The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19

Abstract

Probiotic bacteria are able to modulate general antiviral responsiveness, including barrier functionality and innate and adaptive immune responses. The COVID-19 pandemic, resulting from SARS-CoV-2 infection, has created a need to control and treat this viral infection and its ensuing immunopathology with a variety of approaches; one such approach may involve the administration of probiotic bacteria. As with most viral infections, its pathological responses are not fully driven by the virus, but are significantly contributed to by the host's immune response to viral infection. The potential adoption of probiotics in the treatment of COVID-19 will have to appreciate the fine line between inducing antiviral immunity without over-provoking immune inflammatory responses resulting in host-derived immunopathological tissue damage. Additionally, the effect exerted on the immune system by SARS-CoV-2 evasion strategies will also have to be considered when developing a robust response to this virus. This review will introduce the immunopathology of COVID-19 and the immunomodulatory effects of probiotic strains, and through their effects on a range of respiratory pathogens (IAV, SARS-CoV, RSV), as well as SARS-CoV-2, will culminate in a focus on how these bacteria can potentially manipulate both infectivity and immune responsiveness via barrier functionality and both innate and adaptive immunity. In conclusion, the harnessing of induction and augmentation of antiviral immunity via probiotics may not only act as an ingestible adjuvant, boosting immune responsiveness to SARS-CoV-2 infection at the level of barrier integrity and innate and adaptive immunity, but also act prophylactically to prevent infection and enhance protection afforded by current vaccine regimens.

Keywords: COVID-19; SARS-CoV-2; antiviral immunity; immune evasion; probiotics.

Figure 1

Host antiviral immune response to SARS-CoV-2 infection: recognition, immunity and the gut–lung axis. (A) IR to SARS-CoV-2 infection: infected mucosal epithelial cells elicit several responses which include (1) secretion of AMPs, (2) Ab-mediated neutralisation, (3) DC-Ag processing and presentation, (4) NK cell activation and killing of virus-infected cells, (5) APC-MHC I-Ag presentation and activation of cytotoxic T cells, (6) MHC II-Ag activation of naïve Th cells, (7) cytokine-driven Th₁ differentiation which activate (8) Tc killing of virus-infected cells and (9) DTH activation of Mϕ inflammation and killing responses. (10) Cytokine differentiation and activation of Tfh, resulting in B cell Ab production, (11) cytokine differentiation and activation of Th₁₇ and Nϕ activation–inflammation. (12) Virolysis/cell necrosis resulting in immune activation and (13) virus-induced apoptosis and ACAMP-induced anti-inflammatory cytokine production to limit antiviral responsiveness. (B) Reception, infection, and viral replication. SARS-CoV-2 spike protein binds to surface viral receptors ACE2 (grey) and CD147 (yellow). Upon S protein binding to ACE2, (1) TMPRSS2 protease (membrane-bound blue boxes) cleaves S protein, allowing S2 facilitation of virus envelope fusion with the cell membrane; (2) virus entry in endosomal compartment and (3) release of +sense strand vRNA which is (4) transcribed by ribosomes and (5) post-ER and Golgi processing of viral proteins, leading to (6) virion construction and (7) release of virus from infected cell by exocytosis. (C) Gut–lung axis of viral, microbiome, and immune cell/molecule transport. Mucosal infection of lung tissue can result in viral translocation to the GIT, which primes dysbiosis of the microbiome and influences IR and Th₁₇ bias, resulting in CCL25 and CCR9 transport from GIT to lung. CCL25 chemoattracts CCR9⁺ cells, which also include Mϕs, DCs, IELs and IgA⁺ B cells.

Figure 2

The potential of probiotic bacteria to initiate and augment IR either directly or indirectly via modulation of the gut microbiome. Probiotic bacteria positively stimulate immunity (1) via several mechanisms, which include (2) enhancement of barrier functionality (AMP secretion, mucin expression, and cytokine production), (3) activation of NK cell killing, antiviral IFN responses, and Mϕ inflammation, (4) Ag processing/presentation via MHC I, II, and B7 expression and Ag-specific adaptive immunity responses by (5) CMI—Tc, DTH and Th₁₇ responses as well as (6) Tfh-mediated B cell humoral responses, producing virus-specific Abs, capable of initiating complement activation, ADCC and neutralisation of infectivity. Probiotic initiation of 3–6 facilitate (7) adjuvanticity and efficacy of anti-S protein SARS-CoV-2 vaccines. Probiotic bacteria can also affect immune responsiveness indirectly by (8) influencing the microbiome, where a homeostatic microbiome positively (arrow—black, pointed) influences antiviral immunity (9), and dysbiosis potentially suppresses (blunted green line) antiviral immunity (10). Finally, probiotic bacteria may suppress viral immune escape mechanisms by which SARS-CoV-2 evades host immune protection (11).