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Hijacking Bacterial 'Hypodermic Needles'

Pathogenic bacteria come equipped with an entire arsenal of weapons which are used to harm and kill our body's cells. One of these is the type III secretion system (T3SS), a protein complex which resembles a miniature hypodermic needle. A bacterium can jam this into our body's cells and directly inject a cocktail of toxic proteins. TEM_of_isolated_T3SS_needle_complexes.jpg

Now, in the journal Nature Communications, Yale researchers report that they have hijacked the T3SS for their own purposes, essentially turning the bacteria's weapons back on themselves. Using a particular mutant bacterium, the scientists have devised a clever way to make vaccines.

New types of vaccines are always in development. One kind, referred to as a "recombinant vector vaccine," uses an attenuated (weakened) bacterium as a vector to carry a snippet of DNA from a much more dangerous microbe. The idea is that proteins encoded in the DNA from the dangerous microbe will be expressed in this relatively harmless bacterium, triggering an immune response without causing illness.

But there is a problem with this technique: Because the vector is a live bacterium, it can't be given to young or immunocompromised patients. What scientists would like to have is a bacterium-like blob that triggers a robust immune response, but doesn't actually make anyone sick. Yale researchers have now created these blobs.

Their bacterium of choice was Salmonella, which comes equipped with a T3SS that it uses to inject human cells with toxins. They mutated a gene, called minD, that is essential to proper cell division. Normally, a healthy bacterium doubles its chromosome, elongates and splits into two daughter cells, each of which gets one chromosome. However, with minD knocked out, the bacterium divides unevenly, resulting in one daughter not receiving a copy of the chromosome. This blob (which the authors call a "minicell") still has enzymes and can perform minimal metabolic functions (at least for a while), but without a chromosome, it isn't viable and can't reproduce.

Importantly, these blobs retained several T3SS complexes in their membranes, so they were able to secrete toxins.

But the authors wanted to know if these blobs could secrete foreign proteins of interest. Remember, the whole point of this research is to use blobs as protein factories to crank out desirable proteins to stimulate an immune response. To test this, the authors created a fusion protein. The first part of the protein was a "signal" that says, "Secrete me!", and the second part was a foreign protein called OVA. Not only was the fusion protein secreted, but it also stimulated an immune response in vitro.

Even better, they created a second fusion protein, which consisted of a secretion signal and a protein from the pathogen Listeria monocytogenes. The researchers incubated these blobs with a particular immune cell called a dendritic cell, after which they transferred the dendritic cells into mice. Their hope was that the blobs would inject the fusion protein into the dendritic cells, and then the dendritic cells would respond by triggering an immune response in the mice, conferring immunity to the Listeria bacterium.

They got what they wished for. The mice were challenged with Listeria, and the mice who had received a transfusion of dendritic cells incubated with blobs containing the special fusion protein had much lower levels of Listeria in their livers, indicating at least a partially successful immune response.

Obviously, this research has a long way to go before it could be used clinically. However, the authors have shown how powerful bacterial weapons can be hijacked for a more humane purpose.

Source: Heather A. Carleton, María Lara-Tejero, Xiaoyun Liu & Jorge E. Galán. "Engineering the type III secretion system in non-replicating bacterial minicells for antigen delivery." Nature Communications 4, No.: 1590. Published 12 March 2013. doi:10.1038/ncomms2594

Source: "Types of Vaccines." National Institute of Allergy and Infectious Diseases. Last updated April 3, 2012.

(Image: Type III secretion system courtesy of PLoS Pathogens via Wikimedia Commons)

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