It Takes tRNAs to Tango: How Phages Outsmart Their Hosts

by Rafael Pinilla-Redondo
 

Figure 1. "When microbiologists discover that phages are al­ways at the heart of the mischief." Much like the classic Harry Potter trio, these tiny perpetrators cause (microbial) mayhem, one bacterium at a time.

Have you ever wondered what goes on inside a bacterium when it's attacked by a phage? Ima­gine an epic battle between two armies, like in "The Lord of the Rings" but seen through a mi­croscope. On the one hand, valiant phages try to assault, replicate, and spread to neighboring cells; and on the other, host defenses strive to thwart and contain the tiny invaders. While it's not surprising that phages evolved ways to outsmart their bacterial foes, the elegance of their evasion tactics never fails to impress!
 

For over 50 years, scientists attempted to understand why so many phages carry transfer RNA (tRNA) genes in their genomes. This puzzle – let's call it the "tRNA conundrum" – left research­ers scratching their heads. But now, a new study may have finally cracked the mystery and, sur­prise! – it appears that phage ingenuity is at play (once again).
 

The phage tRNA conundrum

Anyone who took biology in high school learned that genetic information flows from DNA to RNA to protein, a.k.a. the central dogma of molecular biology. tRNAs, a type of small non-coding RNA found in all living organisms, play a crucial role in this process. During protein synthesis, tRNAs "read" the genetic code written in mRNAs and bring the corresponding amino acids to the ribosome, where proteins are assembled.
 

Figure 2. A ribosome hard at work: using tRNAs to turn the genetic instructions of the mRNA into a functional pro­tein. Source

"So, what does this have to do with phages?" you might ask. Well, during infection, phages take on a high-priority mission: to reprogram cells into perfectly orchestrated phage production factories. To achieve this, they must hijack the cell's translation machinery, including bacterial tRNAs, to kickstart the phage protein assembly line. Of course, this raises the question: "Why do many phages carry their own tRNA genes if they can use the host tRNA pools?" This enigma is the subject of much speculation, with multiple hypotheses proposed to explain their func­tion
 

Until recently, the most widely accepted explanation was that phage tRNAs functioned as a means of codon compensation. Like sailors scurrying to shift their weight across a boat to prevent it from capsizing, phage-encoded tRNAs were thought to correct for the compositional differences between the phage and its host. According to this idea, phages would use their own tRNAs to ensure more effective translation of their genes, balancing the tRNA pools by providing tRNAs for codons less commonly used by the host bacterium. Ahoy!
 

But just like any good mystery, it looks like there is more to this process than meets the eye, leaving scientists searching for alternative answers…
 

Figure 3. tRNA clusters in a mycobacterial phage. Like or­­na­ments on a Christmas tree, some phages are pep­pered with tRNA genes – but it's not just pretty, they are life jackets in the face of bacterial tRNases. Source

A fresh look at phage tRNAs: The anti-codon loop loophole

Enter a new study with a fresh perspective on the phage tRNA mystery. The researchers build on previous work that shows how phage tRNAs supplement the pool of host tRNAs, which is often degraded during infection. According to the new hypothesis, phage-encoded tRNAs may be a secret weapon in the phages' arsenal, allowing evasion of bacterial defenses that actively deplete host tRNAs to halt viral infections.
 

By analyzing the mutational patterns of tRNA anticodon loops – the part of the tRNA that binds to the corresponding codon in the mRNA – the team found that tRNAs in a cluster of mycobacterial phages are often predicted to be resistant to host tRNA-degrading enzymes. They also observed a strong counter-selection against tRNAs that are cleaved in the actual anticodon motif, suggesting that phages tend to encode tRNAs that escape targeting by host tRNases. Overall, these results indicate that phages evolve to counteract the pressure exerted by tRNA-depleting defenses.
 

Figure 4. Phages with a tRNA twist. Mutations in phage tRNAs (left) and the proposed mechanism during phage infection (right). While host tRNases destroy the tRNAs in the cell, phage tRNAs are resistant and can refill the tRNAs pools, thereby allowing for phage propagation. Source

Early days, but bright (ph)uture!

While the new findings offer a compelling explanation to the long-standing phage tRNA conun­drum, experimental evidence is still needed to test the hypothesis. And as with anything relat­ed to phages, many outstanding questions remain. For instance, the broad distribution of tRNases and tRNA-encoding phages in the environment suggests this phenomenon is rampant – but how widespread is it? Will we find archaeal viruses employing similar strategies? What about eukaryotic viruses? And how do host cells counteract such stealthy tactics? Hopefully this study piques further interest in the topic and accelerates the answering of these impor­tant questions.
 

Gaining a deeper understanding of how phages evade bacterial immunity can also unlock new possibilities for biotechnology. Just as a cybersecurity firm might study a skilled hacker to de­velop more effective firewalls, the investigation of phage anti-defense tactics could lead to improved phage-derived applications. By engineering phages with enhanced propagation capabilities (e.g., carrying tRNase-insensitive tRNAs), we may be able to improve the efficacy of phage therapy approaches aimed at combating bacterial pathogens in the clinic, agriculture, and beyond.
 

Personally, I think it's just really satisfying to witness a 50-year-old mystery (likely) solved. Once again, the answer appears to be rooted in the arms race between phages and bacteria. Future exploration of this evolutionary treasure trove will undoubtedly keep yielding fascinating dis­coveries with exciting applications. As microbiologists, we can rest easy knowing that phages will keep us employed for the foreseeable future (even if it's on short-term contracts)!
 

Addendum:

I was feeling pretty curious about all the buzz surrounding AI language models, so I decided to challenge ChatGPT with the following task: "write a limerick inspired by the content in this this blog entry: (copy-pasted my article)." Below is what it came up with. Not bad, huh!? Who knew chatbots had a knack for microbiology poetry?
 

In a phage, tRNAs do the tango,
To outsmart their hosts, they'll go toe to toe,
With clever evasion, they'll win the day,
Leaving bacterial foes in dismay.
Their tRNA genes, a clever disguise,
Allow them to evade bacterial surprise.
A Trojan horse, they'll sneak right in,
Replicate and spread with a cheeky grin.
Their tRNA conundrum, now solved with glee,
Phages, it seems, are the ultimate MVP.

Do you want to comment on this post? We would be happy about it! Please comment on Mastodon or on Twitter.
 

 

Rafa is Spanish, a Postdoc researcher at the University of Copenhagen, and currently in New Zealand at the Uni­versity of Otago, escaping the Danish winter. When he's not studying the never-ending arms race between bacteria and their pesky mobile genetic elements, he can be found enjoying the great outdoors or dabbling in the ancient art of analog photography. (Bacteria, beware! Rafa's phage-o-lantern is coming for you this phageoween.)