Patho-Biotechnology; Using Bad Bugs to Make Good Bugs Better
Sleator, Roy D., Hill, Colin, Science Progress
Given the increasing commercial and clinical relevance of probiotic cultures, improving their stress tolerance profile and ability to overcome the physiochemical defences of the host is an important biological goal. Pathogenic bacteria have evolved sophisticated strategies to overcome host defences, interact with the immune system and interfere with essential host systems. We cool the term 'patho-biotechnology' to describe the exploitation of these valuable traits in biotechnology and biomedicine. This approach shows promise for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications as well as the development of novel vaccine and drug delivery platforms.
Keywords: patho-biotechnology, probiotics, pathogen, Listeria, virulence factor, stress, infection, drug delivery, vaccination
"Trust not yourself, but your defects to know. Make use of every friend and every foe"
Alexander Pope (1688-1744)
Pathogenic bacteria, with lifecycles oscillating between the host and external milieu, have evolved sophisticated stress management strategies allowing them to succeed and thrive in both environments (1-4). We coined the term 'Patho-biotechnology' to describe the commercial exploitation of these valuable traits in biotechnology, food and medicine (5). This concept encompasses three broad areas; firstly, the use of selected bacterial pathogens (e.g., Listeria monocytogenes) as effective vaccine and drug delivery platforms (6,7) either through the generation of conditional auxotrophic mutants (8) or by the selective elimination of key virulence factors (9). The second approach involves the isolation and purification of pathogenspecific immunogenic proteins (e.g., listeriolysin) for direct application (10-12), thus removing the necessity for potentially harmful bacterial carrier platforms. The third area, and the primary focus of this review, provides an alternative to using either the attenuated pathogen or pathogen-derived proteins for disease prevention or therapy. This approach involves equipping non-pathogenic bacteria with the genetic elements necessary to survive the many stresses encountered outside the host (e.g. spray and freeze drying; experienced during product formulation (13,14) as well as the myriad of antimicrobial hurdles faced during host transit and/or colonisation (e.g. gastric acidity, bile, low iron and elevated osmolarity (15)).
Pathogenic and probiotic bacteria face an almost identical set of challenges from the host physico-chemical defences (Figure 1) and must also be able to interact with or modulate the host immune system in order to have an impact on human health (16) (either positively or negatively). Thus we can conceive of employing well characterised pathogenic species as a reservoir for stress and virulence associated genes to significantly improve the clinical effectiveness and technological robustness of potentially probiotic strains. The ability to confer additional stress tolerance on what are often process sensitive cultures may be an important first step in the development and delivery of viable probiotics with maximal efficacy (17).
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Rational design of improved probiotics
The human gut contains more bacteria than there are eukaryotic cells in the body (18). Collectively, this gut flora represents a virtual organ with a metabolic activity m excess of that of the liver (19) and a microbiome (total genome of constituent microorganisms) more diverse than that of the human genome (20). Some members of this commensal flora, defined as probiotics (21), have been demonstrated to beneficially affect the host by influencing the composition of the gut microflora (22) and by providing a health promoting or immunomodulatory challenge to the host (23). Indeed, certain bacteria, when administered perorally, have been shown to stimulate the mucosal immune system (24,25), attenuate inflammation and reduce neoplastic lesions associated with auto immune disease states such as Crohn's disease and ulcerative colitis (6), as well as providing a potentially viable alternative for the treatment of chronic gut associated bacterial infections such as Clostridium difficile (27). …