Immunobiotics for the prevention of bacterial and viral respiratory infections

JULIO VILLENA; SUSANA SALVA; NATALIA BARBIERI; SUSANA ALVAREZ

Probiotics: Immunobiotics and Immunogenics

CRC Press

Año: 2013; p. 128 - 168

In recent years enormous efforts have been made to unravel the mechanisms of probiotic actions and various experimental approaches have been developed to characterize the molecular basis of probiotic effects. It has been shown that cell wall components and DNA motifs from immunobiotic LAB can induce the immunoactivation of GALT. Moreover, it was demonstrated that TLR2, TLR9, NOD1 and NOD2 are able to recognize cell wall components and DNA of dietary LAB, thereby contributing to immunoregulation in the GALT. Although significant progress has been made in the knowledge of the mechanisms of probiotics action in the gut, it is not known how some immunobiotic strains are able to stimulate immunity in distal mucosal sites from the gut when orally administered. Recent evidence showed that pattern recognition receptors-mediated sensing of resident commensal microbiota in the steady state regulates the development and function of innate and adaptive immune systems in extra-intestinal sites, and prepares the host to defend against intrusion by pathogenic microorganisms. In mice, depletion of gut microbiota by antibiotics can result in reduced surface expressions of TLR2 and TLR4 in peritoneal macrophages, and less inflammation following intraperitoneal LPS injection in vivo, indicating that intestinal microbiota can constitutively prime peritoneal macrophages in preparation for pathogen invasion. In addition, recognition of peptidoglycan from the microbiota by NOD1 primes systemic innate immunity by enhancing the cytotoxicity of bone marrow-derived neutrophils in response to systemic infection with the bacterial pathogens, S. pneumoniae and Staphylococcus aureus. Moreover, recent studies characterized the cellular and molecular mechanism by which the gut microbiota regulate respiratory tract immune defense against influenza virus infections. Authors showed that commensal microbiota composition critically regulates the generation of virus-specific CD4+ and CD8+ T cells and antibody responses following respiratory influenza virus infection. These authors speculated that a select group of commensal bacteria, mainly neomycin sensitive bacteria (Lactobacilli) could trigger TLRs to stimulate leukocytes either locally or systemically. Then, the factors released by such leukocytes could support steady-state activation of inflammasome-dependent cytokine release by respiratory tract DCs improving their migration to the draining lymph nodes when a viral infection occurs. Collectively, these studies indicate that the gut microbiota support systemic and respiratory immunity by releasing low levels of PRR ligands in circulation. Although our studies do not allow us to discard this mechanism for the strains studied in our laboratory (L. rhamnosus CRL1505 and L. casei CRL431), we propose a different mechanism influencing antibacterial and antiviral immune responses in the respiratory tract. Our results showed that there would be a mobilization of cells from intestine (CD3+CD4+IFN-γ+ T and IgA+ cells) and changes in cytokine profile (IFN-γ and IL-10) that would be able to beneficially modulate the respiratory mucosal immunity. Activation of respiratory immunity by orally administered probiotics would have a complex mechanism, probably related to specific strains. Our studies also suggest that heat-killed LAB are also effective in the immunomodulation of the systemic and respiratory immune system. Therefore, probiotic bacteria in the form of live cells may not be required for this purpose. The effect of non-viable L. casei and other LAB on the respiratory immune system should be examined with more detailed studies, as dead bacteria or their cellular fractions could be an interesting alternative as mucosal adjuvants, especially in immunocompromised hosts in which the use of live bacteria might be dangerous. In addition, heat killed LAB have the advantage of allowing longer product shelf-life as well as easier storage and transportation. Further studies using immunomodulatory LAB strains able to stimulate respiratory immunity as well as their cell components such as non-viable bacterial particles, intact cell walls, cell wall polysaccharide-peptidoglycan complex and chromosomal DNA are necessary to find immunobiotic effector molecules (immunogenics) able to stimulate immunity in distant mucosal sites from the gut.