Bad Guy or Good Guy?: Bdellovibrio bacteriovorus

By: Heeamin Lee and Parvathy Bhushan

When we think of bacteria, words that first come to mind might be infection, sickness, germs and a plethora of other words with a negative connotation. But what if the bad guy wasn’t so bad after all? What if the bacteria was harmful to other bacteria but not humans?

Figure 1: Bdellovibrio bacteriovorus is being hailed as a possible ‘savior’ to help us fight against antibiotic resistant bacteria using its pathogenic properties. Adapted from bbc.co.uk

Bdellovibrio bacteriovorus is a pathogenic bacteria that preys upon Gram-negative bacteria in different environments. Imagine a thief entering your home. Upon breaking in, they find that there is another thief who had broken in earlier and is now taking away your most prized possessions. Upon seeing this, the second thief, instead of collaborating and sharing the wealth, begins attacking the first thief. You wake up all of a sudden upon hearing the commotion and decide to help the second thief fight the first one. Within a short span of time, your team emerges victor and ensures that the first thief has disappeared. Tired from your victory, the second thief slowly disappears too and order is restored in your home.

In this story, the first thief represents the bacteria Shigella while the second thief represents the bacteria Bdellovibrio bacteriovorus. We see that the Bdellovibrio also creates infection to hijack human cell machinery but we are surprised to find that they thrive on destroying other ‘thieves’ or bacteria. In other words, this thief derives satisfaction from destroying the livelihood of other thieves!

The first thief, Shigella flexneri is a gram negative, rod shaped, antibiotic-resistant human pathogen that a recent study by Willis et al. used to investigate the benefits of Bdellovibrio. They carried out multiple experiments by injecting Bdellovibrio into zebrafish, to observe its pathogen killing capabilities in the presence of Shigella, in collaboration with the host immune system.  

As part of this study, researchers injected Shigella tagged with Green Fluorescent Protein into the hindbrain of zebrafish larvae (Fig. 2). This infection was followed by a second injection of Phosphate-Buffered Saline (PBS) as control or Bdellovibrio tagged with mCherry, another tag to visualize the infection.

Figure 2: Zebrafish brain visualized using fluorescence microscopy either with Shigella and PBS (control) or Shigella and Bdellovibrio. Adapted from Figure 1 E of study.

The control experiment showed increased fluorescence of Shigella with time, demonstrating the increased invasiveness of the pathogen in zebrafish (first panel of Fig. 2). In the experiment with Bdellovibrio, the fluorescence of Shigella diminished with time and this can only be explained by the predatory characteristics of Bdellovibrio (second panel of Fig. 2). The zebrafish survives from an otherwise lethal infection, as in the case of the control fish. Bdellovibrio hijacks the cell machinery of Shigella, causing them to form rounded cells, a feature often seen in dying cells, as opposed to its common rod shape.

Without Shigella, Bdellovibrio does not exert any harmful effects on the zebrafish. In fact, when observed over a period of 24 hours, the levels of Bdellovibrio decreased significantly. In other words, without its prey, Bdellovibrio cannot survive for a long period in zebrafish and is cleared away by the immune system.

How is Bdellovibrio cleared away by the host immune system? As described by the analogy in the beginning, the team(or just you) that emerges to help fight off the first thief would represent the host immune system. As in humans, zebrafish have a highly homologous immune response mediated by white blood cells, namely neutrophils and macrophages.

Figure 3: Zebrafish brain visualized using fluorescence microscopy by labeling neutrophils or macrophages, and Bdellovibrio. Part A shows labeling of neutrophils merged onto fluoresced Bdellovibrio, while B shows macrophages merged onto the bacteria. Both were observed at 30 minutes, 6 hours, and either 14 or 20 hours post infection. Adapted from figure 3A and 3B of the study.

First, to investigate the interaction between Bdellovibrio and the white blood cells, the authors labeled zebrafish larvae with GFP-neutrophils and mCherry-macrophages. Imaging of hindbrain injections of Bdellovibrio in zebrafish showed that both types of white blood cells localized at the site of the infection (third and sixth columns of Fig. 3). From this, the authors supported the idea that immune cells must work together with Bdellovibrio to fight off Shigella. Just like in our analogy, the second robber works together with a team to fight off the first thief.   

Okay, so what happens once the second thief protects the home from the first one, just as Bdellovibrio fought off the Shigella? Through this study, it is shown that the bacteria are engulfed by both neutrophils and macrophages. They conducted an experiment using a zebrafish transcription factor that drives myeloid gene expression, thereby suppressing the number of white blood cells. This helps us observe the effects of Bdellovibrio in immunocompromised zebrafish. After addition of Bdellovibrio to larvae depleted of white blood cells, the number of bacteria remained largely unchanged. In the immunocompetent control fish, a decreased number of bacteria was observed (as shown in red above Fig. 3). This supports the idea that the bacteria are eventually engulfed by the immune cells of the host. What’s more is that the survival rate of zebrafish in the control and mutant did not significantly vary, further supporting the idea that Bdellovibrio is not harmful to the health of the host organism. In the case of humans, this could be crucial, meaning the difference between life and death.

    

These experiments show that there might be an alternative to antibiotics. Overuse of antibiotic medication has led to the development of antibiotic resistant bacteria. Certain bacteria also possess natural ways to combat antibiotics, such as taking up genes from its environment. The need of the hour then is to find an alternative to fight bacterial infections. Using pathogenic bacteria such as Bdellovibrio might allow us to specifically target medically resistant bacteria without creating other resistant bacteria and or causing harm to our body.

In addition, there are a couple of examples in current research using pathogenic microbes. One is the use of poliovirus to fight off brain cancer. Polio, or poliomyelitis is a human virus that causes paralysis if not treated. Once the modified virus is introduced into cancer cells, it tricks the immune system to perceive it as a virus and starts to attack the cancer cells. Just like Bdellovibrio in attacking Shigella, poliovirus is designed to help break down cancer cells, by teaming up with host immune cells.

Another recent example is the use of phage therapy. Bacteriophages are viruses that can target specific strains of bacteria. This form of therapy provides promise because it does not affect good or harmless bacteria, like those that exist in the gut microbiome. At the same time, it is able to effectively wipe out disease causing bacteria. For a long period of time, researchers were reluctant to conduct studies of this nature as subjects were often uncomfortable with having a live virus administered to them. However, necessity is the mother of invention and rise in antibiotic resistance has forced researchers to take another look at phages. Initial rounds of studies have shown that phages are able to effectively kill E. coli containing specific antibiotic resistant genes, leading to survival of model organisms. For more information on the first human trials for phage therapy, click here.

It is interesting to look at the evolution of scientific research, especially when it comes to using something scientists were very reluctant to work with. Initial studies have only shown the effects of Bdellovibrio on Shigella infection. More conclusive studies on the use of Bdellovibrio as a pathogenic bacteria to fight off other infections remain to be done in the future. However, change in the reputation of a formally “harmful” bacteria or virus to one that holds promise demonstrates the leaps and miles science has travelled just in the past few decades.

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About the authors:

Heeamin is a senior at Mount Holyoke College majoring in Neuroscience and Behavior. She is passionate about microbiology and believes that the companionship between microbiology and neurobiology can help to reveal yet undiscovered information about the human brain.

Parvathy is also a senior at Mount Holyoke College, majoring in Biology. She is fascinated by cell and microbiology and confesses that her exposure to these fields in college helped her find her passion. According to her, microbes hold the key to the future in solving the world's most pertinent problems!