Mucosal immunity: The missing link in comprehending SARS-CoV-2 infection and transmission

Abstract

SARS-CoV-2 is primarily an airborne infection of the upper respiratory tract, which on reaching the lungs causes the severe acute respiratory disease, COVID-19. Its first contact with the immune system, likely through the nasal passages and Waldeyer's ring of tonsils and adenoids, induces mucosal immune responses revealed by the production of secretory IgA (SIgA) antibodies in saliva, nasal fluid, tears, and other secretions within 4 days of infection. Evidence is accumulating that these responses might limit the virus to the upper respiratory tract resulting in asymptomatic infection or only mild disease. The injectable systemic vaccines that have been successfully developed to prevent serious disease and its consequences do not induce antibodies in mucosal secretions of naïve subjects, but they may recall SIgA antibody responses in secretions of previously infected subjects, thereby helping to explain enhanced resistance to repeated (breakthrough) infection. While many intranasally administered COVID vaccines have been found to induce potentially protective immune responses in experimental animals such as mice, few have demonstrated similar success in humans. Intranasal vaccines should have advantage over injectable vaccines in inducing SIgA antibodies in upper respiratory and oral secretions that would not only prevent initial acquisition of the virus, but also suppress community spread via aerosols and droplets generated from these secretions.

Keywords: COVID-19; SARS-CoV-2; immunoglobulin A; infection; mucosal immunity; transmission.

Figure 1

The common mucosal immune system, illustrating the origin of antigen-stimulated, IgA-committed B cells and cognate T cells in inductive sites, mainly the organized mucosa-associated lymphoid tissues of the respiratory and intestinal tracts, i.e., the palatine, tubal, and lingual tonsils and adenoids, and the gut-associated lymphoid tissues (GALT) i.e., small intestinal Peyer’s patches and large intestinal follicles, respectively. Note that bronchus-associated lymphoid tissue (BALT) does not usually occur in healthy adults, but can be found in children, or be induced by infection (52). Antigen-stimulated B and T cells emigrate and traffic through mesenteric lymph nodes into the circulation, and ultimately home into the lamina propria of respiratory, intestinal, and genital tracts and stroma of salivary, lacrimal, and lactating mammary glands, etc. Homing of cells into mucosal effector sites is orchestrated by the expression of vascular endothelial addressins and production of chemokine ligands in mucosal effector sites, and corresponding integrins and chemokine receptors expressed on B and T cells induced in mucosal inductive sites. Terminal differentiation of B cells into pIgA-secreting plasma cells occurs in these effector sites with help from T cells and locally produced cytokines. SIgA is formed by the pIgR-mediated epithelial transport of this locally synthesized pIgA into the secretions, the extracellular part of pIgR becoming the secretory component of SIgA.