I’ll be back to phage therapy (bated breath, I know) next week or whenever it’s time for me to write about biology again, but in the meantime, take this thing: bacterial “vaccines.” Sounded strange to me when first heard about it too.
Let’s talk about it.
A high-frequency phenotypic switch links bacterial virulence and environmental survival in Acinetobacter baumannii [Chin et al. 2018]
(I talked with the first author of this paper, actually. Odd flex, I know)
Title translation: The ability of bacteria A. baumannii to swap its physical composition is responsible for said bacteria’s capability to cause disease and survive in hostile environments
In brief: This paper explores the reasons why a subpopulation of A. baumannii is more virulent than another, specifically exploring differences in physical appearance/phenotype and gene expression. Taking advantage of the latter, the researchers are able to force the bacteria to remain in its more benign form. Mice that are injected with this tweaked strain are able to survive infection by regular A. baumannii, which usually kills the mice in 2 days.
Yeah, so
Here’s the deal. Acinetobacter baumannii is no joke, particularly if you are an immunocompromised individual (e.g. an elderly person). This is because A. baumannii is classified as one of the “ESKAPE” pathogens.
Yes...ESKAPE. It’s apparently an acronym for all the bacteria that not only cause the majority of hospital infections in the United States, but they also are capable of “escaping” the effects of antibiotics (Boucher et al. 2009). The “A” in ESKAPE is for Acinetobacter, you see. The “P” is for Pseudomonas. If you’ve got a particularly sharp memory, you might recall that Pseudomonas aeruginosa was the bacterial star of the last blog post. It all ties together you see. Scientists are focusing on these bugs for a reason, that reason chiefly being antibiotic resistance.
But forget about P. aeruginosa for now, cause the topic of the moment is A. baumannii and bacterial vaccines.
There’s a subpopulation of A. baumannii that seems to be the main source of the trouble. The main physical difference between this subpopulation and “normal” A. baumannii is that it’s got an extra armor package, so to speak, a thicker capsule surrounding the bacterial cell. Twice as thick as the normal A. baumannii, to be exact.
( ͡° ͜ʖ ͡°)
Ahem. Well, the researchers call this subpopulation of A. baumannii “opaque,” versus the “translucent” normal type. The more specific designations are VIR-O (for virulent, opaque) and AV-T (for avirulent, translucent). The names are pretty self-explanatory. VIR-O, cloudy, bad. AV-T, not so cloudy, not so bad. Take a look at this set of pictures from the paper.
Left shows some VIR-O cells, right shows AV-T. You can see now why the former is called “opaque,” and the latter “translucent.”
Critically, it appears that an A. baumannii bacterial cell can swap back and forth between these two types.
But back to the VIR-O population of A. baumannii. What else besides appearance is special about the VIR-O bacteria? Well, hospital disinfectants have been shown to be not that effective against them. They don’t mind being desiccated, or being dried out, for a few days. They actually seem to do better when exposed to antimicrobials found naturally in the human lungs (I’m not really sure why that’s the case, it seems the researchers aren’t exactly sure why either).
***Notably, there is nothing special about the growth rate of VIR-O A. baumannii (although one might have thought that was why it was more virulent than AV-T): VIR-O and AV-T A. baumannii were shown to grow equally fast, at least in media (the soup stuff used to grow bacteria).
Also, as suggested by their designations, it seems that VIR-O is the type of A. baumannii chiefly present when infecting hosts. Take a look at this figure from the paper.
Fig 1d Mice were infected with a 1:1 mixture of VIR-O (red) and AV-T (blue) strains. At 24 h post-infection, organs were harvested and plated to assess the percentage of VIR-O and AV-T cells present.
The (slightly modified) figure caption is pretty self-explanatory I think. As the caption says, 24 hours after mice were infected, examination of their organs revealed that the VIR-O strain was predominant. This does not necessarily mean that the inputted AV-T bacteria switched to the VIR-O state, it could just mean that VIR-O A. baumannii is simply better at surviving inside a host. However, the point still stands that VIR-O is the form of A. baumannii chiefly present during an infection and is thus most likely its cause.
Finally (and perhaps most importantly) though, is the fact that different genes are expressed by the VIR-O population of A. baumannii compared to the AV-T population.
You might have reasonably assumed that the genomes of these two populations were different. After all, I did say that one population had a thicker capsule than the other. However, remember that a different phenotype does not necessarily mean a different genotype is present. That may very well be the case, but not always. Recall from high school biology that different cells of your body may look different, but for the most part, they all have the same genetic material (Yes, some cells of your body have different genetic material due to either viruses or gamete creation with meiosis, your biology teacher lied to you so they didn’t have to confuse you with exceptions).
So that was a rather long way of getting to the point that for AV-T and VIR-O A. baumannii, the difference is not in genetic composition, but in genetic expression.
Like a light switch
There was a very special (at least in the context of A. baumannii) gene that the researchers were interested in: ABUW_1645. There are many genes that change the amount that they are expressed once the switch from AV-T to VIR-O is made, but critically, ABUW_1645 is apparently a transcription factor. What you need to know is that basically, there are genes, then there are bosses of genes. ABUW_1645 is one of these bosses. 70% of these genes that change expression levels when switching phenotype, according to Chin et al., are controlled by ABUW_1645.
Furthermore, they found that AV-T cells express ABUW_1645 60 times higher than their VIR-O counterparts. This is important, as it strongly suggests that the expression of this gene is responsible for the maintenance of the AV-T phenotype. Most interestingly, when VIR-O A. baumannii cells were forced to “overexpress” ABUW_1645, they started looking like AV-T cells and also lost their unique resistance to desiccation and disinfectants. VIR-O and AV-T cells that were forced to overexpress ABUW_1645 were “locked” in the AV-T state. In short, ABUW_1645 seems to be the master switch for regulating the change between AV-T and VIR-O states.
Now we get back to this set of pictures. This time, look at the bottom left picture, which I cropped out last time to avoid confusion. Here’s where things get interesting. This is a picture of those VIR-O A. baumannii cells that had their ABUW_1645 gene overexpressed. Notice how they look virtually indistinguishable from the normal AV-T cells, proving that a sort of switch had been made.
Now about those vaccines...
So finally we get to the bit about vaccines. The researchers injected mice with the modified VIR-O A. baumannii and found that it was incapable of causing a lethal infection. Encouraged, they performed a second experiment in which 37 days after the mice were inoculated with the apparently harmless VIR-O/1645, these mice were “challenged” with the real deal, unmodified VIR-O. They survived, indicating that exposure to VIR-O/1645 was sufficient to alert the mice immune systems to the threat represented by the virulent form of A. baumannii.
For your gratification, here is the original figure:
You can see that the control mice, who were only inoculated with a strain of E. coli, were not as fortunate as the VIR-O/1645 vaccinated group (they all died after the second day VIR-O infection). Meanwhile, all the mice survived in the VIR-O/1645 vaccinated group, which is good of course.
So yeah, bacterial vaccines!
This work seemed really exciting, given the apparent prevalence of A. baumannii in US hospitals, so I asked Chin how soon we could expect to see clinical trials. She laughed and said something to the effect of “We’ve got a long way to go yet.” She said that they have yet to determine the exact nuts and bolts of the mice immune response to this modified strain of A. baumannii. But she and the rest of the authors of the paper remain optimistic that the methods used on A. baumannii could be used on other strains of bacteria, and possibly even fungi that exhibit similar swapping of states. It’s just a matter of finding the right regulatory gene.
Thanks for reading!
- BJW
Citations!
Chin CY, Tipton KA, Farokhyfar M, Burd EM, Weiss DS, Rather PN. A high-frequency phenotypic switch links bacterial virulence and environmental survival in Acinetobacter baumannii. Nat Microbiol. 2018;3: 563–569.
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48: 1–12.
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