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Review
. 2024 Aug 30:15:1358885.
doi: 10.3389/fimmu.2024.1358885. eCollection 2024.

Mucosal immunity in upper and lower respiratory tract to MERS-CoV

Khalid J Shrwani  1   2 , Waleed H Mahallawi  3 , Abdulrhman I Mohana  4 , Abdullah Algaissi  5   6 , Nabil Dhayhi  7 , Nouf J Sharwani  8 , Eyad Gadour  9   10 , Saeed M Aldossari  11 , Hasan Asiri  12 , Nader Kameli  13 , Ayad Y Asiri  14 , Abdullah M Asiri  15 , Alaa J Sherwani  16 , Nigel Cunliffe  1 , Qibo Zhang  17
Affiliations
Review

Mucosal immunity in upper and lower respiratory tract to MERS-CoV

Khalid J Shrwani et al. Front Immunol. .

Abstract

Introduction: Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged as a deadly pathogen with a mortality rate of up to 36.2%. MERS-CoV can cause severe respiratory tract disease and multiorgan failure. Therefore, therapeutic vaccines are urgently needed. This intensive review explores the human immune responses and their immunological mechanisms during MERS-CoV infection in the mucosa of the upper and lower respiratory tracts (URT and LRT, respectively).

Objective: The aim of this study is to provide a valuable, informative, and critical summary of the protective immune mechanisms against MERS-CoV infection in the URT/LRT for the purpose of preventing and controlling MERS-CoV disease and designing effective therapeutic vaccines.

Methods: In this review, we focus on the immune potential of the respiratory tract following MERS-CoV infection. We searched PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar using the following terms: "MERS-CoV", "B cells", "T cells", "cytokines", "chemokines", "cytotoxic", and "upper and lower respiratory tracts".

Results: We found and included 152 studies in this review. We report that the cellular innate immune response, including macrophages, dendritic cells, and natural killer cells, produces antiviral substances such as interferons and interleukins to prevent the virus from spreading. In the adaptive and humoral immune responses, CD4+ helper T cells, CD8+ cytotoxic T cells, B cells, and plasma cells protect against MERS-CoV infection in URT and LRT.

Conclusion: The human nasopharynx-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) could successfully limit the spread of several respiratory pathogens. However, in the case of MERS-CoV infection, limited research has been conducted in humans with regard to immunopathogenesis and mucosal immune responses due to the lack of relevant tissues. A better understanding of the immune mechanisms of the URT and LRT is vital for the design and development of effective MERS-CoV vaccines.

Keywords: MERS-CoV; chemokines; cytokines; immune cells; lung; mucosal; tonsils; upper and lower respiratory tracts.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic structure of the MERS-CoV genome (18). (A) Schematic structure of the MERS-CoV virion (ssRNA) and its major structural proteins; N protein, M protein, E protein, and S glycoprotein. (B) MERS-CoV genomic structure, with the untranslated region (UTR) 5′ and 3′; open reading frame regions ORF1a, ORF1b, ORF3, ORF4a, ORF4b, ORF5, and ORF8; S glycoprotein; E protein; M protein; and N protein.
Figure 2
Figure 2
Schematic representation of the extra/intracellular immune response to MERS-CoV infection (34). The communications (interactions) between invading viruses and host cells lead to the generation and release of robust immune effective mediators. (A) Extracellularly, MERS-CoV binds its target DPP4 receptors on the cell membrane of the target cells, leading to the presence of genomic materials in the Th-0 cells. Consequently, the CD4+ T lymphocytes are activated and differentiate into Th-1, Th-2, and Th-17 subsets that secrete high amounts of subset-specific cytokines valuable in immune response enhancement. The cytotoxic effect of CD8+ T cells for the clearance of MERS-CoV is supported by the production of IFN-γ and the cytolytic granules containing mainly perforin and granzyme B. Plasma cells are responsible for the production of MERS-CoV-specific antibodies, some of them being able to neutralize the virus, stopping its dissemination. The duration of virus-specific antibody responses is not yet known. The binding of MERS-CoV S protein to DPP4 receptors on the target host cells causes the release of virus genomic RNA in the cell cytoplasm. (B) Intracellularly, host immune responses to double-stranded ribonucleic acid (ds-RNA) can be partially produced during viral replication. The presence of ds-RNA activates the endosomal TLR-3, which prompts the signaling pathways to activate NF-κB via TRAF-6 and IRFs via TRAF-3 to produce both IFN-I and pro-inflammatory cytokine markers. The production and activation of IFN-I plays a key role by enhancing and releasing specific antiviral proteins to warn and protect un-infected cells during MERS-CoV infection. The activation of pro-inflammatory cytokines through the MyD-88-dependent signaling pathway may occur via the interactions between the TLR-4 and MERS-CoV S protein. The production and secretion of large amounts of cytokines and chemokines, such as IP-10, IL-10, and MCP-1, are stimulated to intracellularly target the MERS-CoV infection. Consequently, lymphocytes and leukocytes are recruited by these cytokine and chemokine markers to the site of infection to clear the virus.
Figure 3
Figure 3
Schematic representation of the host immunity to MERS-CoV infection in the human lung (–90). This figure shows the potential immunopathogenesis during MERS-CoV infection. Initially, host–viral entry was found at alveoli epithelial. The initial virus entry into the lung was observed in alveolar epithelia after binding of S glycoprotein RBD to the DPP4 receptor. The presence of the MERS-CoV particles leads to pro-inflammatory cytokine production from several ILCs, resulting in regulation of both innate and adaptive immune cells and accelerating the recruitment of immune effector cells at the site of infection for controlling and clearing the viral infection. CD4+ T cells and CD8+ cytotoxic T cells are recruited to the site of infection to kill virus-infected cells in the lungs. Activated B cells differentiate into plasma cells that can produce MERS-CoV-specific antibodies efficient in the lung not only by stopping the virus dissemination, but also by entering into blood circulation, thus conferring protection to other mucosal sites.
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