Ecological Basis for Rational Phage Therapy

Abstract

Understanding the mutual interactions of bacterial and phage populations in the environment of a human or animal body is essential in any attempt to influence these complex processes, particularly for rational phage therapy. Current knowledge on the impact of naturally occurring bacteriophages on the populations of their host bacteria, and their role in the homeostasis maintenance of a macro host, is still sketchy. The existing data suggest that different mechanisms stabilize phage-bacteria coexistence in different animal species or different body sites. The defining set of parameters governing phage infection includes specific physical, chemical, and biological conditions, such as pH, nutrient densities, host prevalence, relation to mucosa and other surfaces, the presence of phage inhibiting substances, etc. Phage therapy is also an ecological process that always implies three components that form a complex pattern of interactions: populations of the pathogen, the bacteriophages used as antibacterial agents, and the macroorganism. We present a review of contemporary data on natural bacteriophages occuring in human-and animal-body associated microbial communities, and analyze ecological and physiological considerations that determine the success of phage therapy in mammals. KEYWORDS bacteriophages, phage therapy, human body microbiota, animal body microbiota, bacteriophage ecology ABBREvIATIONS GIT -gastro-intestinal tract, PFU -plaque-forming unit, which corresponds to a one viable bacteriphage particle, if the efficiency of infection in these conditions and in this strain is close to 1; CFU -colony-forming unit, which corresponds to a one viable bacterial cell.

Phage Therapy: Eco-Physiological Pharmacology

“…See Figure 6 for facile illustration of how particularly it is ecological interactions, as mediated through the physiologies associated with multiple organisms that give rise to the pharmacology associated with phage therapy. See also Letarov et al [ 107 ] for a complementary treatment of eco-physiological issues as they pertain to phage therapy. For general overviews of various aspects of phage ecology as well as phage impact on bacteria, see Abedon [ 108 , 109 ].…”

“…and also whether any physical blocks on virion movement are present, including, for example, anatomical divisions between compartments as found in animals. These latter distribution issues are complex, varying as a function of phage properties, the site being treated, how phages are applied, and the extent to which disease as well as medical intervention may modify phage movement within bodies; see, for example, [ 85 , 93 , 107 , 111 , 112 ].…”

“…With phages, such inactivation is seen in terms of the immune system's impact, which includes both innate actions and the actions of antibodies, but inactivation also can occur in the course of infection of otherwise resistant bacteria. Elimination as a means of phage depletion from the body, particularly by the kidneys, by contrast is not considered to play as large role in phage loss [ 107 ], though this route has been explored by a number of authors [ 111 , 127 – 131 ].…”

“…Relevant to whether such activity is even an issue for phage therapy, however, are the following points. (i) In practice, antibody-mediated inactivation of phage virions during phage therapy does not appear to be recognized as an important issue [ 107 ], (ii) phages are diverse in terms of their immunogenicity such that application of one phage isolate to an animal will not necessarily result in the production of cross-reacting antibodies to another phage isolate [ 133 ], (iii) systemic application of phage types to which a body can mount a severe immune reaction is problematic for reasons that go well beyond the issue of virion survival though with phages such severe immune reactions following systemic application nonetheless do not necessarily occur [ 134 ], (iv) organisms actually are exposed over their lifespans to numerous phages both topically and systemically and there is no evidence that this has a significant impact on health [ 87 , 107 ], (v) application of phages per os (orally but with systemic intentions) seems to reduce the immunogenicity of phage formulations [ 135 ], (vi) for tailed phages, only a small fraction of virion surfaces represent epitopes through which neutralization can be effected such that not all antibody reactions will result in phage inactivation [ 107 ], (vii) virion inactivation is less of a concern given local rather than systemic phage application, and (viii) one approach to combatting phage losses is to simply supply more phages [ 136 ].…”

“…For additional, ecologically relevant phage therapy articles by this same group, see [ 52 , 188 , 211 , 212 ]. See also Weld et al [ 213 ], consideration of the role more generally of ecology in understanding phage therapy [ 214 ], and also the general review by Letarov et al [ 107 ] on ecological as well as physiological aspects of phage therapy (see also [ 65 ]). The phage therapy literature otherwise has numerous if equivocal references to the “ecology” of various organisms or treated areas of bodies.…”