Listeria monocytogenes: Can Bad Bacteria go Good?

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Abstract

Bacteria have plagued humans and animals since they first walked the earth, but what no one realized until recently is how beneficial members of this domain can be. They help people produce vitamins, digest different foods, and some can even prevent pathogenic bacteria from colonizing and destroying the human or animal body (1). The realization that bacteria are not all harmful pushed scientists to wonder how they might aid the good bacteria and reduce the bad. Taken a step further, and with a bit of creativity, researchers now consider ways to alter and use harmful bacteria to benefit humans. Seven researchers from the departments of Microbiology and Immunology, and Radiology at Albert Einstein College of Medicine in New York, did just that. They thought they might be able to target cancer with attenuated Listeria monocytogenes (L. monocytogenes) and recently released their results (4).

In this research study, “Nontoxic radioactive Listeria-at is a highly effective therapy against metastatic pancreatic cancer,” attenuated L. monocytogenes (L. monocytogenes-at) was effectively used to reduce pancreatic cancer tumor and metastasis sizes in mice (4). Though this is not the first scientific venture into using bad bacteria for good, it is one with highly positive results. Other success stories include the use of bacteria to initiate an animal’s immune response against tumor cells and to deliver chemotherapy. To accomplish the former, researchers used several different types of bacteria, including a Listeria CRS-207-created protein.

In addition, some Salmonella sp. kill cancer cells. Cancer researcher and University of California at San Diego surgeon Robert M. Hoffman, works extensively with Salmonella (5). Affiliated with the biotechnology and research organization AntiCancer, Inc., he produces a strain of Salmonella typhimurium A1-R, which targets tumor cells, but is attenuated so that it cannot maintain a continuous infection in normal cells (3).

Listeria monocytogenes

Members of the domain bacteria comprise more than 50 different phyla, which divide into many hundreds of genera and into thousands of species (7). Listeria, a Firmicutes, was first isolated and described in the early 1900s from a rabbit liver sample. It is a short bacillus that moves by the roll and tumble method, is hemolytic, Gram-positive and one of seven Listeria species (2). Natural reservoirs are soil and GI tracts of humans, other mammals and birds (6).

As a pathogen, the organism is generally acquired from food, though it can be transmitted in other, less common ways. Once inside the digestive tract, it is engulfed by phagocytic macrophages which, though they seek to destroy it, unknowingly give it a place to hide from the body’s immune system, where it is also protected from antibiotics. L. monocytogenes is one of two Listeria species that contains listerolysin O, a virulence factor which perforates the macrophage’s vacuole, helping it escape. Once free, it replicates in the cell’s cytoplasm, ironically using the immune cell to harm the host (2).

One important thing to know about L. monocytogenes in relation to the aforementioned research, is that it targets hypoxic environments, where it is better able to create reactive oxygen species (4). This is relevant, because of how cancer metabolizes products to create adenosine triphosphate, or energy. Researcher Otto Warburg’s 1956 hypothesis is still used today to make decisions in searching for a cancer cure. He discovered that cancer cells, though they are able to choose between fermentative and, much more energy-profitable, aerobic respiration, almost always select the former – making these fermentative cancer cells the hypoxic environment in which L. monocytogenes prospers (10).

L. monocytogenes, in its normal virulent form, causes listeriosis in humans which, among an array of other problems, can induce fever, gastrointestinal issues, sepsis, brain swelling and abscesses. In livestock, this pathogen leads to circling disease, which affects the host’s central nervous system. As are many pathogens, L. monocytogenes is much harder on immunocompromised individuals than on the average person. This is especially true in those with malignant or benign neoplasms that offer L. monocytogenes a hypoxic environment (2).

The Study

In “Nontoxic radioactive Listeria-at is a highly effective therapy against metastatic pancreatic cancer,” researchers targeted pancreatic tumor cells in mice. Pancreatic cancer runs its course quickly (4). Though it is a relatively rare form of cancer, it is particularly virulent. As of 2010, only about 6.7 percent of patients with this type of disease live five years past the diagnosis (9) – mainly because, in most cases, it metastasizes prior to detection. At this point there are two main FDA-approved drugs – and those give patients only about six additional months to live (4). Bacteria, it seems, may be up to a challenge our drug arsenal cannot yet tackle.

After initiating pancreatic cancer development in the test mice, researchers turned their attention to L. monocytogenes. They attenuated the bacteria to prevent it from causing listeriosis, and ran tests to make sure the species could handle the addition of radioisotope 188 Rhenium. In the first set of experiments, they used attenuated bacteria without 188 Rhenium. They injected tumor-filled mice intraperitoneally with Listeria-at and evaluated the results at specific intervals one, three, and seven days after the injection.

The mice were able to purge the bacteria from normal tissues in less than five days. However the slightly immunosuppressed, hypoxic tumor cells maintained infection longer, as the rodent immune systems were not able to fight it in that location. One week after their final treatment, the mice were free from radiation and Listeria in cancer and normal cells.

The reactive oxygen species created by L. monocytogenes kills tumor cells, leading attenuated bacteria to reduce tumor and metastasis sizes without additional assistance (4). Add 188 Rhenium, a radionuclide commonly used to treat skin, bone and liver cancers (8), and the tumor and metastasis reduction levels were even higher. With a short half-life, this isotope matches pancreatic cancer’s quick onset and action speed as it destroys the cancer cells (2). It takes action against the tumor and metastases and is quickly degraded, causing no known permanent damage (4).

L. monocytogenes-at, without the aid of cancer-killing 188 Rhenium, reduced the number of metastasized cells by 50 percent and primary tumor weight decreased by 20 percent. Radioactive L. monocytogenes-at reduced the number of metastasized cells by 90 percent and primary tumor weight by 64 percent (4). These results, among the other success stories prove that bacteria may need to be a primary part of our defense arsenal.

References

1. American Society for Microbiology. Microbe World (Beta). Copyright 2014. Web. <http://www.microbeworld.org/types-of-microbes/bacteria> Retrieved 14 Oct. 2014.
2. Brachman P, Abrutyn E. Bacterial Infections Of Humans [Electronic Resource] : Epidemiology and Control / Edited By Philip S. Brachman And Elias Abrutyn ; Formerly Edited By Alfred S. Evans And Philip S. Brachman [e-book]. New York : Springer Science+Business Media, c2009.; 2009. Available from: Louisiana State University, Ipswich, MA. Accessed October 14, 2014.
3. Hoffman, R. M. (2013). Tumor growth control with IDO-silencing Salmonella –letter. Cancer Research, 73(14), 4591. doi:10.1158/0008-5472.CAN-12-4719.
4. Quispe-Tintaya, W., et al. “Nontoxic radioactive Listeria is a highly effective therapy against metastatic pancreatic cancer,” Proceedings of the National Academy of Sciences, doi:10.1073/pnas.1211287110, 20.
5. Richards, S., “Tumors Fall to Radioactive Bacteria: Researchers use bacteria to deliver radiation to shrink pancreatic tumors in mice,” Web. The Scientist, Published April 22, 2013. <www.The-Scientist.com> Retrieved October 11, 2014.
6. Scott, P. R., et. al. The Merck Veterinary Manual: Overview of Listeriosis. Edited March 2014. <www.merckmanuals.com>. Retrieved October 12, 2014.
7. Tree of Life Web Project. Copyright © 1995-2004. Web. <www.tolweb.org> Retrieved 20 Oct. 2014.
8. United States Department of Energy – Office of Science. Oak Ridge National Laboratory. Web. <http://web.ornl.gov/sci/nsed/fcid/nuc_med/rhenium.shtml> Retrieved 12 Oct. 2014.
9. United States Department of Health and Human Services. National Cancer Institute website. National Institutes of Health. <http://seer.cancer.gov/statfacts/html/pancreas.html> Retrieved 20 Oct. 2014.
10. Warburg, O. (1956). On the Origin of Cancer Cells. Science, (3191). 309.