Immunobiotic Lactobacilli Improve Resistance of Respiratory Epithelial Cells to SARS-CoV-2 Infection

Abstract

Previously, we reported that immunomodulatory lactobacilli, nasally administered, beneficially regulated the lung antiviral innate immune response induced by Toll-like receptor 3 (TLR3) activation and improved protection against the respiratory pathogens, influenza virus and respiratory syncytial virus in mice. Here, we assessed the immunomodulatory effects of viable and non-viable Lactiplantibacillus plantarum strains in human respiratory epithelial cells (Calu-3 cells) and the capacity of these immunobiotic lactobacilli to reduce their susceptibility to the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immunobiotic L. plantarum MPL16 and CRL1506 differentially modulated IFN-β, IL-6, CXCL8, CCL5 and CXCL10 production and IFNAR2, DDX58, Mx1 and OAS1 expression in Calu-3 cells stimulated with the TLR3 agonist poly(I:C). Furthermore, the MPL16 and CRL1506 strains increased the resistance of Calu-3 cells to the challenge with SARS-CoV-2. L. plantarum MPL16 induced these beneficial effects more efficiently than the CRL1506 strain. Of note, neither non-viable MPL16 and CRL1506 strains nor the non-immunomodulatory strains L. plantarum CRL1905 and MPL18 could modify the resistance of Calu-3 cells to SARS-CoV-2 infection or the immune response to poly(I:C) challenge. To date, the potential beneficial effects of immunomodulatory probiotics on SARS-CoV-2 infection and COVID-19 outcome have been extrapolated from studies carried out in the context of other viral pathogens. To the best of our knowledge, this is the first demonstration of the ability of immunomodulatory lactobacilli to positively influence the replication of the new coronavirus. Further mechanistic studies and in vivo experiments in animal models of SARS-CoV-2 infection are necessary to identify specific strains of beneficial immunobiotic lactobacilli like L. plantarum MPL16 or CRL1506 for the prevention or treatment of the COVID-19.

The role of respiratory microbiota in the protection against viral diseases: respiratory commensal bacteria as next-generation probiotics for COVID-19

“…Furthermore, we showed that the improved antiviral immunity induced by D. pigrum 040417 or C. pseudodiphtheriticum 090104 was related to their capacities to stimulate CD11c + CD11b high MHCII + and CD11c + CD103 + MHCII + lung dendritic cells (DCs) and enhance the response of respiratory CD3 + CD4 + IFN-γ + T cells [ 55 , 57 ]. We recently extended and complemented those previous findings by showing for the first time that D. pigrum 040417 regulates the response of respiratory epithelial cells to TLR3 activation [ 58 ]. In our experiments, higher levels of IFN-β and IL-6 and lower concentrations of CXCL8, CCL5, and CXCL10 were found in Calu-3 cells pretreated with D. pigrum 040417 and then challenged with poly(I:C) in comparison with respiratory epithelial cells stimulated only with the TLR3 agonist.…”

“…So, the early production of type I IFNs in the respiratory epithelium or exogenous therapeutic administration of them is thought to efficiently counteract SARS-CoV-2 replication [ 89 ]. Furthermore, the early improved production of IFN-β and subsequently enhanced expression of the ISGs TLR3, DDX58, Mx1 , and OAS1 induced by D. pigrum 040417, L. plantarum MPL16, or L. plantarum CRL1506 in Calu-3 cells would be associated with the lower SARS-CoV-2 replication observed in our experiments [ 58 , 83 ].…”

“…Thus, we speculated that immunomodulatory L. plantarum or D. pigrum strains would be capable of interacting with epithelial cells, inducing molecular changes that enhance their antiviral defenses. Our recent experiments showed that our hypothesis was correct [ 58 , 83 ]. We showed that the pretreatment of Calu-3 cells with immunomodulatory L. plantarum (strains MPL16 or CRL1506) modulated the innate antiviral immune response of the respiratory epithelial cells triggered by SARS-CoV-2 infection, reducing the virus replication [ 58 ].…”

“…Our recent experiments showed that our hypothesis was correct [ 58 , 83 ]. We showed that the pretreatment of Calu-3 cells with immunomodulatory L. plantarum (strains MPL16 or CRL1506) modulated the innate antiviral immune response of the respiratory epithelial cells triggered by SARS-CoV-2 infection, reducing the virus replication [ 58 ]. We also reported for the first time that an immunomodulatory respiratory commensal bacterium, D. pigrum 040417, was capable of regulating the innate antiviral immune response of respiratory epithelial cells, conferring improved protection against SARS-CoV-2 [ 83 ].…”

The Beneficial Role of Probiotic Lactobacillus in Respiratory Diseases

“…Notably, in vitro experiment has demonstrated that L. fermentum 90 TC-4 pretreatment increases the activity of SARS-CoV-2-infected Vero E6 cells (grass monkey kidney cells) ( 61 ). Pretreatment of L. plantarum MPL16 and CRL1506 can also inhibit the proliferation of SARS-CoV-2 in human lung epithelial cell line Calu-3 ( 62 ). In Central Europe, it has been reported that low death rate of COVID-19 patients is associated with the consumption of fermented vegetables containing many Lactobacilli species ( 63 ).…”