By Kelly A. Reynolds, MSPH, PhD

Microbial communities in the environment are a complex mixture of species, interacting at various levels in cooperative and competitive interactions. Scientists have long recognized that microbes can be manipulated to produce beneficial products (i.e., foods, medicines) and remediate polluted environments. In addition, copious amounts of microbes are being strategically applied to a variety of environments (including soil, water and the human body), where they reduce harmful contaminants, treat infections, destroy biofilms and replace more hazardous species. Research is underway to better define microbial populations and direct their role in treating diseases, improving food safety and protecting water supplies.

Balanced by nature
Billions of microscopic organisms are present in a single gram of soil. A healthy soil biome includes a combination of viruses, bacteria and fungal species that appear to exist in a highly balanced state. When contaminants are introduced, species diversity and concentration tend to decrease. Eventually microbial populations again increase in concentration, generally dominated by contaminant-resistant species. The ability of some fraction of microbes to survive in polluted environments is the basis for bioremediation, where those surviving populations can be isolated and applied to similarly tainted environments. Through microbial metabolism and nutrient processing, contaminants may be reduced or eliminated.

Typically when we consider viruses, we think of human health hazards. There are many more viruses existing in nature, however, that infect bacterial rather than human cells. Any environment where a large population of bacteria can be isolated, viruses capable of infecting and destroying those specific bacteria will also be found. This is considered nature’s way of keeping bacterial populations from growing too large.

Viruses of bacteria are known as phage, a Greek word meaning to devour. Therefore, bacteriophage literally means bacteria eater. In the early 20th century and before the advent of antibiotics, bacteriophage were being investigated as treatments for human infections. Unfortunately phage effects in the body were unpredictable and studies were not well quantitated as per current pharmaceutical research standards. Their use as an antibacterial treatment in the US was largely halted in the 1940s as antibiotics were popularized. With the evolution of antibiotic-resistant strains of bacteria, however, phage treatments are again being re-evaluated.

The food and agricultural industry has further capitalized on phage applications for targeting human and animal disease-causing microbes. For example, pre-slaughter treatment of food animals has demonstrated control of Salmonella and E. coli infections in chickens and cattle, respectively. Many phage have already been approved for use in the food industry, where they effectively extend the shelf life of a variety of meat, dairy and produce products by targeting spoilage bacteria.

Competing for space
Competition is another driving force in nature to maintain  balanced microbial populations. There are only so many nutrients and a finite amount of space that microbes can occupy. Thus, nutrient deprivation and metabolic waste production eventually work to prevent continued microbial growth. Utilizing competitive forces of microbes, scientists have successfully replaced hazardous microbes with less hazardous counterparts. One example is the widespread problem of Aspergillus flavus in agricultural crops. Peanut, pistachio and corn crops in particular are commonly plagued by a naturally occurring mold species known as Aspergillus flavus. Some strains of A. flavus produce a potent toxin (aflatoxin) that is a known human carcinogen. Keeping indigenous molds from growing in production fields and contaminating foods with toxin residues above strict regulatory limits is an economic priority and a public health need. A non-toxin-producing strain of A. flavus, known as AF36, has been isolated in Arizona and Texas and is being used worldwide as a natural pesticide against toxin-producing A. flavus strains. By applying copious amounts of the non-toxin producing strain to agricultural fields, the indigenous strains become overwhelmed by the new competition and are essentially replaced by the less toxic strain.

Applications in water treatment
Targeted phage applications and competitive pressure successes in the food industry have inspired additional applications in the water and wastewater treatment field. Bacterial populations capable of digesting organic matter in wastewater have long been an essential component in wastewater treatment. Maintaining the health of the microbial biofilm is a priority for proper system design and execution. At question is if or how knowledge of microbial competition of phage/bacterial relationships can be used to improve drinking water quality. Researchers at the University of Missouri recently used bacteriophage to kill colonies of Pseudomonas aeruginosa, a potentially harmful bacterial agent found in water distribution systems. Reportedly, the MU researchers are the first to combine use of chlorine and bacterial viruses to destroy biofilms. The combined chlorine/phage treatment resulted in a 97-percent biofilm reduction compared to 40- percent and 89-percent reduction, respectively, when each treatment was used alone. Additional biocontrol applications in water treatment are expected to evolve.

Messing with Mother Nature?
While the targeted use of phage to control unwanted bacteria appears to be a gift from nature, it is also natural to wonder about the ecological upset that could occur with widespread use. Despite decades of research, scientists are still only able to culture an estimated one-tenth of one percent of the total soil microbial community. Thus, relatively little is known about the abundant and varied populations of microbes in the environment or the human body.

The human gut is a complex mixture of bacteria and bacteriophage that varies across populations and individuals. When humans are first born, the gut is essentially sterile but becomes rapidly colonized. The gut microbiome tends to be similar among family members, suggesting environmental and/or genetic relatedness plays a role in the formation of microbial populations. The gut microbiome continues to evolve with diet and life stages but a subset of microbes tends to be common even in highly dispersed global populations. What is not really known, however, is if these microbial ecosystems can be permanently altered by alternative and deliberate exposure to competing innocula and if that would always be beneficial.

Environmental and laboratory trials in the past suggest that phage cannot completely wipe out host bacteria. Instead a balance may be inherently reached where large populations of hosts are needed before phage can be isolated. During the process of phage attack, bacteria are able to assimilate some of the phage DNA. These stored genomes help the bacteria to recognize phage attackers and perhaps mount a defense in a sort of bacterial immune reaction. Studies in the early 80s, where phage were sprayed in calf rooms to prevent E. coli infections, also showed that phage-resistant E. coli mutants evolved. While not considered a direct threat to human health, future biocontrol applications should always be cognizant of the overall ecosystem impact.

References

  1. Goodridge, L. and Abedon, S.T. “Bacteriophage biocontrol and bioprocessing: Application of phage therapy to industry.” Society for Industrial Microbiology News, vol. 53, pp. 254-262, 2003.
  2. Merril, C.R.; Scholl, D. and Adhya, S.L. “The prospect for bacteriophage therapy in Western medicine.” Nature Reviews Drug Discovery, vol. 2, pp. 489-97, 2003.
  3. University of Missouri-Columbia “Viruses help scientists battle pathogenic bacteria and improve water supply.” Science Daily, 24 September 2012. [Online]. Available: http://www.sciencedaily.com/releases/2012/09/120924145145.htm. [Accessed 9 October 2012].
  4. Zhang, Y. and Hu, Z. “Combined treatment of Pseudomonas aeruginosa biofilms with bacteriophages and chlorine.” Biotechnology and Bioengineering, p. DOI: 10.1002/bit. 24630, 2012.
  5. Stern, A.; Mick, E.; Tirosh, I.; Sagy, O. and Sorek, R. “CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome.” Genome Research, vol. 22, pp. 1985-1994, 2012.

About the author
Dr. Kelly A. Reynolds is an Associate Professor at the University of Arizona College of Public Health. She holds a Master of Science Degree in public health (MSPH) from the University of South Florida and a doctorate in microbiology from the University of Arizona. Reynolds is WC&P’s Public Health Editor and a former member of the Technical Review Committee. She can be reached via email at reynolds@u.arizona.edu.

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