How do viruses outwit cellular immune systems?

Weizmann Institute scientists publish research showing the autonomous immune system that individual bacteria cells have.

 Bacteriophages attacking a bacterium. (photo credit: PROF. GRAHAM BEARDS)
Bacteriophages attacking a bacterium.
(photo credit: PROF. GRAHAM BEARDS)

We’re used to thinking of the immune system as a separate entity – almost a distinct organ – which fights intruders that get into the body or mistakenly regards one’s own tissue as an invader. But the truth is more complicated.

Breakthroughs in recent years – some resulting from research performed in Prof. Rotem Sorek’s lab at the molecular genetics department in the Weizmann Institute of Science in Rehovot – have shown that individual bacterial cells possess their own autonomous, innate immune system that can identify, locate and deal with intruders.

In a paper just published in the journal Nature under the title “Viruses inhibit TIR gcADPR signaling to overcome bacterial defense,” Sorek and her team – along with collaborators from Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston – have revealed both the way in which viruses overcome a cell’s immune system and the chemical composition of a mysterious molecule that’s inherent to the process.

How do viruses attack our bodies?

The viruses that cause bacterial cells to raise their defense shields are called phages. Their modus operandi is to inject their DNA into a bacterium, manipulating the cell to replicate the phage dozens of times. At that point, the newly-born phages kill the bacterium, then break out and go hunting for other nearby bacterial cells. The bacteria are not defenseless, however, employing their autonomous immune system to combat this threat.

Previous research at Sorek’s lab showed that an immune protein segment called TIR is the one in charge of identifying a phage invasion – and that once a phage is detected, the TIR produces a mysterious signal molecule that triggers the immune response. The TIR segment was initially discovered in the immune systems of plants and animals, but Sorek’s group was able to show that a similar mechanism exists in bacteria. Still, the mystery signal molecule remained undetected.

 Jeremy Garb, Prof. Rotem Sorek, Dr. Azita Leavitt, Dr. Gil Amitai, Erez Yirmiya and Dr. Ehud Herbst. (credit: WEIZMANN INSTITUTE OF SCIENCE) Jeremy Garb, Prof. Rotem Sorek, Dr. Azita Leavitt, Dr. Gil Amitai, Erez Yirmiya and Dr. Ehud Herbst. (credit: WEIZMANN INSTITUTE OF SCIENCE)

How do phages overcome immunity?

This time, her team found how phages can overcome TIR immunity. When studying a group of very similar phages, they were surprised to discover that while TIR immunity did provide protection against some of them, others proved victorious and managed to kill the bacteria. Looking into the victorious phages, the team found that they contain a special gene that encodes a protein that neutralizes TIR immunity, thus allowing the phage to gain the upper hand.

“We will not be surprised if viruses that infect our body use the exact same mechanism as the one we found in phages,” Sorek said.

When the scientists examined the protein, now dubbed Tad1, they found that it captures the signaling molecule immediately after it is produced by the TIR protein. “It was as if the protein quickly swallowed the molecule, not letting the immune system get even a glimpse of it,” Sorek says. “This kind of immune evasion mechanism was never seen in any known virus.”

 The Tad1 protein, produced by the phage, captures an immune signaling molecule. In the figure: A pair of Tad1 proteins and two signaling molecules trapped inside them. (credit: WEIZMANN INSTITUTE OF SCIENCE) The Tad1 protein, produced by the phage, captures an immune signaling molecule. In the figure: A pair of Tad1 proteins and two signaling molecules trapped inside them. (credit: WEIZMANN INSTITUTE OF SCIENCE)

The group then realized that if the molecule is locked inside the phage protein, they might be able to “see” it by looking within the structure of the protein. Together with their Harvard collaborators, Prof. Philip Kranzusch and Allen Lu, the team was able to determine the spatial structure and chemical composition of the molecule using crystallography. “We have sought this mysterious immune molecule for several years now,” muses Sorek. “Ironically, we couldn’t have found it without an assist from the phage.

“We discovered a new way in which viruses can deactivate immune systems that rely on signaling molecules,” she noted. “These immune systems aren’t exclusive to bacteria – they exist in the cells of plants and human beings.”

Understanding how phages are able to adapt and evolve could help us fare better against the bacterial immune system by identifying the same mechanisms in the cellular structure of the viruses that trouble us.

“We will not be surprised if viruses that infect our body use the exact same mechanism as the Tad1 we found in phages,” Sorek says. If this is the case, then it could have direct consequences on our ability to protect ourselves from viruses that are scheming to outsmart our immune system.