MIT researchers discover bacteria's new antiviral defense system

Specific proteins in prokaryotes detect viruses in unexpectedly direct ways.
Baba Tamim
Enterobacterias.
Enterobacterias.

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  • Bacteria use a variety of defense strategies to fight off viral infection.
  • STAND ATPases in humans are known to respond to bacterial infections by inducing programmed cell death in infected cells.
  • Scientists predict that many more antiviral weapons will be discovered in the microbial world in the future.

Scientists have discovered a new unexplored microbial defense system in bacteria.

Researchers uncovered specific proteins in prokaryotes (bacteria and archaea) that detect viruses in unexpectedly direct ways, recognizing critical parts of the viruses and causing the single-celled organisms to commit suicide to stop the infection within a microbial community, according to a press release published in the official website of the Massachusetts Institute of Technology (MIT) on Thursday.

The discovery was made by a team of scientists led by researchers at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT.

"This work demonstrates a remarkable unity in how pattern recognition occurs across very different organisms," said Feng Zhang, senior author and James, and Patricia Poitras Professor of Neuroscience at MIT.

"It's been very exciting to integrate genetics, bioinformatics, biochemistry, and structural biology approaches in one study to understand this fascinating molecular system."

Bacteria use a variety of defense strategies to fight off viral infection, and some of these systems have led to groundbreaking technologies, such as CRISPR-based gene editing.

The study is the first to show that organisms in all three domains of life — bacteria, archaea, and eukaryotes (which includes plants and animals) — use pattern recognition of conserved viral proteins to defend against pathogens.

A pathogen is an organism that causes disease.

Microbial armory

In a previous study, the researchers scanned data on the DNA sequences of hundreds of thousands of bacteria and archaea, discovering thousands of genes with microbial defense signatures.

In the new study, they focused on a few of these genes that encode enzymes from the STAND ATPase family of proteins, which are involved in the innate immune response in eukaryotes.

STAND ATPase proteins in humans and plants fight infection by recognizing patterns in the pathogen or the cell's response to infection.

The researchers wanted to know if the proteins in prokaryotes work the same way to defend against infection.

They selected a few STAND ATPase genes from the previous study, delivered them to bacterial cells, and then challenged those cells with bacteriophage viruses. The cells survived after a spectacular defensive response.

The scientists then wanted to know which part of the bacteriophage caused that response, so they delivered viral genes to the bacteria one at a time.

Two viral proteins elicited an immune response: the portal, a component of the virus's capsid shell that contains viral DNA, and the terminase, a molecular motor that aids in virus assembly by pushing viral DNA into the capsid.

Each of these viral proteins activated a different STAND ATPase to protect the cell.

The discovery was startling and unprecedented. Most known bacterial defense systems detect viral DNA, RNA, or cellular stress caused by infection. Instead, these bacterial proteins were directly sensing critical components of the virus.

The researchers then demonstrated that bacterial STAND ATPase proteins could recognize different phage portal and terminase proteins.

"It's surprising that bacteria have these highly versatile sensors that can recognize all sorts of different phage threats that they might encounter," said co-first author Linyi Gao, a junior fellow in the Harvard Society of Fellows.

The proteins also function as DNA endonuclease enzymes, cutting up a bacterium's own DNA and killing the cell, limiting the virus's spread.

Similarly, STAND ATPases in humans are known to respond to bacterial infections by inducing programmed cell death in infected cells.

"It's quite exciting to see a connection in prokaryotes to a system that's also inside of us," said co-first author Jonathan Strecker, a postdoctoral researcher in the Zhang lab.

Structural analysis

The researchers used cryo-electron microscopy to examine the molecular structure of the microbial STAND ATPases when bound to the viral proteins to understand better how they detect the viral proteins.

"By analyzing the structure, we were able to precisely answer a lot of the questions about how these things actually work," said co-first author Max Wilkinson, a postdoctoral researcher in the Zhang lab.

The team discovered that the virus's portal or terminase protein fits into a pocket in the STAND ATPase protein, with each STAND ATPase protein grasping one viral protein.

The STAND ATPase proteins then form tetramers, which bring together key components of the bacterial proteins known as effector domains. This activates the endonuclease function of the proteins, shredding cellular DNA and killing the cell.

The tetramers bound viral proteins from other bacteriophages just as tightly, indicating that the STAND ATPases detect the three-dimensional shape of the viral proteins rather than their sequence. Explains how a single STAND ATPase can recognize dozens of distinct viral proteins.

STAND ATPases in humans and plants also function by forming multi-unit complexes that activate specific cell functions.

Scientists predict that many more antiviral weapons will be discovered in the microbial world in the future.

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