Friday, May 9, 2025
5/9/2025
Bacteriophage diversity, dynamics, function, and exploitation - Bacteriophages are the most numerous biological entities in the biosphere. The phage population is also dynamic, old, and not surprisingly, enormously diverse genetically. Bacteriophage genomes are replete with genes of unknown function and because of their overall diversity, phage genomes represent the largest reservoir of novel genes of unknown function. Although a small number of phages have been studied in enormous detail, our lack of a deeper understanding of the broader diversity of phages represents a substantial limitation. In particular, as the threat of antimicrobial antibiotic resistance continues to swell, the therapeutic use of phages to control bacterial infections has garnered substantial attention, but a greater understanding of phage biology and the determinants of phage-bacterium interactions is now imperative. The dynamic interaction between bacteria and their viruses has markedly shaped the genomic profiles of both bacteria and bacteriophages. Lytic infection of bacteria by their phages typically results in cell death, imposing a strong selection for survival mechanisms. The discovery of restriction-modification (R-M) system marked the beginning of the elucidation of bacterial defense systems, but other systems quickly followed, and CRISPR- Cas phage defense has become widely recognized. It is notable that although these genetic systems were discovered by exploring the basis of host preferences of the phages, R-M and CRISPR-Cas have fueled major revolutions in biotechnology, harnessing the great enzymatic efficiency and specificity, finely tuned by billions of years of evolution. The discovery of new phage defense systems has been an especially active area of discovery, with dozens reported in the past few years, and seemingly many more awaiting recognition. A collection of over 22,000 individual phages isolated on bacteria within the phylum Actinobacteria – 4,400 of which are completely sequenced and annotated – provide a powerful resource for investigating bacteriophage diversity, evolution, origins, and dynamics. A second and newer major resource is a collection of over 500 individual clinical isolates of nontuberculous mycobacteria (NTM), including the opportunistic pathogen Mycobacterium abscessus. M. abscessus infections are prevalent among people with cystic fibrosis and some other immune disorders and are intrinsically resistant to most antibiotics and clinically very difficult to treat. The therapeutic use of phages for treating these infections shows some promise, but broader implementation is restricted because of the extreme and unpredictable variations in the phage infection profiles of M. abscessus isolates. These dual resources thus provide a powerful system for exploring the determinants of phage host range at a strain-specific level, in which bacterial defense systems, prophage-encoded defense systems, and plasmids all play critical roles. Exploring these dynamics will provide key insights into the drivers of microbial diversity and evolution and advance the prospects of bacteriophages to become key elements in the treatment of diseases caused by Mycobacterium pathogens.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).