Future SARS-CoV-2 vaccines could hijack commensal bacteria in the gut–lung axis to confer immunity

By Neha MathurJul 18 2022Reviewed by Aimee Molineux

In a recent study published in Biotech, researchers screened bacterial mucosal vaccine vectors from 2015 to the present to identify a promising candidate to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein or its fragments.

Background

A greater understanding of the interplay between the host and commensal bacteria in mucosal niches and specific host immunoregulation pathways could help extend the target repertoire in reverse vaccinology (RV).

Concerning SARS-CoV-2, the commensal microbial communities in the gut–lung axis could potently induce innate cell-mediated immunity through an interaction with the mucosal epithelium. Such co-existence could help achieve homeostasis and enhance immunological tolerance. Therefore, next-generation coronavirus disease 2019 (COVID-19) vaccines using specially designed bacterial mucosal vaccine vectors could potentially manipulate and hijack the commensal bacteria in instigating specific immune responses.

The study

In the present study, researchers specifically searched and described research discussing bacterial vaccine vectors derived from the gut–lung axis and under testing as mucosal vaccines. Further, they focused on three subdivisions of the mucosal-associated lymphoid tissue (MALT) viz., the gut-associated lymphoid tissue (GALT), bronchus-associated lymphoid tissue (BALT), and nasopharynx-associated lymphoid tissue (NALT), and their interplay with the microbiome in the gut-lung axis.

The dendritic cells (DCs) in the gut are CD103⁺, and they respond to T and B cells through a retinoic acid receptor-dependent mechanism. Immature DCs engulf pathogenic bacteria in the lumen and initiate the accumulation of new DCs to increase the engulfment rate. Further, these DCs induce T helper cells, viz., Th1, and Th17 cells, which favor a pro-inflammatory microenvironment.

To suppress this inflammatory state or mucosal inflammation, immature DCs become tolerogenic DCs (tolDCs) that facilitate the formation of regulatory T helper cells (Treg). Recurring exposure of the same antigen to DCs induces an immune tolerance state. The gamma delta T cells (γδ T-cell) also play a crucial role in mucosal tissues of the lung and intestine.

Furthermore, DCs activate B cells in a T-cell-dependent or independent way. Likewise, secreted immunoglobulin A (SIgA) is a critical player in the GALT and promotes immune exclusion. For instance, breastfeeding passes SIgA from a lactating mother to her infant and prevents gastrointestinal and respiratory tract infections. Additionally, IgG isotype binds to the bacteria and destroys it through lysis and activating complement system.

Tissue injury due to pathogens releases danger-associated molecular patterns (DAMPs), such as heat-shock proteins (HSPs), fibrinogen, etc. However, only pathogen-associated molecular patterns (PAMPs) elicit an immune response, especially viability-associated (vita)-PAMPs, and hence are promising candidate targets for developing new bacterial-based mucosal vaccines.

The authors found research citing several vita-PAMPs, such as bacterial pyrophosphates, quorum-sensing molecules, cyclic-diguanylate, etc., as vita-PAMPs. In a study by Yang and co-workers, they observed that filamentous bacteria (SBF) induce the production of Th17 via its antigen but produced Th1 instead when Listeria monocytogenes expressed the same antigen.

Studies have found that the lung is defended by highly specialized immune cells, including alveolar macrophages and DCs, a mucus barrier, ciliated epithelial cell types I and II, goblet cells, et cetera. Based on a load of dead bacteria and other pathogens that reach the lung, the mucociliary clearance system (MCC) and macrophages induce an anti-inflammatory state in the lungs. Therefore, whenever the average load of any colonizing species naturally present in the upper respiratory tract increases, it elicits a lung response; this could aid the development of mucosal vaccines for respiratory infections.

The gut–lung axis could be a good place for the mucosal vaccine vectors. The use of streptococci species is not yet well-studied. Marchisio and co-workers used Streptococcus salivarius as a prophylactic species and found that their recolonization correlated to a decrease in otopathogens and acute otitis media (AOM) events. In another study, Shekhar and co-workers demonstrated that genetically engineered strains of Streptococcus mitis produced a more targeted response than their wild counterparts in combating pneumococcal lung infection in a mouse model.

Similarly, in a study by Wang et al., genetically engineered recombinant strains of Salmonella and Lactobacillus, especially L. plantarum expressing the receptor-binding domain (RBD) of the SARS-CoV-2 S protein elicited mucosal IgA in the respiratory and intestinal tract. Jia and co-workers used a live attenuated Francisella tularensis subspecies holarctica vector to express SARS-CoV-2 S, envelope, membrane, and nucleocapsid proteins.

Conclusions

Future studies should focus on identifying the dominant microbial species in several distinct niches (e.g., the upper respiratory tract) for insights into host–bacterial and interbacterial association networks. Knowledge of resident microbes, including their pathogenicity, colonization span, growth rate, etc., is necessary for host protection and immune homeostasis and designing bacterial mucosal vector-based vaccines with longer and stronger immunization profiles. Most importantly, studies should identify resident commensal species that release byproducts and probiotics with a protective function. They represent significant potential in activating the immune system maximizing the effect of mucosal vaccines.

Since the mechanism of action and limitations of current COVID-19 vaccines are unclear, the scientific community needs to continuously observe, prepare, and develop anti-SARS-CoV-2 prophylactic, diagnostic, and therapeutic tools. Additionally, it would require new approaches to fortifying natural mucosal and systemic immune defenses.