Oral Cavity during Viral and Bacterial Infections: Comparison
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Varias Senfermedadesveral virales suelen afectar a la cavidad bucal; por ejemplo, la infección por el diseases often affect the oral cavity; for example, human immunodeficiency virus de la inmunodeficiencia humana (VIH) puede p(HIV) infection may initially presentarse inicialmente con with oral lesiones orales, la infección por el virus del papiloma humano (VPH) a menudo aumenta el riesgo de desarrollars, human papillomavirus (HPV) infection often increases the risk of developing oral squamous cell carcinoma, and oral de células escamosas, y se ha amage has been documentado daño oral durante las infecciones por eled during hepatitis B and C virus de la hepatitiinfections B y C. 

  • COVID-19
  • cavity buccal
  • oral lesion

1. Introducción

La enfermedad pCor coronavirus disease 2019 (COVID-19) es la patología causada por el síndromis the pathology caused by severe acute respiratorio agudo severoy syndrome coronavirus 2 (SARS-CoV-2), que es unwhich is a virus que contiene en suthat contains in its genetic material genético una sola hebra de ARNa single strand of RNA [ 1 ] . AlgunSos de los signos y síntomas clínicos más comunes deme of the most common clinical signs and symptoms of COVID-19 son fiebre, dolor de garganta, dolor de cabeza, dificultad para respirar, tos seca, dolor de estómago, vómitos y, a veces,are fever, sore throat, headache, shortness of breath, dry cough, stomach pain, vomiting, and sometimes diarrhea [ 2 ] . El rAngioteceptor 2 de la enzima convertidora de angiotensina nsin-converting enzyme receptor 2 (ACE2) es uno de los principalesis one of the major receptores conocidos del s known for SARS-CoV-2 para ingresar a las células de los pulmones, el hígado, los riñones, el sistema to enter cells in the lungs, liver, kidneys, gastrointestinal e incluso en elsystem and even on the endotelio de los vasos papilares dérmicos y en el epitelio. superficies de las glándulas sudoríparahelium of dermal papillary vessels and epithelium. sweat gland surfaces [ 3 ]. SeA han descrito diversasvariety of skin manifestaciones cutáneas en pacientes contions have been described in patients with COVID-19, que incluyending pseudosabañones, lesiones mumps, varicelliformes, lesiones similares al erits, erythema multiforme, forma de -like lesions, urticaria form, maculopapular, púurpura y petequias, moteado y lesiones similares a la land petechiae, mottling, and livedo reticularis-like lesions [ 4 ] [ 5 ] . EIn la cavidad oral, la ACE2 sethe oral cavity, CEA2 is expresa en lased in the oral mucosa oral, especialmente y en mayor cantidad en la superficie lingual y en las glándulas ly and in greater quantity on the lingual surface and in saliva-productoras de saliva en relación con laing glands relative to the mucosa de la boca o el paladarof the mouth or palate [ 6 ] . La diDysgeusia es el primer síntoma oral reconocido deis the first recognized oral symptom of COVID-19 informado en el 38 % de los pacientereported in 38% of patients, especialmente en nortealy in North Americanos y europeos y en pacientes con enfermedad de gravedad leve a moderadas and Europeans and in patients with mild to moderate disease severity [ 4 ]. DSincesde que se describieron las primeras the first oral manifestaciones bucales asociadas altions associated with COVID-19, se han publicado varios were described, several reportess have been published describiendo una ampliang a wide variedad dety of lesiones, donde la manifestacións, where the most frequent oral lesional bucal más frecuente es la manifestation is ulceraciótion [ 7 ] , in además de placas blancasddition to white plaques, petequias, lengua geográfica, máculas , nódulos,chiae, geographic tongue, macules, nodules, bullous angina ampollosa, enfermedad, necrotizing periodontal necrosante, ampollas y lesiones similares a eritdisease, blisters, and erythema multiforme-like lesions [ 8 ] [ 9 ]. SLoss of taste ha informado que la pérdida del gusto y/u olfaand/or smell has been reported to persiste hasta por 14 días y for up to 14 days and to progresa más rápidamente en pacientes mayores; la recuperación de lasss more rapidly in older patients; recovery of oral lesiones bucales ocurre al mismo tiempo que los pacientes se recuperan des occurs at the same time as patients recover from COVID-19, lo que representa una asociación entre las ing an association between the manifestaciones de todas lastions of all clinical lesiones clínicas que aparecen en la boca y la infección por s appearing in the mouth and patients' SARS-CoV-2 de los pacientesinfection. [ 10 ] .
DadoSince que lasthe clinical manifestaciones clínicas de tions of COVID-19 más allá del daño pulmonar causado por la inflamación aún no se comprenden adecuadamente, lasbeyond lung damage caused by inflammation are still not adequately understood, the oral health condiciones de salud oral asociadas contions associated with COVID-19 continúan estudiándose para obtener una mejor aue to be studied to gain a better appreciación de lastion of the oral manifestaciones orales. La tions. The crisis que el mundo sigue enfrentando por el that the world continues to face from COVID-19 ha resaltado las highlighted the importancia de comprender las condiciones implícitas que conducen a los resultados relacionados con el e of understanding the implicit conditions that lead to COVID-19, principalmente la -related outcomes, primarily mortalidad, así como laty, as well as positividad y la gravedadty and severity [ 11 ] [ 12 ] [ 13 ] [ 14 ] .

2. LThe ora cavidad oral y su papel en la inmunidadl cavity and its role in immunity

The oral cavity has three major host defenses against microbial invasion: the oral mucosa, nonspecific (innate) immunity, and adaptive (acquired) immunity. The oral mucosa consists of a layer of interconnected epithelial cells containing mainly keratinocytes resting on a basal membrane and provides a physical barrier that protects the underlying tissues from microorganisms and environmental threats in the oral cavity [15][16][17]. Cells of the immune system and oral keratinocytes in the lamina propria of the oral mucosa detect some pathogen-associated molecular patterns that have been conserved by evolution in specific classes of microorganisms [18][19]. Pattern recognition receptors distinguish between different molecular structures of microorganisms and thus prevent the generation of immunoinflammatory responses against these microorganisms [20][21]. Pattern recognition receptor families have been described in some reports, in which have been included for example the toll-like receptor family (TLR-1 to TLR-10) and the C-type lectin receptor family (Dectin-1, Dectin-2, dendritic cell specific intercellular adhesion molecule 3-grabbing nonintegrin) [22]. The initiation and determination of the type of specific adaptive immune responses induced by pattern recognition receptors also dictate the magnitude and duration of the responses and whether or not memory T cells are activated [20]. The specificity, type, and sensitivity of pattern recognition receptor-mediated adaptive immune responses are determined by the nature of the infectious agent, for example, if they are viruses, bacteria, fungi, and/or protozoan [23]. By the microenvironment characteristics, the type of cells expressing each family of pattern recognition receptors, the anatomical site where these cells are located, and the combination of interactions that occur between these factors [24]. Warning signals generated by some tissue-damaging factors, including hypoxia, radiation, and trauma to some extent affect the speed and magnitude of the immune response [25].

3. Oral Cavity during Viral and Bacterial Infections

Several viral diseases usually affect the oral cavity; for example, human immunodeficiency virus (HIV) infection may initially present with oral lesions, human papillomavirus (HPV) infection often increases the risk of developing oral squamous cell carcinoma, and oral damage has been documented during hepatitis B and C virus infections [26][27][28][29].
There is a combination of proteins with complementary dynamics in virus and/or bacterial infection in the oral cavity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be significantly stimulated in response to infections that are primarily viral in origin [30]. Interferon gamma-induced protein-10 (IP-10) levels are generally slightly elevated in patients with bacterial infections and highly elevated in patients with viral infections. It is also known that C-reactive protein (CRP) levels are commonly found to be increased in patients who have developed infections of bacterial origin and that CRP levels are less elevated in patients who have developed infections caused by viruses (Figure 1) [31].
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Figure 1. Selective host response against bacterial and viral infections. Different molecules and signaling pathways are dynamically involved in complementing the response to virus and bacterial infections (including CRP, IP-10 and TRAIL). IL-6: interleukin-6; LPS: lipopolysaccharide; PAMPs: pathogen-associated molecular patterns; PGN: peptidoglycan; ssRNA: single-stranded RNA; dsRNA: double-stranded RNA. Adapted with permission from Oved, K. et al. (2015) [32], which was distributed under the terms of the Creative Commons Attribution License https://creativecommons.org/licenses/by/4.0/; accessed date 28 November 2021.
Some drugs used in the treatment of viral infections can also contribute to damage to the oral cavity. High doses of corticosteroids may trigger fungal infections such as oral candidiasis; antiviral drugs can cause dry mouth, aphthous ulcers, and stomatitis; and the use of antiviral drugs can cause dry mouth [33]. Additionally, many patients have been prescribed antibiotics that are effective against Gram-negative and Gram-positive bacteria, which usually has a direct impact on the homeostasis of the mouth and all microorganisms found in this cavity [34].

Oral Cavity and SARS-CoV-2 Infection

As mentioned before, SARS-CoV-2 is an RNA-positive virus with an icosahedral morphology that possesses S proteins that are the binding site for ACE2 in humans [1], which, in addition to the lungs, pancreas, adipose tissue, liver, or kidney, this receptor is also expressed in salivary glands [35]. The oral cavity is a gateway for many pathogens, and SARS-CoV-2 is not the exception. This virus is detected in the saliva of all COVID-19 patients even with more sensitivity than that of nasopharyngeal testing [36].
When the ACE2 protein of the host cell and the S protein of SARS-CoV-2 bind, an interaction occurs that allows the coronavirus to use the machinery of these host cells to replicate and subsequently destroy these same cells, triggering the oral symptoms and signs [37]. In addition to this mechanism, which explains the cause of several manifestations of oral lesions caused by COVID-19, it is also possible that these lesions are the result of opportunistic infections that facilitate immune system alterations and may also be facilitated by possible systemic damage and adverse effects that can be triggered by treatment [38]. Figure 2 represents the location of ACE2 in different tissues and structures of the oral cavity, as well as those interacting with SARS-CoV-2.
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Figure 2. Location of ACE2 on oral cavity and its interaction with the SARS-CoV-2. Binding between the SARS-CoV-2 S protein and the ACE2 protein allows entry of the coronavirus, which subsequently allows its replication and the immediate activation of a possible innate immune response against the virus, including the infiltration of a myriad of immune cells and the subsequent production of many proinflammatory cytokines. This triggers the manifestation of symptoms and signs in the oral cavity of patients with COVID-19 (a). Various spaces and surfaces in the oral cavity where the virus and its receptors are detected, such as the oral mucosa, periodontal tissues, salivary glands, and tongue (b).
Cellular analyses of ACE2 expression as a SARS-CoV-2 entry factor revealed that no oral epithelial subpopulations are at particular risk. The ACE2 receptor was detected in nine oral epithelial cell groups, including basal 1–3, basal cyclic, salivary gland ducts, serous salivary glands, and mucous salivary glands, indicating that multiple oral epithelial cell subpopulations are prone to infection [39]. Coexpression of the most important entry factors ACE2 and TMPRSS2 in mucosal and salivary gland epithelial cells was rare in salivary gland acini and ducts [40]. The clinical development of chemosensitivity disorders usually occurs at the beginning of the infection phase in which the first symptoms are already present, usually within the first three days [41]. Two theories have been described on the pathophysiological factors causing dysgeusia and loss of olfaction in the course of COVID-19 infection: the first theory indicates that SARS-CoV-2 infects neurons using active cellular transport to gain access to the central nervous system [42]. LaThe segunda teoría sugiere que estas disfunciones se deben a la cond theory suggests that these dysfunctions are due to inhibición deltion of the ACE2 receptor ACE2; ya se ha informado que los; it has already been reported that inhibidores de estators of this proteínain inducen ageusia a través de un mecanismo complejo que involucra el canal dthrough a complex mechanism involving the sodioum channel presente en las papilas gustativas y el in taste buds and the G protein-coupled receptor acoplado a proteína G; tras la ; upon interacción entre eltion between SARS-CoV-2 y los and host cell receptores de la célula huésped, estos últimos se inactivan, lo que provoca la pérdida de la señalización química del gusto en sus potenciales de acción y, por lo tanto, de las, the latter are inactivated, resulting in the loss of chemical taste signaling in their action potentials and, therefore, of the correcta sensory percepción sensorial del gustotion of taste [ 41 ] .

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