HMN 2026: How Vaccinia virus breaks textbook rules by ditching its cap

A research team led by Václav Vopálenský and Martin Pospíšek from the Faculty of Science, Charles University, has discovered a surprising way in which the vaccinia virus handles its genetic messages.

Their study, published in Nature Communications, shows that the virus produces large amounts of mRNA without the protective “cap” that had until now been considered a given. At the same time, it raises new questions: how exactly the cell reads these “unmarked” messages and whether this viral peculiarity could be exploited in the fight against viral infections.

Let us imagine mRNA as a letter containing instructions according to which the cell produces proteins. For such a letter to reach its reader (the ribosome) and not be destroyed along the way, it usually carries a protective seal at its beginning—the so-called 5? cap.

The vaccinia virus itself played a key role in the past in the discovery of this cap. All the greater, then, is the surprise brought by the new study showing that this virus often sends its “letters” completely without a seal.

The team from the Faculty of Science at Charles University examined viral mRNA individually, molecule by molecule. It turned out that while at the beginning of infection the virus still plays by the rules and produces capped mRNA, it later seems to change its strategy.

In so-called intermediate and late genes, another type of message begins to prevail—one without a cap but with a long chain of adenosines at the beginning, a so-called poly(A) leader sequence. The longer this “polyadenosine tail,” the smaller the chance that the mRNA has a cap at all. For some viral genes, almost every mRNA molecule lacks a cap.

The results suggest that the vaccinia virus gradually switches from the standard, “official” mode of reading genetic information to an emergency mode that the cell probably uses only rarely. Thanks to this, the virus is able to produce its proteins even when normal cellular production is suppressed.

This trick gives it a significant advantage and helps explain why poxviruses are so successful at taking over the host cell. The virus thus behaves a bit like a hacker who has discovered that it is possible to break into a system even without an official access card—it is enough to know a shortcut.

The study rewrites the long-held view of how viral mRNAs function and shows that even seemingly fundamental biological rules can have surprising exceptions.

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