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Candida species, except for C. galbrata, are dimorphic fungi yeast form and filamentous form. Candida yeasts are oval or round cells that are easily cultured under most laboratory conditions, and proliferate via budding. Under certain situations, the yeasts can transform into filamentous form by producing pseudohyphae or hyphae. Pseudohyphae are yeast cells that have long branched chains and constrictions at the interface of elongated blastoconidia, while hyphae are highly elongated yeast cells with separation of perpendicular septal walls. The transformation of Candida between the two forms is believed to form their virulence, and cause disease in humans . Although Candida species are potential pathogens, they are normal microbial flora on human body surfaces like skin, intestinal tract, and cervix of women. About 30% of the population carry the Candida without any clinical manifestation at any time .
Prerequisite of pathogenesis and infection routes
Among all the Candida species, C. albicans is reported most frequently to be involved in human diseases . Non-albicans can also be harmful, but not the same serious as C. albicans. It survives on human body as normal microbial flora without any immune response. As long as this balance between the C.albicans and human immune system goes well, no disease would arise. However, in some conditions, the balance can be impaired, like patients of malignant cancer receiving many harmful chemotherapies, HIV patients, asthma patients using large amounts of glucocorticoids, and infectious patients with long-time usage of broad-spectrum antibodies. Then C. albicans is able to proliferate a lot and becomes pathogenic. Typically, in a healthy and immunocompetent individual, the disease will take a benign course of mucocutaneous candidiasis. However, in immunocompromised patients, C. albicans becomes an opportunistic pathogen that cause chronic candidiasis or invasive, disseminated systemic disease that would be fatal. With a high mortality of up to 30-40%, candidemia and disseminated candidosis is a significant source of sepsis . In the past, people believed that C. albicans mainly invade human via body surfaces like skin, or accompany invasive medical procedures (catheters). However, recently consensus has been made that the major way C. albicans used in candidemia and disseminated candidiasis is translocation from the intestinal colony .
Medical importance of C. albicans
Today, the number of HIV patients is still increasing, and more and more harmful chemotherapeutics are applied to patients with tumors. Fungal
infection has become a significant cause of death in immunocompromised patients. C. albicans is one of the most common fungal pathogens, and can cause diseases from superficial (mucocutaneous) candidiasis, like oral, gastrointestinal, and vaginal candidiasis, to severe fatal disseminated infection, leading to millions of death worldwide. For example, up to 75% women have suffered from vaginal candidiasis at least once during childbearing age . About 50% of HIV patients and 90% AIDS patients have oral manifestation of Candida infection . Some paper even considers Candida infection as the 3rd or 4th most common hospital-acquired bloodstream infection, as medically important as some mainstream bacterial infection like E. coli and Pseudomonas spp . It is also said, in the USA, about 2.6 billion dollars are spent on healthcare for systemic fungal infection yearly, including 1.8 billion dollars on Candida infection . Therefore, Candida species do cost a lot of lives and money, making an immense health burden on human beings, and have become a major challenge in medical field worldwide.
Host defense mechanism against Candida albicans infection
The interaction between Candida species and human immune system is complex, as the fungi can grow smoothly on human body as a normal microbial flora, and also can become opportunistic pathogens and cause diseases. Questions come up before we discuss about the immune response to the Candida infection that how does the host discriminate between commensal and pathogenic microbes.
Immune discrimination of C. albicans between commensal and pathogenic microbes
Figure 1. Epithelial cell recognition of C. albicans
As discussed above, C. albicans can grow on human body in two forms, either in yeast form or filamentous form. In immunocompetent individuals, the immune system can suppress the pathogenic ability of C. albicans. However, in immunocompromised patients, there will be a switch of C. albicans between the yeast form and the filamentous form, which is considered as a notable characteristic of its virulence. Also, this switch should be related to its pathogenesis. But it is still an open question that whether it is the yeast form or filamentous form that is responsible for the pathogenicity. Many factors have been presumed to play a role in the infection of C. albicans, but among these studies a widely accepted viewpoint is the hypha formation causes invasion, as Figure 1 showed above . Understanding this is very important to future research on the mechanisms the fungus uses to escape from the immune responses and to cause diseases when host defense is impaired.
Interaction between immune system and C. albicans
It is well understood how T-cells recognize their antigens and how they are activated via TCR on the cellular surface. However, not until the discovery of Toll-like receptors (TLRs) as pattern recognition receptors (PRRs) in the late 1990s did we have a new understanding of how innate immune cells, like neutrophils, dendritic cells (DCs) and macrophages, are activated, and now we know that pathogens can be recognized via pathogen associated molecular patterns (PAMPs) by PRRs . Since the discovery of TLRs, more and more other characterized PRRs as part of the innate immune system have been found, like C-type lectin receptors (CLRs), Nacht-like receptors (NLRs), and RIG-like receptors (RLRs) . Through human body, different locations, tissues, and cell types show different expression of PRRs. In each of the four receptor families, there are many different kinds of sub-receptors. Every single PRR can recognize specific PAMPs, like Table 1 below shows . The
Table 1. PRRs that sense fungal-associated PAMPs
uneven distribution of different PAMPs is very important in that it determines
the distributions of different microbes. They can keep growing there as commensal friends, rather than a pathogenic enemy, as the PRRs there on the host cellular surfaces cannot recognize the PAMPs on themselves. This can also explain the mechanism of pathogenicity of C. albicans when it becomes opportunistic fungus and translocates from its normal area to others like bloodstream. Once the normal C. albicans invades where they should not be and get recognized by immune cells via interaction between PRRs and PAMPs, immune responses are activated and Candidosis comes out.
PAMPs of C. albicans recognized by PRRs
The structure of C. albicans cell wall is shown as Figure 2 bellow . Some papers show that mannoproteins are the main composition of the outer layer of the cell wall of C. albicans, and represent 30-40% of the cell wall dry weight. The skeleton of C. albicans inner cell wall is mainly formed by chitin and β1,3- andβ1,6-glucans . Other PAMPs of C. albicans have also been reported as phospholipomannan and proteins that are modified with long-chain and highly branched N-linked mannosyl residues as well as short linear chains of O-linked mannosyl residues . As we can see from the table above, in the TLRs family, TLR2 can recognize phospholipomannan, and TLR4 can recognize both mannan and O-linked mannan residues. In the CLRs family, Dectin-1 receptor can bind β1,3-glucans and mannose receptor can bind mannan. Therefore, host cells with the specific PRRs that can recognize PAMPs of C. albicans may activate immune responses.
Figure 2. The structure of the C. albicans cell wall
Cells with the right PRRs will recognize C. albicans
In human immune systems, both the innate immune and the adaptive immune, many cells have the right PRRs that can recognize the PAMPs of C. albicans, like monocytes, neutrophils, macrophages, dendritic cells (DCs), and CD4+ T-cells, as Figure 3 shown below . Then, which one is the initiator?
Figure 3. Cell populations and PRRs involved in C. albicans recognition
ECs start the recognition of C. albicans
It is true that in the case of fungal infection, especially C. albicans, the predominant immune cells involved in the defense against mucosal infection are neutrophils, as many recently discovered PRRs are expressed on them . However, little evidence is available that the fungus interacts directly with neutrophils or macrophages at the first stage . Instead, epithelial cells (ECs) are the real initiators . Although many PRRs have been found expressed on the surface of ECs, like TLRs, Dectin-1 and galectins, the exact PRRs used by them to bind PAMPs of C. albicans are not clear yet . In some studies, TLR2, TLR4 and Dectin-1 were blocked to test the ability of ECs to recognize C. albicans. The result showed that ECs could continue to response to C. albicans, which proved that the three receptors were not involved in the activating process. However, it partially explained why neutrophils and macrophages cannot start the immune response to C. albicans. There should be some other PRRs used by ECs to bind the specific PAMPs of the fungus, which might be a topic for research in future.
Epithelial signaling pathway used by ECs
The interaction between PRRs of ECs and PAMPs of C. albicans is only the first step to initiate the immune response. The PRRs will be activated after
binding the PAMPs, and will induce passing the outside information to the inside via some signaling pathways, as Figure 4 shown below . Although it is not completely clear whether the PRRs used by ECs belong to the TLRs or CLRs family, it is accepted widely that ECs use the MAPK and NF-ΚB pathways to pass the outside information of Candida infection. In a study both of the two pathways are confirmed as important mechanisms ECs used to discriminate between the yeast (commensal) and hyphal (pathogenic) form . While the NF-ΚB signaling increases linearly, the MAPK signaling shows a biphasic response. The early response via ERK1/2 and JNK signaling rises c-Jun activity in response to the presence of Candida (hyphae or yeast), and the second late response occurs in response to hyphae via further ERK1/2 and p38 signaling, finally leading to synthesis of cytokines . The most important discovery is that the second response of MAPK can only be induced when the hyphae burden becomes high enough, which means a threshold level of activation needs to be reached before ECs can activate any immune response . This well explains the whole story. When host immune is strong enough to keep the balance with the existence of C. albicans, the hyphae burden is suppressed at a low level, and the second MAKP response inside ECs cannot
Figure 4. Signal pathway activation by the main TLR and CLR receptors that detect Candida.
be activated leading to no immune response to this fungus. Once host immune
is impaired and the balance is broken, the hyphae burden of C. albicans will increase until the late MAKP response is induced with immune information flowing smoothly downward. What's more, this mechanism strongly proves the importance of ECs in the initiation of immune response to C. albicans.
ECs cytokine production and mucosal surface immune responses
The final result of ECs activation is the production of proinflammatory cytokines and chemokines, like IL-1α/β, IL-6, G-CSF, GM-CSF, and TNFα, as well as the chemokines RANTES, IL-8, and CCL20, however, ECs do not produce IL-12, IFN-γ, IL-4 or IL-13 , which are main product of CD4+ T-cells to enhance the immune response to antigens. But the secretion of cytokines and chemokines by ECs will contribute a lot to the next immune response. They can activate many immune cells like neutrophils, DCs and T-cells, which are involved in both innate and adaptive immune response. Among all of them, IL-8 is very important in that it recruits neutrophils to the epithelium , and helps start the neutrophil-dependent mucosal defense against C. albicans. Another significant chemokine is CCL20 which will recruit Th17 T-cell . Th17 T-cell is much useful that, on the one hand, it produces IL-17 that can act on ECs and neutrophils to enhance their functions; on the other hand, it will contribute to the response of secreted Ig-A at the mucosal surfaces which is known to function well to inhibit the adherence of many antigens, including C. albicans, to epithelial cells. Once the mucosal immune response is activated, more and more cytokines and chemokines will be produced, and more immune cells will be involved in the defense against C. albicans as Figure 5  shown below. Both innate and adaptive immune will take part in the fight against the infection of C. albicans.
Figure 5. Recognition of C. albicans at the membrane level.
Functions of neutrophils and DCs
As we have discussed, neutrophils have been considered as very significant in the defense against C. albicans. On the one hand, neutrophils can directly kill the fungus via ingestion and killing, degranulation, or through Neutrophils extracellular Traps (NETs) that is discovered recently ; on the other hand, neutrophils can affect the adaptive immune response via controlling the fungus burden or its production of IL-12 and IL-10 . Both of the two have great influence on the differentiation of T-cells. IL-12 can induce the differentiation of T-cells towards Th1 cells, which will produce more cytokines to enhance the immune response, like IFN-γ and IL-2. They can continuously to stimulate the differentiation and proliferation of macrophage and CD8+ T-cells. In contrast, IL-10 will decrease the differentiation of T-cells towards Th1 cells and down regulate the immune response to avoid over-reaction. DCs are the most important antigen-presenting cells, and can activate the CD4+ cells via the recognition of antigen/MHC II complex by TCR.
Result of host immune defense against C. albicans
In immunocompetent individuals, C. albicans are kept as normal microbes without causing any disease. In immunocompromised patients, the balance is broken and the C. albicans becomes pathogenic. If the subsequent immune response is strong enough, the fungus can be eliminated completely. Or chronic candidosis will occur, including oral candidosis, pseudomembranous candidiasis, acute/chronic erythematous candidosis, chronic hyperplastic candidosis, angular cheilitis and median rhomboid glossitis . Sometimes, the infection can be serious enough to be fatal, like disseminated systemic candidasis.
1. Candida albicans is a dimorphic fungi with yeast or filamentous form (commensal or pathogenic condition)
2. When host immune is impaired, C. albicans can become pathogenic
3. ECs recognize C. albicans via interaction of PRRs and PAMPs
4. Epithelial cytokines response and mucosal response are activated
5. Cytokines from ECs activate neutrophils and other immune cells
6. Neutrophils kills C. albicans directly and activate adaptive immune response
7. Both innate and adaptive immune responses are involved in host defense against C. albicans
8. If host immune system fails to clear C. albicans, chronic candidasis occurs. Sometimes, the infection can be fatal