Introduction

Coronavirus disease 2019 (COVID-19) is a looming, expeditiously growing pandemic, carried out by the enveloped positive-sense single-stranded RNA viruses severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2; βCoVs). It has created an associate degree of unprecedented threat to public health, and prosperity globally since December 2019. As over 128 million COVID-19 cases and 2.82 million deaths till June, 2021 have been reported globally with re-imposed lockdowns and/or curfews, indicates the onset of the second wave and also a continued threat to society [1]. As this virus infects different mammals, humans, and avian species, together with companion animals and livestock, are not solely a public health but also a veterinary as well as an economic concern. Coronaviruses, like human coronavirus OC43 (HCoV-OC43) and HCoV-229E, along with recently discovered HCoV-HKU1 and HCoV-NL63 have been circulated in the human population for a considerable time and are known to cause mild respiratory tract infections associated with the seasonal “common cold” symptoms. Contrary to this, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2, are highly pathogenic [2]. Infectious source, route of transmission, and a susceptible population—are three vital steps for contagious disease development. Due to the fabrication of higher quantities of virus in the upper respiratory tract (URT) amidst the pre-symptomatic period, persons with SARS-CoV-2-infection act as the major source of virus transmission. As the viral load detected in asymptomatic individuals and symptomatic patients is similar, indicating that asymptomatic infections have also the potentiality for transmission [3]. Transmission of SARS-CoV-2 infections are caused by person-to-person close contact, aerosol droplets, and potentially fecal-oral transmission. Although the predominance and transmissibility of SARS-CoV-2 are much greater than MERS and SARS, the severity extent and mortality rates among patients with SARS-CoV-2 infections are comparatively lesser than those with MERS and SARS [4].

In humans, by infecting the mucosal surface, mainly the lungs (pneumocytes, URT cells, and bronchial epithelial cell) or the intestine, SARS-CoV-2 infections can develop into severe lung injuries and life-threatening respiratory pathologies. This pathogenesis is driven by an exaggerated immune response for which no specific therapeutic, as well as a prophylactic treatment, has been approved to date. So far, the immunological analysis of this disease has focused mainly on the systemic immune response found in the blood, but gaining insights into the local mucosal response will help to understand viral pathogenesis along with vaccine efficacy. As the COVID-19 is new to mankind, it is crucial to develop not only a safe but also an effective vaccine strategy to successfully manage the pandemic situation and reinstate normalcy [3, 5].

SARS-CoV-2 infection and progression of disease at mucosal site

The largest integrant of the entire immune system is the mucosal immune system which is augmented to provide a defense mechanism against various environmental pathogens at the mucosae. In humans by causing the infection through mucosal surfaces of the mouth, respiratory tract, or digestive tract, the conjunctival surface of the eye and at the pneumocytes, bronchial epithelial cells, and URT cells, SARS-CoV, SARS-CoV-2, and MERS-CoV are able to develop acute, life-threatening respiratory pathologies and/or lung injuries. Upon any viral infection nasopharynx-associated lymphoid tissue (NALT) and mucosa-associated lymphoid tissue (MALT) act as the primary-line defenses. To induce the immune response against invading microorganism, NALT plays a significant role in activation of immune cells like dendritic cells, T helper1 (Th1) and Th2 cells, macrophages, innate lymphoid cells, resident M cells, B cells, immunoglobulin A (IgA) as well as immune mediators such as cytokines, beta-defensins, collectins, etc. Gut-associated lymphoreticular tissues (GALT) encompass the similar activity as NALT. Extensive research and clinical studies have been manifest COVID-19 as a “multisystem disease” instead of localized “respiratory infection”. It is also apparent that the progression of this disease involves a complex interplay between inflammatory, coagulative, and immunological cascades. So far, no therapeutic or specific prophylactic treatment has been approved for such conditions [1–3].

Initial steps of viral infection depend upon the distinct binding of the viral protein to the host cellular entry receptors, such as SARS-CoV-2, SARS-CoV, and HCoV-NL63 binds with angiotensin-converting enzyme 2 (ACE2), HCoV-229E with human aminopeptidase N (APN), and MERS-CoV interacts with dipeptidyl peptidase 4 (DPP4). The tissue distribution and expression of entry receptors play a major role in controlling pathogenicity as well as viral tropism. Generous expression of ACE2 is found on the lung and intestine epithelial cells, especially secretory goblet cells (nasal mucosa), type II pneumocytes (lung), and absorptive enterocytes (small intestine) which allows the spike (S) proteins to bind with it and establish the host tropism. Along with receptor binding, proteolytic cleavage by the host cell-derived proteases such as transmembrane serine protease 2 (TMPRSS2; cell-surface serine protease), cysteine proteases cathepsin L (CatL), and endosomal CatB is essential by the coronavirus S proteins for priming and entry, within the host cell. Further studies also have shown that TMPRSS2 is profusely expressed in the human respiratory tract, and plays a major role in the transmission and pathogenesis of SARS-CoV-2. So, inhibition of TMPRSS2 by inhibitors such as nafamostat mesylate and camostat mesylate was sufficient to prohibit the SARS-CoV-2 entry in primary lung cells and lung cell lines [5]. Moreover, the presence of a polybasic cleavage site (PRRAR) at the S1-S2 boundary of the SARS-CoV-2 S protein also allows the efficient cleavage by the proprotein convertase called Furin. Such proteolytic cleavage leads to increased infection transmissibility, zoonotic potential, and cell tropism [1, 3]. Inside the host cell coronaviruses integrate and replicate their large (> 30 kb) genomic RNA and produce full-length copies of the genomic RNA, later on, which are integrated within the newly produced viral particles.

In addition to ACE2, other different attachment and entry factors, such as integrins, cellular glycans, and/or neuropilin 1 (NRP-1), have a great impact on the establishment of zoonotic potential. CD147 or extracellular matrix metalloproteinase inducer (EMMPRIN) or Basigin is a transmembrane glycoprotein belongs to the immunoglobulin superfamily, and act as the binding site for SARS-CoV-2. CD147 was identified as red blood cell (RBC) receptor for the parasite Plasmodium (Malaria causing) infection in humans [6, 7]. It also plays a major role in Plasmodium invasion, tumor development, bacterial and viral infection. A recent study by Wang and co-worker [6] demonstrated that SARS-CoV-2 S protein is capable to binds to CD147 along with ACE2 and help in viral invasion and dissemination within the host cell. A phase II clinical trial process is underway for the development of anti-CD147 humanized Meplazumab for injection against SARS-CoV-2 [7]. CD147 is proposed to be a marker protein of untransformed lung stem and progenitor cells, undifferentiated embryonic stem cells, mesenchymal stem cells and act as stimulators of matrix metalloproteinases (MMPs) [6, 7]. Cellular tropism of SARS-CoV in ACE2 expressing residing lung stem cells suggests that failing in repair of the lung injury mainly involves the immobilization as well as un-differentiation of lung stem and progenitor cells. Additionally, during SARS-CoV-2 infection upon viral invasion and loss of lung stem cells, CD147 expressing regenerative cells in lung deposit excessive extracellular matrix (M) proteins and leads to fibrotic diseases such as fibrous stripes and pulmonary fibrosis due to aberrant expression of transforming growth factor-beta1 (TGF-β1). In fact, current clinical pieces of evidence consider the pulmonary fibrosis and/or fibrous stripes in the injured alveolar zone as COVID-19 related complications [8, 9]. Presence of acquired along with genetic disparity in the host immune system further aggravates the host repertoire verging to wide heterogeneity in the clinical outcome.

Prognosis of SARS-CoV-2 infection predominantly occurs at the respiratory and/or oral mucosae where it has interacted along with the immune system, at both inductive as well as effector phases. The mucosal immune system is the biggest integrant of the entire immune system which imparts protection at the main sites of infectious threat—the mucosae. Moreover, glycosylation present on the coronavirus S proteins helps in shielding epitopes, allows the immune evasion from viral-induced neutralizing antibodies within the host cell [10]. Uncontrolled and rapid SARS-CoV-2 replication plays a pivotal role in evading the host’s innate immune activation results in aberrant and enhanced pro-inflammatory responses, infiltration of immune cells in the lungs followed by a severe form of tissue damage and other clinical manifestations. Studies also revealed that coherent presence of SARS-CoV-2 infection modulates the transcriptional landscape of infected cells and induces inflammatory cytokine and chemokine that triggers the inflammation and immunopathologies [11, 12]. IgA is the most heterogeneous immunoglobulin isotypes derived from bone marrow found in three molecular forms (polymeric, secretory, and monomeric), two subclasses such as IgA1 and IgA2, along with numerous glycoforms. IgA-producing mucosal B cells are generated by mucosal inductive site tissues that help in differentiation in polymeric IgA (pIgA)-secreting plasma cells at the mucosal effector sites [13, 14]. In addition to this in the tonsil (home to peripheral lymphoid tissues) IgG-producing B cells are differentiated and secrete IgG for circulation. In the sub-epithelial spaces of the mucosae, pIgA is selectively transported [polymeric Ig receptor (pIgR) mediated pathway] and being released as secretory IgA (sIgA). In nasal passages, trachea, and bronchi, the environmental virus encounters a mucosal immune system-mediated sIgA-dominated environment and sustains a non-inflammatory milieu [15]. However, the terminal airways and alveoli are controlled by circulation-derived IgG. Moreover, plasma-derived IgG appeared in the URT and the lower respiratory tract (LRT), where it helps in the induction of effector mechanisms such as the confrontation of phagocytes [neutrophils and macrophages along with natural killer (NK) cells]; activation of the complement system, etc [16]. The extreme pathological condition related to COVID-19 is enhanced in the terminal airways of the lungs, where circulating IgG intensifies the inflammation by encompassing the cells recruited by virus-induced chemo-attractants. Cytotoxic CD8⁺ T cells and CD4⁺ (a cellular arm of the adaptive immune response), are delivered through the circulation to curtail further propagation of the infection by destroying the infected cells [16, 17]. Although, ongoing researches on the development of an effective vaccine against COVID-19 extensively concentrate on systemic injection that is poorly competent at generating mucosal immune responses. Systemic injections are able to activate the production of cytotoxic T cells along with circulatory IgG antibodies whereas mucosal routes of immunization (partly compartmentalized) such as NALT in the URT, GALT in the gastrointestinal tract are able to induce mucosal immune responses [17, 18].

The alveolar epithelial cells, vascular endothelial cells along lymphocytes, act as the main destination for the virions [19]. Upon replication by RNA polymerase enzyme system SARS-CoV-2 virus releases a large number of virions (infect the neighboring target cells) and viremia (cause embellished systemic and pulmonary inflammatory response) [20]. The production of interferons (part of cellular defense mechanisms) gets interrupted by the virus which results in shock, acute respiratory distress syndrome (ARDS), and coagulopathy, i.e., the clinical presentation of severe COVID-19. The complement pathway through C3a and C5a (potent pro-inflammatory component) also plays a pivotal role in the hyper inflammation by triggering inflammatory cell recruitment along with activation of neutrophils. Crosstalk between several pathways, such as Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor kappa B (NF-κB), and the macrophage activation pathway leads to the release of TNF-α, IL-6 along with other cytokines and chemokines [21, 22]. Such hyper-inflammatory condition contributes to the “cytokine storm”, the hallmark of SARS-CoV2 infection [23]. The extensive production of unregulated interleukins, especially IL-6 (a key player in the cytokine storm), form “positive feedback loops” that stimulate other downstream pathways, and increase the reactants such as C-reactive protein (CRP) production. The persistence of such conditions leads to severe immunopathological conditions of COVID-19 [24].

Effects of co-morbidity factors on COVID-19

Diabetes, SARS-CoV-2 infection and impaired immunity

Diabetes is one of the chronic, non-communicable pandemic diseases worldwide signalized by unusually high blood glucose levels due to disablement in insulin secretion and/or insulin action. Over a period of time, a high level of blood glucose can desecrate tiny to large blood vessels, resulting in increased risk for macrovascular or microvascular complications [59]. Destruction of insulin-producing β-cells by the autoimmune system is associated with type 1 diabetes (T1D), whereas, a combination of a defect in insulin secretion from β-cell, and insulin resistance results in T2D. Overweight/obesity, hyperlipidemia, hypertension, cardiovascular disease and chronic kidney disease are the most frequent conditions in patients with T2D. In the ongoing pandemic, late diabetes conditions like ischemic heart disease and diabetic kidney disease might play a major role by making individuals with diabetes frailer along with increasing the severity of COVID-19 disease [60, 61].

Studies have shown that in patient with T2D insulin deficiency and hyperglycemia is associated with disrupted host immune response, altered cellular immunity and the damaged natural barrier at the mucosal site (due to neuropathy). Diabetes-related impairment of host’s defense against pathogens include various alter expression of immune cells like defects in phagocytosis, suppression of cytokine production, failure to kill microbial proteins, altered neutrophil chemotaxis and dysfunction of other immune cells. In patients with T2D, infection with SARS-CoV-2 can lead to aggravated expression of inflammatory mediators in the blood, such as inflammatory cytokines toxic metabolites, and lipopolysaccharide. Infection with SARS-CoV-2 accentuates the apoptosis of lymphocytes such as CD3⁺, CD4⁺, and CD8⁺ T cells infect circulating immune cells, delays activation of Th1/Th17 modulates the activity of NK cell and IFN-γ production finally leads to lymphocytopenia. Moreover, the SARS-CoV-2 infection leads to increased production of reactive oxygen species (ROS) that are related to vascular endothelial damage, lung fibrosis, and ARDS (Figure 1). Moreover, COVID-19 patients with associated T2D show altered NALT (CD4⁺ and CD8⁺ T cell reduction), aggravate OD and increased rate of susceptibility and severity of the disease [62]. Dysfunction of NALT can impair the development of B cell as well as the production of antibody for clearance of SARS-CoV-2 pathogen [63, 64].

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Figure 1. 

Schematic representation showing different mechanisms involved in T2D mellitus (T2DM) and/or obesity related COVID-19 severity and complications. DIC: disseminated intravascular coagulation; RAS: renin-angiotensin system; RAAS: renin-angiotensin-aldosterone system; PAL-1: plasminogen activator inhibitor 1; HSPG: heparan sulfate proteoglycan; UPR: unfolded protein response; csGRP78: cell surface glucose related protein 78

In T2D patients, SARS-CoV-2 infection initiates a crosstalk between different signaling systems which in turn control the molecular activity of innate immunity. In hyperglycemic patients the complex signaling system of advanced glycation end products (AGE)-receptor for AGE (RAGE) provides the first barrier against pathogens and plays a pivotal role in chronic vascular complications. Proteins, high mobility group box-1 (HMGB1) and S100 acts as the ligand for RAGE signaling system contribute to the inflammatory response by immune cells, like NK cells, macrophages, and dendritic cells, or passively released from damaged cells [65, 66]. In short, due to coronavirus infection in T2D patient crosstalk between different signaling molecules might arbitrate an injurious pulmonary inflammatory response including derangement of the epithelial barrier, lung oedema, neutrophil infiltration that contributes to respiratory failure as well as the death of the patient [67].

Targeted activation of mucosal immune response

The common mucosal immune system (CMIS), which is described as an integrated network of tissues, cells, and effectors molecules that protect the host against infection and environmental harm at mucous membrane surfaces, has received a lot of attention (Figure 2). Mucosal surfaces are immunologically distinctive in that they serve as the principal interface between the host and the physical environment while also serving as an important barrier against pathogens. The mucosal immune system appears to be a system-wide organ, according to a growing body of research. The stimulation of one compartment of the mucosal immune system has been shown to cause changes in distal locations, according to studies [68]. Understanding the connectivity across mucosal locations is critical for disease characterization and vaccine development in the following phase. Finding out what elements link one section of the mucosal immune system to another, as well as the complexities of this communication, will help us appreciate the mucosal immune system as a global organ. This is an issue that must be addressed as soon as possible. Based on their functional and anatomical properties, CMIS can be divided into initiation sites and effector sites. Mucosal vaccination extorts the immune responses not only at the delivery site of antigens but also at the distant, multiple mucosal effector sites.

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Figure 2. 

Schematic representation showing NALT, bronchus-associated lymphoid tissue (BALT), MALT, GALT provided first line of immunity against SARS-CoV-2 infection. GIT: gastrointestinal tract; FOXP3: forkhead box P3

Upon SARS-CoV-2 entry within the host cell, the host immune system triggers the adaptive immune responses by initiating specific virus antigen recognition and presentation processes to control viral reproduction and tissue damage. Tertiary lymphoid tissue, i.e., NALT via dendritic cells and macrophages can initiate innate immunity response, as the first line of mucosal host defense against SARS-CoV-2 along with the prevention of OD and recovery of olfactory function (OF). They help in capture as well as the internalization of virus-specific antigens for T cells presentation at secondary or tertiary lymphoid organs [68, 69]. Additionally, priming of naive T cell maturation (differentiate into antigen-specific effector T cells) and B cell activation which strives the effects at virus infection sites are mainly dependent upon maturing dendritic cells (DCs) migration from the mucosal infection site to NALT. Furthermore, induction of CD4⁺ Th1 cells and CD4⁺ Th2 cells are required for amplification of the immune response via macrophages activation and IFN-γ secretion, and the antigen-specific IgA-producing cells generation in NALT respectively. SARS-CoV-2 specific CD8⁺ T lymphocytes (CTLs) are able to generate high levels of cytotoxic molecules (perforin and granzyme B) and effective cytokines (IFN-γ and TNF-α). More importantly, SARS-CoV-2 neutralization takes place with the help of specific plasma cells that are able to secrete atopic monoclonal antibodies (e.g., IgM, IgA, and IgG) and thereby completely cure the COVID-19 [68–70]. Most B cells within NALT are sIgM⁺ IgD⁺ phenotyped naive B cells which depend upon antigen presenting cells (APCs) for their differentiation into committed B cells for the immune response against the anti-viral antigen. Therefore, an impairment of B cell development and/or reduction in B cell quantity could result in antibody production deficiencies, results in failed SARS-CoV-2 clearance [64].

On the other hand, mucosal inductive sites, such as GALT encompass a MALT. The GALT is organized into three compartments: beneath the intestinal epithelium in the lamina propria, within the epithelial compartment itself, and in organized lymphoid follicles like Peyer patches. It helps guard against external stimuli that pass the luminal mechanical barrier. The MALT consists of B cell-enriched areas that contain a plethora of surface IgA⁺ B cells, T-cell zones, and a subepithelial area with APCs (site for specific immune responses initiation) act as a continuous source of memory T and B cells to mucosal effector sites. A follicle-associated epithelium comprises differentiated microfold epithelial cells, lymphoid cells, and columnar epithelial cells. The hallmark of microfold cells is the lack of secretion of mucus as well as the glycocalyx, which helps them in enabling endocytosis activity and also makes them a suitable vehicle for transferring antigens from luminal to inductive MALT sites. Initiation of mucosal immune response takes place in microfold cells by taking up the viral antigen from the nasal mucosal or intestinal lumen. Later on, these microfold cells transport them to the underlying APCs, like DCs via transcytosis and activate T cells [71–73]. However, relocation of these primed T cells to the germinal centers helps in the secretion of cytokines which in turn promote the B-cell isotype switching for the production of IgA antibodies.

The lungs are the predominant infection site for SARS-CoV-2, it is critical to developing a vaccine that may elicit mucosal protection. Enhancement of mucosal immunity might intensify the production of effective specific IgA at the mucosal site, specific memory T-cell response, and neutralizing IgG. The local mucosal immune response especially the presence of tissue-specific memory T-cells in nasal epithelial and lungs is essential to mitigate the replication of the SARS-CoV-2 virus and also a chance of secondary infection in the host. So, in the case of respiratory infections like COVID-19, the nasal route is more appropriate for the direct administration of vaccines [73, 74]. Although mucosal administration is not contemplating as the usual route for vaccination, certain pharmaceutical companies and research institutes have considered the mucosal formulations of the COVID-19 vaccine as a better alternative (Figure 3).

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Figure 3. 

Schematic representation showing targeted activation of mucosal immune system by mucosal vaccine. FAE: follicle associated epithelium; TFH: follicular helper T cell

According to Brandtzaeg [74], a Norwegian immunologist intranasal administration of vaccines would elicit the regional immune effect on the upper airways by producing a plethora of both mucosal and systemic IgA and systemic IgG immunoglobulins. Furthermore, the adenoids and tonsils are important components of the NALT or Waldeyer’s ring, which is a CMIS. This mucosal-related lymphatic tissue is found under the nasal mucosa’s lamina propria. They act as the primary induction site for the secretory immune system by producing memory-type IgA⁺ B cells and sIgA by plasma cells. Additionally, current studies have shown the presence of isolated lymphoid follicles (ILFs) in the mouse small intestine, which has been recognized as a part of GALT especially mucosal inductive tissue [75]. These ILFs primarily consist of microfold cells, DCs, and B cells in the overlying epithelium. Conjunctiva-associated lymphoreticular tissue (CALT), Larynx-associated lymphoreticular tissue (LALT), Salivary duct-associated lymphoreticular tissue (SDALT), and Tear duct-associated lymphoreticular tissue (TALT) are all mucosal inductive tissues, according to other recent investigations. IgA-producing plasma cells and B and T cells, i.e., antigens-specific mucosal effector cells, are found in mucosal effector locations such as the upper respiratory (UR), lamina propria areas of the gastrointestinal (GI), secretory glandular tissues, reproductive tracts, and intestinal intraepithelial lymphocytes [76, 77].

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a mucosal vascular addressin that is expressed predominantly by venular endothelial cells at lymphocyte extravasation sites in mouse mucosal lymphoid organs and lamina propria. Activated T lymphocytes express CC chemokine receptor 9 (CCR9) and 47 as gut-homing receptors in Peyer’s patches (PPs) for migration into the intestinal lamina propria. In this regard, MAdCAM-1 acts as ligand that aids in T-cell recruitment into the intestinal endothelium. Furthermore, recent studies also demonstrated the role of the mesenteric lymph nodes (MLNs) and retinoic acid-producing DCs in PPs as the enhancer of α4β7 and CCR9 expression by antigens-specific effector CD4⁺ T cells. In addition to the mucosal T-cell homing, retinoic acid-producing DCs in PPs also take part in the regulation of T cell-independent IgA class switching and expression of gut-homing receptor on B cells [78, 79]. Such findings confirm that CMIS has a distinct role in induction as well as regulation of sIgA antibody responses in mucosal effector tissue.

Both monomeric serum IgA and polymeric (pIgA) (dimmers, tetramers, pentamers, and multimers), are produced by plasma B cells. This multivalency of the IgA antibody results in greater avidity for viral peptides compared to IgG and also significantly prevents the intrusion of pathogens by immune exclusion. The secretory component (SC) of the pIgR helps in the active transportation of pIgA as a secretory (sIgA) complex across the cell membrane of the secretory epithelium. Upon reaching the surface of the uninfected cell, the secretory (sIgA) complex gets separated from SC and gets them diffuse into the mucus layer and impart the protective mechanisms. Studies in vitro demonstrated that free SC is able to bind and inhibit IL-8-mediated recruitment of neutrophils [80]. It also helps in the prevention of neutrophil-dependent extracellular traps in the upper airways. During the presence of any viral infection, sIgA plays a role in the neutralization of the pathogens or toxins in the mucosal environment by following three mechanisms such as—excretion, immune exclusion, and intracellular neutralization. Upon systemic and mucosal vaccination, sIgA along with IgG, and transudate IgA are generated and contribute to local surface defense in the LRT and in the genitourinary mucosa as these areas are more permeable to serum-derived antibodies than to the intestine. For providing protection against pathogens, such antibodies deploy a distinct range of effector functions such as—the neutralization of toxins; antibody mediates opsonization and phagocytosis for internalization of invading pathogens. If sIgA-dependent eradication of pathogen is unsuccessful, transudated IgG as well as Serum IgG antibodies exert their immunopathological effect and take part in viral clearance from systemic circulation [80, 81].

Despite the fact that IgA is one of the most widely produced antibodies in the body, MALT tissue synthesis falls with age, which is a characteristic of immunosenescence. The elderly is the most vulnerable population in the current COVID-19 pandemic due to the immunosenescence of IgA antibodies. A study in mice has disclosed that the aging process affects the GI-associated lymphatic tissue to a greater degree than the NALT result in the retaining of immune-competent cells in the nasal mucosa to provide an effective immune response. Nonetheless, it is the need of the hour to design an appropriate, safe and effective mucosal vaccine strategy that uses the combination of proper mucosal adjuvants, delivery systems as well as optimization of the immunization schedule along with different routes of mucosal immunization [81, 82].

Discussion and conclusion

The COVID-19 pandemic has caused significant public health issues, widespread psychological, economic, and sociological damage across the globe. In humans, SARS-CoV-2 infection is associated with ARDS, severe respiratory tract infections, multi-organ failure, and death. The primary infection site for SARS-CoV-2 is the mucosal surface, mainly the lungs and/or the intestine, where the epithelial cells get infected with the virus. The CMIS, NALT, BALT, MALT, and GALT provide the primary line of defense agonists viral infection. The tissue distribution and expression of entry receptors play a serious role in controlling pathogenicity as well as viral tropism. ACE2 has been considered as an entry receptor in coronavirus infection, followed by replication within the host cell. The SARS-CoV-2 entry into the cells favors the progression of inflammatory and thrombotic processes by down-regulates the expression of ACE2 receptors. The loss of ACE2 is directly associated with lung edema, enhanced vascular permeability, and severe lung injury induced by activating the renin-angiotensin system. So, treatment by blocking the ACE2 receptor probably increases the chance of a negative effect along with a poor druggable target. In addition to ACE2, EMMPRIN or CD147 acts as SARS-CoV-2 binding along with the host cell. Moreover, in COVID-19 patient’s pulmonary fibrosis can be observed that is driven by extensive differentiation of resident lung progenitor/stem are into myofibroblasts. The process of pulmonary fibrosis might be associated along with the direct invasion of SARS-CoV-2 into the progenitor/stem cells via CD147 or ACE2, which could decrease the cellular stocks result in failing lung repair. Therefore, a combination strategy of pharmacological along with MSC therapy will be more efficient against COVID-19 and other viral diseases.

An elevated level of cytokine IL-6 and CRP in blood serum considered as the biomarker of severe β-coronavirus infection. The extensive production of unregulated interleukins, especially IL-6 (a key player within the cytokine storm), forms “positive feedback loops” that are able to stimulate other downstream pathways. The persistence of such conditions results in severe immunopathological conditions of COVID-19. So, expression of the inflammation biomarker panels of IL-6, IL-1β, CRP, procalcitonin, D-dimer, and fibrinogen might be considered as more authentic in the prediction of disease severity. Since an appropriate immune response depends upon a balance between cytokines. As excessive enlargement of adipocytes due to lipid overloading promotes mechanical stress and inflammation, results in alteration of secretory function, and induction of necrotic cell death [104–107]. However, in obese patients, IL-6 has associated with the activation of multiple cytokine pathways in a pro-inflammatory state and shuffles this essential balance. In the case of obese patients, disruption of lymphoid tissue integrity and alterations in activity and development of leukocytes could lead to the incoordination of adaptive as well as innate immune responses [51]. Efficient differentiation of preadipocytes to mature adipocytes has a fundamental role in hyperplastic fatty tissue expansion and thus, successfully modulates the whole-body glucose and lipid homeostasis in obesity states. Higher expression of ACE2 receptor in AT might function as a SARS-CoV-2 reservoir. Moreover, obesity might cause hyperglycemia by inducing insulin resistance. In the case of T2D patients, in coagulation homeostasis, and innate immunity, the RAGE system act as a critical player, therefore, by targeting this system it is possible to halt the thrombotic manifestations and cytokine storm combined with dysregulated immune responses to SARS-CoV-2 infection. In COVID-19 patients with co-morbidity factors, dysfunction of NALT can impede the development of B cells along with the production of coherent antibodies for clearance of the SARS-CoV-2 virus. Therefore, reinforcement of NALT not only will help us to understand the antigen presentation process but also will shed light on the effects of nasal vaccination by improving the prognosis along with retrieval of olfactory function in COVID-19 [52, 62, 63].

SARS-CoV-2 virus infection affects adversely on the host lungs and intestine. From the primary attack site, they are transmitted through the respiratory tract or digestive tract and precisely infect the host pulmonary epithelial or intestinal epithelial cells. These act as a causative agent to lung and/or intestinal tissue damage and revoke a systemic immune response. After causing a serious injury to the lungs, SARS-CoV-2 can cross the mucosal immune barrier and move through the “gut-lung axis” and affect the intestine, or vice versa. Cross talk between these two mucosal sites of the host cell might take place through blood and/or lymphatic circulation. Persistent excessive inflammatory response, intestinal tissue damage, and/or dysfunctional immune response can cause disorder to the intestinal microbial flora. Although studies have suggested that use of the probiotics, personalized diet, beneficial metabolites, and elimination of harmful bacteria can provide resistance against such adverse effects. With an emerging number of data, it is very evident that the gut microbial flora plays a major role in blood proteomic biomarkers’ prediction and also in determining the severity of COVID-19 in individuals. Activation of mucosal immunity through the mucosal vaccine required detailed understanding of primary mucosal sites, gut microbial flora, cross-talk between “gut-lung axis”, and their effect on different varieties of coronavirus.

Understanding the connectivity across mucosal locations is critical for disease characterization and vaccine development in the following phase. Moreover, efficient and safe mucosal vaccine development depend upon several factors like the type of antigen, administration route, formulation, choice of adjuvant, and appropriate animal model (safety and efficacy evaluation), etc. A systematic and rational approach of vaccine formulations needs a great knowledge on biophysical characterization as well as immunogenicity of antigens, antigen-adjuvants (use of appropriate viral vectors or nano-based one) interactions, detailed assessment of safety and stability (especially thermostability especially for poor countries) measure. Mucosal immunization has the potential to be more effective than the traditional parenteral vaccination in terms of triggering immune resistance in both mucosal and systemic tissue to protect mucosal surfaces from pathogen invasion. The recent intuitiveness in the innate immune response and the highly vaccine-induced adaptive immune response should be considered. In the coming future, the clinical trial of new mucosal vaccines will be in need. So, the improved formulations along with modern and effective delivery technologies will be considered as the main part of the mucosal vaccine development platform [83].

In this review, we summarize the different aspect of mucosal immunization and their probable prospect against the COVID-19 pandemic. Finally, the most reliable and efficient options must be considered further in clinical trials against SARS-CoV-2 variants. It might consist of either monotherapy or combinational therapies consist of an efficient mucosal vaccine, and novel, broad-spectrum, antiviral drugs active against different variants of coronavirus. Plant-based lectins especially glycan-binding lectins have great potential to bind with SARS-CoV-2 S protein and are considered attractive vaccine adjuvant candidates [108]. Further study on the formulation of nasal spray or inhaler with such plant bioactive molecules or engineered antibodies will be a potent therapeutic and prophylactic strategy in the prevention of a larger array of SARS-CoV2 with reduced side effects.