Encyclopedia
Please note this is a comparison between Version 1 by Hamid Tebyaniyan and Version 2 by Lindsay Dong.
The natural flora of the mouth is very diverse. After the large intestine, it has the second highest complexity in terms of microorganisms, including more than 700 microorganisms. Each tissue has specific microbes that are different from adjacent tissues’ microbes. Still, these microbes can be displaced under certain conditions, such as the effects of cytotoxic drugs, oral cancer, or epithelial atrophy. The oral flora is divided into two categories, static and transient, which regularly balance with the host and protect against pathogenic microorganisms. The static flora on oral cavity surfaces is known as biofilm that can improve or protect oral health against pathogens, increase the virulence of potentially harmful microorganisms, and reduce the effectiveness of antimicrobial agents. Infections caused by bacteria in the mouth include caries and periodontitis. Microorganisms can attack different parts of the mouth via different mechanisms.
- oral infections
- orofacial infection
- orofacial microbes
1. Introduction
The tongue is the primary source of microbes in saliva and the major oral site for microbial growth [1][2]. Some bacterial, viral, and fungal agents can affect the skin and mucous membranes in the orofacial area. These factors can cross natural barriers and cause lesions of varying degrees. Some of them can even be life-threatening. The local and systemic factors determining the microbiota and genetics, as well as the individual factors such as diet, teeth brushing habits, dentures, dental procedures, mouthwashes, medications, etc., can be involved in the occurrence of orofacial infections [2][3][4][5][6][7][1,3,4,5,6,7]. Oral infections can occur under certain conditions, such as poor oral hygiene, antibiotic consumption, trauma, and dry mouth, and can damage the oral cavity. These infections also may spread into the nearby tissues and turn into systemic infections. For example, chronic oral infections are known to be a risk factor for cardiac disease [1][2].
2. Herpes Simplex Virus
Herpes simplex virus [8][16] is one of 200 species of the Herpesviridae family and belongs to the subfamily Alphaherpesvirinae, the genus Simplexvirus. Despite differences in host and morphology, this family is thought to be originated from a common ancestor with tailed bacteriophages [9][17]. These viruses are about 120 to 200 nanometers in diameter. Structurally, they include a circled DNA containing a unique long (UL) segment and a unique short (US) segment (opposite repeats) [9][10][17,18]. In addition, they have an icosahedral symmetric capsid, protein coating, and a lipid bilayer cell-like envelope. Genome transcription and replication and the formation of new capsids occur in the host cell’s nucleus [10][18]. These viruses’ short reproductive cycle helps them rapidly destroy the host cells [9][17]. During the infection procedure, the envelope releases the capsid into the host cell’s cytoplasm after fusion with its plasma membrane. HSV can attack nerve tissue and multiply there (neuro-virulence). Eighty-three percent identical nucleotides and fifty percent homology in the sequence display a strong association between the two types of herpes virus: HSV-1 and 2 [9][17]. HSV is also recognized for its latency ability in trigeminal and sacral ganglion nuclei of the ganglia structures [9][11][17,19]. HSV fuses to the axon termini to establish latency and moves retrogradely along the sensory fibers (Figure 1) [9][17]. Then, it generates latency-associated transcripts (LATs) that enhance axon regeneration, reduce viral gene expression, and prevent nerve cell apoptosis [12][20].
Figure 1. The latent infection of HSV-1 leads to permanent arrest in an G0/G1-like state in the sensory ganglia that will never reenter mitosis ①. During reactivation, virus genes are expressed in cells in the most permissive state ②. Then, reactivated virions travels in axons ③ to termini on the epidermis ④, and then transmitted to the spinosum and granulosum strata layers of the epidermis ⑤ [9][17].
The disease has no clinical signs at the initial acquisition or during periods of reactivation. However, symptoms occur in the active periods of the disease, following asymptomatic periods, on a rotating basis [13][23]. Clinical symptoms of the first episode of the disease include headache, fever, muscle aches, and inflammation of the lymph nodes [13][23]. Then, classic lesions are created that include fluid-filled vesicles that become purulent and dry. Genital herpes includes small blisters resulting in benign ulcers, whereas, in cold sores, several small blisters are aggregated [13][23]. Other vital clinical signs of common gingivitis include bleeding gums with edema and friable erythematosus. In addition, sores on the buccal mucosa and gums may be yellow based on a red halo. These oral lesions are often associated with anorexia. Symptoms in young children can include drooling, halitosis, and dehydration [13][23]. Herpetic vitiligo is another manifestation, which is painful, erythematous, and swollen lesions often occur in the distal phalanx of the hand, caused by HSV-1 or HSV-2. This lesion mainly affects the fingers (thumb) and rarely the palm [13][23]. HSV-1 eczema herpeticum of Kaposi varicelliform eruption is caused by poor immunity due to atopic dermatitis, burns, or topical immunosuppressants. The disease includes vesicular skin lesions [14][24]. HSV eye keratitis and HSV encephalitis are other complications caused by this virus. Eye involvement can lead to sensitive retinal necrosis, conjunctivitis, blepharitis, or chorioretinitis. Reaching this viral infection to the brain parenchyma leads to extensive hemorrhagic necrosis and vascular occlusion. Encephalitis is the worst outcome that can occur in a healthy person following this infection [14][15][24,25].
Because most people with HSV-2 do not have the classic clinical symptoms, genital herpes is more challenging to diagnose than oral herpes and can be confused with related diseases such as fungal infections, lichen planus, atopic dermatitis, and urinary tract diseases. Diagnosis is confirmed by laboratory tests, including polymerase chain reaction (PCR), skin biopsy, immunofluorescence, and virus culture polymerase chain reaction (PCR). Blood and urine cultures determine previous and ongoing infections, respectively. PCR is more sensitive and accurate for diagnosing HSV in mucosal surfaces than vesicular fluid culture. In patients with a history of genital ulcers lacking active lesions, serological diagnostic tests are conducted [16][27].
Although antiviral drugs, including acyclovir, valaciclovir, famciclovir, and penciclovir, reduce the disease’s incidence, duration, and severity, no way exists to remove the virus from the body. Painkillers and topical anesthetic treatments can relieve pain/fever and itching, respectively; however, their efficiency has been controversial [17][28]. In addition, intravenous infusion of acyclovir is recommended for eczema herpeticum to be limited and prevented from spreading to the eye [15][25]. Seizure control, fluids management, and intracranial pressure control will improve results in HSV-based eye keratitis [14][15][24,25]. Suppressive therapy, such as corticosteroids, is commonly used to improve pain and tenderness at the onset of symptoms. Oral acyclovir has a positive therapeutic effect on primary and recurrent HSV genital infections [15][25]. Some studies have discussed the antiviral activity of some essential oils on the HSV spp. (even acyclovir-resistant strains) through different mechanisms, such as inhibiting cell attachment.
3. Human Papilloma Viruses
Papillomaviruses have a wide genetic diversity. Human papillomavirus (HPV) viruses use human cellular proteins to reproduce and survive [18][52]. The virus genome consists of open reading frames [19][53] and long control regions (LCR) to regulate the replication and transcription of primary genes [20][54]. The main reservoir of HPV is inflamed gums, salivary gland epithelium, and cryptal epithelium of tonsils, oral border, and oropharynx. The most clinically important genus of HPV is the alpha genus of human papillomavirus [18][52]. In high-risk HPV, placing the virus genome in the host genome breaks the virus genome at the E1 and E2 sites, and losing E2, in turn, causes E6 and E7 to lose control that, inhibits the regular function of p53 and pRb, respectively, and interfere with the cell cycle [21][55].
HPV infection can be transmitted from the mother’s cervix (sexual and non-sexual fomite transmission) and produces clinical or subclinical lesions. Oral HPV lesions include a range of benign oral lesions, lichen planus, fibroma, hyperplastic, papillomatous, verrucous, and carcinoma lesions. Generally, flat, exophytic, or wart-like white lesions in the oral mucosa, exophytic, wart-like, or papillary proliferations can be considered clinical manifestations of HPV [22][58]. Oral sex is the main transmission root in these diseases, and soft-circumscribed sessile nodular lesions and koilocytosis are some of their pathological and cellular manifestations [23][59]. The latent location of HPV in the mouth is usually in the gingival pocket because it is the only place where basal cells are in direct contact with the environment [24][60]. In about one-fourth of patients with periodontal disease in a clinical survey, the gingival samples have been associated with HPV [24][60].
There are several diagnostic methods for HPV. Immunohistochemical analysis-specific antibodies (e.g., p16INK4A and p16 IHC) and HPV mRNA/DNA-detecting PCR are the sensitive and cost-effective diagnostic methods for HNSCC tumor specimens. However, studies have shown that mRNA tests are the best approach for confirming the diagnosis [25][63]. Serological biomarker tests cannot be used for detecting HPV infection in the oral cavity. Their examination in oral fluids is useful for identifying and examining the incidence and course of the disease as they are low-cost, non-invasive, and local-specific [26][64].
Syrjänen discusses that HPV particles only get inactivated at temperatures 75–80 °C [27][62]. Preventive approaches such as vaccination and routine screening of HPV antibodies in the saliva are among the most effective ways to prevent HPV-associated head and neck diseases. Cold therapy, electrosurgery, surgical resection, laser therapy, and trichloroacetic acid are the usual treatments for papillomas/condyloma, verocroas, and FEH occurred by HPV [18][52].
4. Candida albicans
More than 200 species of the genus Candida are usually non-pathogenic in humans. However, in immunocompromised individuals, Candida is the most frequent cause of oral mucosal infections, commonly due to antibiotics and the consequent change in the bacterial microbiota. In addition, suppressing the local or systemic immune system prepares the environment for infection. This group’s most common pathogen species is C. albicans, which accounts for more than 90% of oral lesions [28][65]. Morphological control between yeast and hyphae by C. albicans is involved in its pathogenesis. C. albicans co-adhesion with oral bacteria such as S. mutans helps it to colonize, persist, and grow by receiving a carbon supply. Vice versa, Candida reduces the bacteria’s oxygen stress, promotes better bacteria adhesion, and prepares stimulatory growth factors [29][30][66,67].
Pseudomembranous, erythema, hyperplasticity, mucosal irritation, and edema are the symptoms of primary oral candidiasis [31][32][70,71]. In more severe cases, hemodynamic instability, positive blood cultures, fever, shock, and tachycardia may occur [31][70]. Pseudomembranous Candidiasis (thrush) is found on the white plaques, buccal mucosa, oropharynx, and junction of the hard and soft palate and is the most common form of candidiasis. Although some patients may experience a sour taste, burning sensation, and bleeding in the affected areas, most patients are asymptomatic [32][71]. Candidiasis may be hyperplastic or atrophic and occurs in either chronic or acute forms [31][33][70,72]. Different types of candidiasis can be asymptomatic or ulcerous [31][70]. Hyperplastic candidiasis resembles leukoplakia and may involve the labial commissures and become malignant [33][72]. Its chronic form is challenging to diagnose since the hyphae may hide in any rough surface in the oral cavity, such as papilloma, epithelial dysplasia, and squamous cell carcinoma [33][72]. Acute atrophic candidiasis is usually iatrogenic (such as antibiotic consumption) and especially common in HIV patients, whereas chronic atrophic candidiasis is iatrogenic mainly due to orthodontic retainers or dentures that do not adequately fit in place [31][70]. Chronic atrophic candidiasis and inflammatory papillary hyperplasia [34][73] may also accompany due to iatrogenic candidiasis because of taking biopsies from median rhomboid glossitis, smoking, and inhaled steroids, for instance [31][70].
Candidiasis suspicion is based on examining mucosal changes, stained smears with Schiff’s reagent or KOH, and histopathological biopsies, searching for the hyphae or epithelial parakeratosis with polymorphonuclear leukocytes [35][78]. Transcribed internal distance sequencing [36][40] can be used to identify emerging candidate species and the historical course of candidiasis. For the rapid diagnosis of invasive candidiasis, serological biomarkers, including antibodies against mycelium, β-d-glucan (BDG), mannan antigen (Mannan-Ag), and mannan antibodies, are evaluated [37][79]. Endoscopy is also necessary for esophageal candidiasis suspicion patients [31][70].
Polyenes and azoles are two types of antifungal drugs [38][39][80,81]. Polyenes (with conjugated double bonds) bind to sterols (mainly ergosterols) and change the cell membrane transfer temperature. Then, the leakage of monovalent ions (K+, Na+, H+, and Cl2) and small organic molecules lead to cell death [38][80]. On the other hand, azole stores α-methylase enosterol to prevent the lanosterol to ergosterol conversion. These topical drugs have no pharmacological systemic side effects since they have no systemic absorption. In cases where topical drugs do not respond, systemic drugs are used [39][81]. Studies have shown that probiotics may affect the toxicity of C. albicans.
