Detection of SARS-CoV-2 and Its Immune Response: History
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Contributor:
Nayeli Shantal Castrejón-Jiménez
,
Blanca Estela García-Pérez
,
Nydia Edith Reyes-Rodríguez
,
Vicente Vega-Sánchez
,
Víctor Manuel Martínez-Juárez
,
Juan Carlos Hernández-González

Los coronavirus son una gran familia de patógenos bien establecidos de varios huéspedes, incluidos animales domésticos, animales salvajes y humanos.

  • lateral flow immunoassay
  • biosensors
  • COVID-19

1. Descripción general del SARS-CoV-2

Los coronavirus son una gran familia de patógenos bien establecidos de varios huéspedes, incluidos animales domésticos, animales salvajes y humanos [ 1 ] . Los virus que causaron brotes anteriores en humanos, causando enfermedades respiratorias graves, lesiones pulmonares y la muerte, son el SARS-CoV (coronavirus del síndrome respiratorio agudo severo) en 2003 y el MERS-CoV (coronavirus del síndrome respiratorio de Oriente Medio) en 2012 [ 2 ] . Un análisis genómico reciente con varias herramientas bioinformáticas demostró que el SARS-CoV-2 tiene un genoma muy similar al del coronavirus Bat y el dominio de unión al receptor (RBD) de la glicoproteína espiga como el coronavirus del pangolín malayo [ 3 ]. Esta evidencia indica que el murciélago de herradura es el reservorio natural, y la evidencia principal sugiere que el pangolín malayo es un huésped intermediario [ 3 ] .
El SARS-CoV-2 es un virus envuelto con un ARN monocatenario de sentido positivo. El tamaño del genoma de este patógeno varía de 29,8 kb a 29,9 kb [ 4 ] . El virus codifica al menos 29 proteínas. Las proteínas estructurales son proteínas de espiga (S), membrana (M), envoltura (E) y nucleocápside (NP) [ 5 ] . Las proteínas no estructurales (nsps) tienen funciones necesarias para la replicación y transcripción en el ciclo de vida del virus [ 6 ] . El tamaño de las partículas virales oscila entre 80 y 120 nm [ 7 ] .
El mecanismo de infección viral en humanos es a través de gotitas y aerosoles, que pueden viajar por el aire [ 8 ] . La infección ocurre en células que expresan ACE2 (enzima convertidora de angiotensina 2) y TMPRSS2 (proteasa de serina transmembrana 2) [ 9 ] . La proteína S del coronavirus se une a ACE2, el principal receptor del SARS-CoV-2 que media la entrada del virus en las células, y TMPRSS2 escinde la proteína S (en las subunidades S1 y S2) del SARS-CoV-2, lo que facilita la fusión del SARS- CoV-2 y membrana celular [ 9 ] [ 10 ] [ 11 ]. Además, se ha demostrado que las cisteína proteasas catepsina B y catepsina L endosomal también pueden contribuir a este proceso [ 10 ] [ 12 ] [ 13 ] . En el tracto respiratorio, ACE2 y TMPRSS2 se expresan en las células secretoras y ciliadas de la nariz, las células secretoras y ciliadas de las vías respiratorias conductoras, en las células alveolares de tipo II en los pulmones y en la conjuntiva corneal del ojo [ 14 ] [ 15 ] [ 16 ] [ 17 ] .
The etiological virus of the pandemic has continuously evolved, with many variants emerging worldwide. Variants are categorized as the variant of interest, variant of concern, and variant under monitoring [18]. There are five SARS-CoV-2 lineages designated as the variant of concern alpha, beta, gamma, delta, and omicron variants [19]. These variants increase transmissibility compared to the original virus and potentially increase disease severity [20].

2. Immune Response against SARS-CoV-2 in Brief

The SARS-CoV-2 infection involves diverse stages in the individual: start of infection, disease development, recovery, or systemic compromise. Each infection stage triggers and modulates innate and adaptative immune system mechanisms. Although SARS-CoV-2 is a virus that humanity is learning about, the immune response is equipped with mechanisms capable of dealing with this new threat. In the initial phase of SARS-CoV-2 infection, the individual presents a presymptomatic phase lasting up to 5 days, in which a high viral load is present [21]. In these early days of infection, antibodies may not have been produced. Therefore, innate immunity is the first activated. The innate immune response comprises soluble and cellular components that respond nonspecifically against the virus. The cellular compounds include dendritic cells (DC), monocytes, macrophages, neutrophils, natural killer (NK) cells, and other innate lymphoid cells (ILCs) [22]. Whereas soluble components include complement systems, soluble proteins, interferons, chemokines, and naturally occurring antibodies [23]. Immune response cells recognize pathogen-associated molecular patterns (PAMPs) of SARS-CoV-2 through pattern recognition receptors (PRRs) such as Toll-like receptors (TLR), RIG-I-like receptors (RLR), and melanoma differentiation-associated protein 5 (MDA5). The viral sensing triggers the activation of signaling pathways which induce the production of immune mediators to generate an antiviral state mainly mediated by type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) [24]. Reports have described that robust IFNs production during the early stage of infection is required to have a protective innate immune response against the virus [25]. On the contrary, an inadequate and slow response to type I and type III IFNs due to virus evasion mechanisms, host comorbidities, or genetic defects cause an exacerbated immune response. This inadequate response induces elevated levels of chemokines (CCL2, CCL8, CXCL2, CXCL8, CXCL9, and CXCL16), high expression of proinflammatory cytokines such as IL-6, IL-10, IL-1, and TNF, in addition to activation, and recruitment of immune cells [26][27]. The called “cytokine storm” leads to unbalanced levels of proinflammatory and antiviral mediators that remain the leading cause of ARDS and multi-organ failure [25][26][28].
On the other hand, the adaptive immune response is orchestrated by CD8+ T lymphocytes, TCD4+, and B lymphocytes, responsible for immunological memory. In response to SARS-CoV-2 infection, it has been shown that non-severe patients or patients with mild symptoms have a low viral load and may not have produced antibodies [29][30]. In contrast, antibodies have been detected by immunoassay tests and biosensors in patients with severe symptoms or cases [29][31]. Patients with a high viral load activate the humoral immune response in the first two weeks of infection [32]. The first seroconversion of antibodies is against protein N, followed by protein S of SARS-CoV-2 in patients with disease symptoms [33]. Immunoglobulins IgA and IgM begin to be detected within the first ten days of infection; however, both antibodies can cross-react with protein N, which is highly conserved among coronaviruses [34][35]. Moreover, high levels of IgG1 and IgG3 are expressed ten to fourteen days after infection in patients with disease symptoms [36][37]. Older adults and seriously ill individuals reach high specificity antibodies concentrations against SARS-CoV-2 S protein.
Due to the urgency of reducing thousands of people’s cases and deaths, scientists have developed several vaccines against COVID-19. Efforts are being made to apply vaccines with emergency use authorization to the world population. Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, the available data show that most approved COVID-19 vaccines protect against severe disease but do not prevent the clinical manifestation of COVID-19 [38]. Instead, it has been demonstrated that new variants with mutations in the spike, the main target of neutralizing antibodies, can escape the neutralization of humoral immunity [39][40].

3. SARS-CoV-2 Detection

Molecular tests or biosensors are the tools for detecting SARS-CoV-2 nucleic acids/ antigens/antibodies against the virus (Figure 1). In the early part of the illness, viral particles and their subunits can be detected; beyond the first two weeks of illness onset, antibodies against the virus could be detected [41]. The SARS-CoV-2 infection stage is highly correlated to the diagnostic technique recommended for the pandemic. Early diagnosis of the disease and isolation of infected people is key to controlling the transmission of SARS-CoV-2 [42][43]. In the initial phase of SARS-CoV-2 infection, the individual presents a presymptomatic phase lasting up to 5 days, in which a high viral load is present [21]. During these early days of infection, antibodies may not be detected. Therefore, since the pandemic began, the diagnostic method has been based on detecting viral genes using the molecular PCR technique, the gold standard worldwide [44][45][46]. The pandemic has exceeded the ability to identify the virus in laboratories using molecular techniques; this has motivated the development of new technologies for the rapid detection of SARS-CoV-2 that are easy to perform compared to molecular tests in clinical laboratories. LFIA has been the unique device approved and available to use in mass worldwide. Biosensors with transducers are developing in SARS-CoV-2 diagnostic. However, most nanomaterials used in these biosensors present interferences with contaminants in human samples compared to performance under experimental conditions. It is important to emphasize that LFIAs have the unique properties of availability, accessibility, economy, and POC (including home use), these characteristics that are not shared by all biosensors with a transducer. In addition, biosensors with transducers require exclusive handling in laboratories certified under the Clinical Laboratory Improvement Amendments of 1998 [47][48]. The FDA have to date approved only one piezoelectric biosensor [47] (Figure 1).
Biosensores 12 00728 g001 550
Figure 1. Principio de la prueba LFIA. La prueba LFIA detecta la molécula objetivo en una membrana absorbente con anticuerpos alineados para formar las líneas de prueba y control. La muestra se coloca en una almohadilla de muestra, luego migra a la almohadilla de conjugado, que contiene el conjugado inmovilizado, generalmente hecho de nanopartículas (oro coloidal, látex coloreado o fluorescente, celulosa coloreada) conjugadas con anticuerpos o antígenos. La muestra interactúa con el conjugado y ambos migran a la siguiente sección de la tira, donde se inmovilizan los componentes biológicos del ensayo (proteínas/anticuerpos/antígenos). En esta sección, se capturan el analito y el conjugado. El exceso de reactivo pasa a través de las líneas de captura y se acumula en la almohadilla absorbente. Los resultados se interpretan en la membrana de nitrocelulosa como la presencia o ausencia de las líneas de prueba y control.

This entry is adapted from the peer-reviewed paper 10.3390/bios12090728

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