CRISPR helps some bacteria evade mammalian immune system

Published on April 18, 2013 at 6:39 AM · No Comments

CRISPR, a system of genes that bacteria use to defend themselves against viruses, has been found to be involved in helping some bacteria evade the mammalian immune system.

The results are scheduled for publication Sunday, April 14 in Nature.

CRISPR is itself a sort of immune system for bacteria. Its function was discovered by dairy industry researchers seeking to prevent phages, the viruses that infect bacteria, from ruining the cultures used to make cheese and yogurt. Bacteria incorporate small bits of DNA from phages into their CRISPR region and use that information to fight off the phages by chewing up their DNA.

Now scientists at the Division of Infectious Diseases of the Emory University School of Medicine and the Emory Vaccine Center have shown that Francisella novicida, a close relative of the bacterium that causes tularemia, and another bacterium that causes meningitis, need parts of the CRISPR system to stay infectious. F. novicida, which grows inside mammalian cells, employs parts of CRISPR to shut off a bacterial gene that would otherwise trigger detection and destruction of the bacteria by its host.

Because disabling CRISPR creates a weakened bacterial strain that is easily recognized by the immune system, the finding could accelerate vaccine development. But it is also a broader reminder that in biology, defensive tools can be co-opted for purposes of stealth.

"CRISPR systems are bacterial defenses, but we've found that bacteria can use them offensively to hide from the host immune system and cause disease," says David Weiss, PhD, assistant professor of medicine (infectious diseases) at Emory University School of Medicine and Yerkes National Primate Research Center.

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system has attracted recent attention among scientists for its potential uses in genetic engineering and biotechnology, but its roles in gene regulation and evading host immunity have remained relatively unexplored, Weiss says.

Weiss first isolated strains of F. novicida that had defects in their CRISPR systems while working as a postdoc with Denise Monack at Stanford. F. novicida infects rodents and only rarely infects humans. It is a model for studying the more dangerous F. tularensis, a potential biological weapon. Weiss was looking for F. novicida genes that are important for virulence: causing disease in a live animal.

Intriguingly, he found a DNA sequence that has recently been shown to encode a protein of the CRISPR system. What they were doing in F. novicida during infection was a puzzle.

"The mutations have a strong effect in the bacteria," Weiss says. "The wild type will kill mice, while the mutants are eradicated after a couple days. But why would the bacteria need to defend against foreign DNA to cause disease in a mouse? It didn't make sense."

The researchers discovered that the bacteria require one of the CRISPR genes to turn off production of a lipoprotein - part of the bacterial cell membrane -- when the bacteria infect mammalian cells. For immune cells, lipoprotein is like blood in the water for a shark. A little whiff excites them. So for the bacteria to survive undetected, they have to silence lipoprotein production.

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