*3.1. Infectious Diseases Involving Virus, Bacteria, and Fungi*

#### 3.1.1. Viral and Bacterial Infectious Diseases

Salivary gland tissue may become infected with numerous viruses and bacteria, thus increasing the susceptibility of candidiasis. Epidemic parotitis is caused by the *Paramyxovirus* (mumps is the most

common infection) and develops parotid edema with systemic symptoms, including fever, anorexia, malaise, and headache [35]. HIV infects the parotid gland and can lead to the formation of benign lymphoepithelial cystic lesions. *Coxsackie* virus and Hepatitis C virus are RNA-bound viruses that can infect the salivary glands and damage host tissues, causing dry mouth [35]. *Cytomegalovirus* (CMV) is a widespread virus with symptoms ranging from asymptomatic to severe-end organ dysfunction. Human CMV infection, usually affecting salivary glands, could be asymptomatic in healthy people, or it could be a life-threatening viral infection to immunocompromised individuals [36]. Recent evidence suggests that salivary glands are a potential target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [37]. The study explains that SARS-CoV-2 infection was found in the salivary glands by identifying the presence of angiotensin I–converting enzyme 2 and cellular protease transmembrane serine protease 2 in the salivary glands [38]. Furthermore, many researchers reported sialadenitis by SARS-CoV-2 infection and the importance of saliva as a diagnostic tool [39–41]. In minor salivary glands, various viral infections also have been reported, such as Epstein–Barr virus, HIV, and human T-lymphotropic virus [42–44].

Bacterial infections are comparatively rare to viral infections. These infections are caused by either a ductal obstruction or a retrograde spread of infection up the duct secondary to decreased salivary flow. Salivary gland bacterial infections develop in patients who have existing conditions, including postoperative recovery, diabetes or immunodeficiency. Radiation therapy or antidepressant medication could reduce salivary flow and consequently induce staphylococcal and streptococcal strains associated with the biofilm on oral mucosa to infect the salivary gland [20]. Untreated bacterial infections could spread beyond the glandular borders and extend between the neck muscles, leading to serious complications, such as sepsis. In attempt to combat bacterial infection, immune cells infiltrate into the salivary gland and may destroy the secretory system resulting in dry mouth, local pain, and edema [45]. Mycoplasma infection affecting the minor salivary glands has been reported to damage the ductal epithelium, disrupt acinar structures, and cause mucus outflow into connective tissue [46]. Salivary gland dysfunction and destruction caused by various viral and bacterial infection can create a vulnerable condition that causes *Candida* infection in the oral mucosa and even in the salivary glands.

#### 3.1.2. Infectious Diseases with *Candida*

A study reported that *Candida* infection of the parotid gland among healthy adults was caused by deep wounds from dentures [47]. Importantly, dentures were found to disrupt the epithelial barrier and induce *Candida* infection, infiltrating below the mucous membrane. Although fungal infection is reported less frequently, *C. albicans*, *Histoplasma capsulatum*, and *Cryptococcus neoformans* are the most common causes of sialadenitis, salivary gland inflammation [48–54]. Signs and symptoms of sialadenitis by *C. albicans* are low grade fever (37.4–37.8 ◦C), painful inflammatory-mediated swelling, and salivary gland duct discharge [10]. Histopathologically, the pus from the parotid gland demonstrated budding yeast cells. The yeast-like cells were between 2 and 4 μm in length within the intra- and extra-cellular space of macrophages [10]. Mostly, salivary gland infection with *Candida* occurs in individuals with impaired immunity, including persons impacted by HIV/AIDS [55]. Additionally, diabetic patients were reported to have increased susceptibility to *Candida* associated parotitis [10,48].

#### *3.2. Non-Infectious Inflammatory Disease*

Sjögren's syndrome is an autoimmune disorder that causes chronic inflammation and fibrosis of the salivary glands. The primary presenting symptoms of Sjögren's syndrome are dry eyes and mouth. A study reported that Sjögren's syndrome is associated with the IgG4 spectrum of disease [46]. As the disease progresses and becomes chronic, salivary glands show atrophy, parenchymal calcification, fat replacement,

cystic destruction, or multiple lymphocyte cysts [47]. Chronic Sjögren's sialadenitis demonstrates ductal stenosis and swelling using sialography [56]. Chronic sclerosis sialadenitis, also known as Küttner's tumor, indicates chronic enlargement of the salivary glands caused by immune-mediated infiltration of lymphoplasmacytic cells [57]. Remarkably, recent works in the literature have shown strong associations with IgG4-related plasma cell infiltration in over 90% of patients with chronic sclerosing sialadenitis [58]. Mikulicz disease's cause is unknown, but it is believed to be autoimmune. The disease resembles Sjögren's syndrome except the fact that salivary and lacrimal secretion is less than that of Sjögren's syndrome [20]. Sarcoidosis is an autoimmune disease of unknown etiology and can affect multiple systems of the body. Large granulomas can develop in the salivary glands. The granulomas appear as masses with several non-cavity characteristics [45]. The loss of salivary function associated with these inflammatory diseases may cause consequent *Candida* infection.

#### *3.3. Secondary Candida Infection with Salivary Gland Tumors*

Salivary gland tumors are often manifested as painless, slow growing, and benign. However, 20% of salivary gland tumors are diagnosed as malignant tumor. Salivary gland tumors are indicated to be benign in 85% of tumors affecting the parotid, 60% of tumors affecting the submandibular, 50% of tumors affecting the minor glands, and only 10% of tumors affecting the sublingual glands [59]. Several studies have reported the association between Epstein–Barr virus infection and salivary gland neoplasm. Epstein–Barr virus may be a major factor in its etiology or pathogenesis [55,60–62]. HIV infection was also found to increase the risk of salivary gland cancers. Salivary gland neoplasms, such as adenoid cystic carcinoma, Kaposi sarcoma, and lymphoma, are reported in HIV infection [63].

*Candida* infection associated with salivary gland neoplasm has been rarely reported. However, *Candida* infection in the development of squamous cell carcinoma has been suspected for years. Common sites for oral squamous cell carcinoma to develop are on the tongue, lips, and floor of the mouth, where minor salivary glands and sublingual and submandibular glands are distributed. *Candida* species are more prevalent in potentially malignant oral mucosa diseases and cancerous oral mucosa lesions than in mucosa with the non-cancerous diseases [64,65]. With *Candida* infection, the rate of malignant transformation in leukoplakia is higher than in leukoplakia without candidiasis. The susceptibility to *Candida* infection often relies on an imbalance between *Candida* virulence factors and the host's defensive immune system [66]. In order for *C. albicans* to penetrate into mucosa, cell surface proteins, called adhesins, must recognize host molecules and adhere to the host cell. After they adhere to the cell surface, the cellular phenotype converts from yeast form to hyphae form by two mechanisms. The first mechanism is the secretion of a protease, a degrading enzyme that can digest epithelial cell surface components. This, in turn, allows physical migration into/between epithelial host cells. The second mechanism is the epithelial cell endocytosis of *C. albicans*. During this process, *Candida* can damage the host epithelium and the host's immune system [19,66,67]. Furthermore, *Candida* can produce carcinogenic compounds, nitrosamines, N-nitrosobenzylmethylamine. Strains with high nitrosamines were isolated from lesions with advanced precancerous changes. In such cases, the yeast cells expand from the mucosal surface toward epithelial cells that exhibit the ability to transport and deposit precursors, nitrosamines, into the deep layer, leading to epithelial dysplasia [65]. An in vivo study reported the carcinogenic susceptibility of salivary glands to nitrosamine [68]. It has also been reported that the workers exposed to nitrosamine have a higher mortality rate from salivary gland carcinoma [69].
