection site to combat the pathogen. But sometimes these immune cells aren’t as effective in eliminating the pathogen, allowing the infection to persist. C. albicans fights back employing diverse tactics to survive within us.
In this article, we will dive into these cunning tactics of C. albicans by which it evades, exploits, and manipulates our immune defences, as well as its adaptation to various environments within the body. We will specifically explain how this pathogenic yeast changes its shape, remodels its cell wall to go undetected by our body’s defences, and modulates our immune responses. Finally, we will discuss the significance of maintaining a healthy balance between C. albicans and other microbes, practising good hygiene, and adopting measures to prevent C. albicans overgrowth.
1.1 Why do we care about C. albicans infections? A serious threat
C. albicans is reported to cause over 150 million mucosal infections and kill around 200,000 people every year worldwide, due to systemic fatal infections that spread to the bloodstream and internal organs. Importantly, it is classified by the WHO as one of the critical priority pathogens in 2022. Moreover, there are limited drugs (only five categories of antifungal drugs) for treating C. albicans infections and the existing treatments are insufficient.
Therefore, C. albicans infections are serious and warrant necessary action. Finding new antifungal drugs is hard due to the close similarities in basic cell biology between fungi and humans, both of which are eukaryotes. This means that if we develop a drug that effectively kills a pathogenic fungus, human cells being eukaryotic, may also be damaged in the process. On top of that, there is emerging resistance of C. albicans to most existing drugs, which makes managing these infections challenging.
Favourite entry points of C. albicans
C. albicans infiltrates the body through various entry points, primarily the skin, mucous membranes, and gastrointestinal tract (Figure 2). It can invade the skin mainly through cuts or areas on the skin affected by conditions like eczema or diabetic foot ulcer. It also thrives on mucous membranes in places such as the mouth and genital tract, leading to infections such as oral thrush and vulvovaginitis, respectively. Additionally, It can enter the body through the gut, especially after surgeries, leading to infections like peritonitis or candidaemia, which occur in immunocompromised individuals and those with disrupted gut microbiota. These various entry routes highlight the flexibility of C. albicans and its ability to cause infections in different parts of the body.
In patients with long-term intravenous catheters, C. albicans can colonise the catheter, forming a protective biofilm that releases this fungus into the bloodstream. This can cause persistent candidaemia and allow the fungus to spread to other organs, resulting in serious infections in the lungs, liver, spleen, kidneys, or eyes.
Immune defences against C. albicans infection
C. albicans, usually a harmless commensal microbe in our body, exploits our weakened immune defences to cause infections, our innate immune system is the first line of defence against this opportunistic fungus. This system works quickly to eliminate any harmful invaders or, if it can't, to hold them off until the adaptive immune system can take over and deal with the infection.
The main innate immune cells acting against C. albicans include macrophages, neutrophils, dendritic cells and monocytes. These immune cells recognise C. albicans through special receptors known as pattern recognition receptors (PRRs), which identify specific markers on the fungal cell wall called pathogen-associated molecular patterns (PAMPs). For instance, Dectin-1 is a C-type lectin receptor (CLR), which detects a component called β-1,3-glucan found in the C. albicans cell wall. When Dectin-1 binds to β-1,3-glucan, it elicits a response by engulfing the fungus via phagocytosis (Figure 3) and releasing substances that help kill it.
Figure 3: Recognition and phagocytosis of C. albicans cell by a human macrophage (RAW264.7). Scanning electron micrograph of RAW264.7 macrophages interacting with C. albicans. With thanks to Lucinda Wight, University of Aberdeen. Scale is shown at the bottom left (Bain et al., 2015)
Different C. albicans species have distinct PAMPs which are detected by the innate immune cells through various receptor families like C-type lectin receptors (CLRs), Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). The innate immune system can differentiate between C. albicans that normally lives in the body and C. albicans that causes infections by recognising these unique PAMPs. These patterns not only vary among C. albicans species but also in their yeast or hyphal forms (described below), enabling the immune system to respond appropriately when C. albicans shifts from harmless to harmful.
Neutrophils and macrophages also produce reactive oxygen species and signalling molecules known as cytokines to boost the antifungal response. This coordinated effort among various innate immune components is crucial for controlling C. albicans infections and preventing them from spreading throughout the body.
Clever strategies of C. albicans to counteract our immune responses
4.1 Adaptation to different niches within the body
C. albicans faces a wide range of stressful conditions within our body such as varying pH, temperature, oxygen concentration and nutrient availability, as well as host immune responses. However, this pathogen possesses clever strategies to tackle these stressors. C. albicans manages to colonise and adapt to various sites in our body, enabling it to thrive in different host niches and establish infections.
4.2 Escape and Exploitation of Immune Defences
Cell Shape Transformation – C. albicans is polymorphic, meaning it can change into various forms or morphologies to escape our immune system (Figure 4). It can mainly switch between three different growth states namely:
a) Yeast form - Oval or round shaped single cells that reproduce asexually by
budding.
b) Pseudohyphal form - Multicellular, branched and elongated chain of cells with constrictions called septa at cell junctions.
c) Hyphal form - Long, multicellular, parallel-walled true fungal filaments, required for nutrient absorption and tissue invasion.
Other morphologies include:
d) White - A common growth state usually found in commensal environments like mucosal surfaces, gut, and skin. Yeast mainly exists in white form and grows as smooth, round, white colonies on a petri plate.
e) Opaque - Linked with mating and may contribute to fungal virulence. It grows as flat, grey-dark colonies on a petri plate.
f) Grey - Represents a transitional state that may occur under certain environmental cues.
g) GUT - Stands for gastrointestinal induced transition (GUT) form and is associated with the gastrointestinal tract. GUT cells are similar in size and shape to opaque cells but lack surface pimples and are wider than grey cells.
h) Chlamydospores - Thick-walled spore-like structures.
To survive under varying environmental conditions like pH change, temperature fluctuations, nutrient availability or depletion, and other factors within our body, C albicans has evolved to adapt its morphology. For example, C. albicans predominantly stays in the yeast form at low pH (below 6), while a high pH (above 7) drives hyphal growth. Moreover, cues such as 37°C, high blood CO2 levels, low nitrogen levels, and the presence of specific compounds (N-acetylglucosamine, peptidoglycan) can switch yeast to hyphae (Figure 4). The WOR1 gene, known as the white-opaque switching regulator 1, is a master regulator that triggers the switch from the white form to the GUT form of C. albicans, allowing its adaptation to the human gastrointestinal tract. Furthermore, the loss of EFG1 can lead to a switch from white to grey cells (Figure 4). C. albicans also utilises quorum sensing—communication among microbial cells to regulate its morphology; high cell densities favour yeast growth, whereas low densities encourage hyphal formation. Key signalling molecules involved in this process are farnesol and tyrosol.
C. albicans shifts from its round yeast form to hyphae/pseudohyphae to avoid immune detection and cause infections in different tissues. This is because hyphae/pseudohyphae can penetrate host tissues more effectively than yeast cells. which helps this fungus with deeper invasion and colonisation.
The structure of β-glucans in the hyphal form of C. albicans is reported to have a “closed shape,” not found in yeast β-glucan and this affects its interaction with the immune system. In the yeast form, these β-glucans are shielded from immune detection by mannoproteins, allowing the fungus to escape recognition and persist longer in the host. However, when C. albicans switches to its hyphal form, the β-glucans become exposed, increasing their visibility to the immune system and causing an attack on the fungus. While the yeast form is more effective at hiding its glucans on its cell wall, the hyphal form may enhance tissue invasion despite heightened immune recognition.
Virulence factors – C. albicans produce virulence factors such as toxins (Candidalysin), inflammatory molecules and enzymes, that hinder the immune system's defences for immune evasion. For instance, it can secrete proteases that degrade complement proteins (C3b, C4b, and C5), which are important for marking the pathogen for destruction and facilitating its engulfment.
Exploitation – C. albicans exploits our body’s immune markers to its own benefits. For example, It can increase the expression of a receptor (Hgt1 protein) that binds to the human immune regulator factor H, allowing it to escape immune detection. By hijacking factor H, it can survive and proliferate in the host despite the immune response. This tactic is crucial for the fungus to cause infections, especially in immunocompromised individuals.
Biofilm Formation: The ability to form biofilms on mucosal surfaces provides a physical barrier against immune cells and antifungal treatments, further complicating host defences.
4.3 Modulation of immune system
Modulation of Immune Response - The transition from yeast to filamentous forms can modulate the immune response by inducing macrophages to switch from a pro-inflammatory M1 phenotype to a less inflammatory M2 phenotype, further aiding in immune evasion.
Manipulation of Cytokine Responses - C. albicans can alter the cytokine environment to favour its survival inside the host. It does so by producing a type of response known as Th2. This Th2 response suppresses another response called the Th1 response. C. albicans mainly lowers levels of a signalling molecule called IL-12p70 that is important for activating the Th1 response. As a result, the Th1 response becomes weaker, allowing the Th2 response to take over and making it harder for the body to fight off the fungal infection.
Manipulation of phagolysosome and inhibition of phagosome maturation: C. albicans in its hyphal form can inhibit the maturation of phagosomes in macrophages, preventing effective degradation of the fungus. This allows it to survive within immune cells that typically would eliminate pathogens.
It is also able to protect itself against attack from toxic hydrogen peroxide and free radicals present within the phagolysosome by upregulating its stress response pathways.
Maintaining a Healthy balance
C. albicans engages in complex interactions with various bacteria in the human body which are crucial for this fungus to colonise and cause infections. These interactions can be categorised into three main types.
First is coaggregation, which is a mutually beneficial interaction where genetically distinct microbial cells attach to each other via specific molecules and clump together. This process helps C. albicans to adhere to oral bacteria, increasing its ability to colonise the oral cavity and form biofilms along with the oral bacteria. Next, it synergistically interacts with Staphylococcus aureus bacterium, which helps enhance its pathogenicity. Finally, it exhibits antagonism, which is a competitive interaction, where C. albicans faces limitations in growth due to the presence of opportunistic bacterium like Pseudomonas aeruginosa. This bacterium can inhibit the growth of C. albicans through secretion of antimicrobial substances or competition for nutrients within the oral cavity.
5.1 Importance of maintaining a healthy balance
A balanced microbiome plays an important role in maintaining host health and is essential for:
a) Prevention of overgrowth: which helps control opportunistic pathogens like C. albicans. This overgrowth can result in various infections, including invasive candidiasis, which is associated with high mortality rates
b) Immune modulation: The interactions between C. albicans and bacteria can affect host immunity and susceptibility to infectious diseases; and
c) Gut barrier maintenance: protects against intestinal invasion by C. albicans.
Hygiene and Prevention Measures
To maintain a healthy microbiome and prevent C. albicans infections, there are a few key steps to follow. First, eating a balanced diet is crucial; foods rich in fibre and probiotics can help support a healthy gut microbiome and prevent the overgrowth of C. albicans. Secondly, it’s important to avoid using antibiotics too often, as they can upset the natural balance of bacteria in your body, increasing the risk of C. albicans infections. Lastly, practising good hygiene is essential; simple actions like washing your hands regularly and taking care of your oral and genital hygiene can help stop C. albicans from taking hold and can help prevent C. albicans infections.
Conclusion
C. albicans employs clever tactics to escape, exploit, and manipulate our immune defences. Understanding these strategies is crucial for developing new preventive measures and antifungal therapies. By maintaining a healthy balance between C. albicans and bacteria through proper hygiene and preventive measures, we can reduce the risk of C. albicans overgrowth and associated infections.
By
Ankita Chattopadhyay
University of Edinburgh
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