黑料吃瓜

Sharks prowl the watery depths for their prey, lions stalk the tall-grass savannah, and bacteriophages have mucus. The thin layer of mucus that coats epithelial cells serves as the hunting ground for phages, viruses that kill and use bacteria to proliferate. Newly published research by scientists at 黑料吃瓜 finds that these phages use a novel hunting strategy known as 鈥渟ubdiffusive motion鈥� to better their chances of finding bacteria within a mucosal surface.

The term 鈥渉unting鈥� here is a bit of anthropomorphism. Viruses, including bacteriophages, aren鈥檛 alive in the strict biological sense. They have no means of independent locomotion. Instead, they float around in their environment and when they encounter a bacterium with the right kind of chemical receptors on its surface, they infect the host cell, hijacking its cellular replication machinery to produce more phages. It鈥檚 not purposeful hunting, but it鈥檚 effective.

These phages provide an unwitting secondary immune system to their mammalian hosts鈥攚hich include humans鈥攑rotecting them from harmful bacteria. Fostering helpful bacteriophages to counter bacteria forms the basis of an emerging type of medical treatment known as phage therapy. 黑料吃瓜鈥檚 Viral Information Institute (VII) is a key player in this nascent field.

BAM kicks it up a notch

by 黑料吃瓜 scientists established the Bacteriophage Adherence to Mucus (BAM) model, which explored how phages attach to proteins in mucus, forming a symbiotic relationship between mammalian host and phage. Within the constantly secreting mucus layer, phages are free to drift about in search of bacteria.

Traditionally, phages were thought to move completely randomly through the mucus by normal diffusion, otherwise known as Brownian motion. But 黑料吃瓜 microbiologist Jeremy Barr, along with an interdisciplinary team of the university鈥檚 biologists, mathematicians, physicists and engineers, wondered if phages might have some method for upping the odds of finding their prey.

in the Proceedings of the National Academy of Sciences鈥攖he first study to officially emerge from the VII鈥攖he researchers describe how they prepared a biochip that emulates the mucosal surface of a human lung epithelial cell. The biochip features lifelike secretion with the outermost mucus layers constantly sloughing off. Into the mucus on these biochips, they introduced E. coli bacteria and one of two types of phages: a normal, mucus-adherent E. coli鈥�targeting bacteriophage known as a T4 phage (sticky phage, for this purposes of this article), or a genetically modified version of the phage that had lost its ability to stick to mucus (non-sticky phage). They also performed a control experiment in which they added bacteria to the mucus but not any phages whatsoever.

Barr and his colleagues observed how well the bacteriophages fared in finding and killing bacteria in the biochip鈥檚 mucus. The genetically modified, non-sticky phage, didn鈥檛 do any better than the control experiment. But the normal, sticky phages had 鈥渁 really drastic antimicrobial effect,鈥� Barr said, providing more than a 4,000-fold reduction in bacteria.

Stick to it

To see whether the normal phages were better than their non-sticky counterparts at persisting in the churning mucosal surface, the researchers performed another series of experiments designed to count phage accumulation and turnover. In the end, they found that the mucus expelled just as many normal phages as the non-sticky ones, meaning something other than mucus adherence must account for the difference.

The researchers then used high-powered microscopes to watch how the phages diffused through different mucus environments. They found that the normal, sticky phage moved around in a more staccato fashion, lingering in one place for a little while, then moving to the next spot, and so on. That is known as subdiffusive motion, and the sticky phages in this experiment were able to accomplish it by weakly adhering to the mucus as they drifted.

Why would subdiffusive motion turn these phages into superior hunters? The answer, Barr said, lies in their prey鈥檚 abundance. When bacterial concentrations are high, random motion as a hunting strategy works just fine, he explained.

鈥淚f you鈥檙e in a mucus layer with really dense bacteria, you鈥檝e got a pretty good chance of finding a host with random motion,鈥� Barr said. 鈥淵ou can鈥檛 help but run into them.鈥�

Slow your roll

When bacteria are scarce in the environment, or if there are a lot of different types of bacteria in abundance, phages that move in a slow, punctuated fashion are statistically more likely to encounter the right kind of bacterial prey.

鈥淲hen bacterial diversity is high, it becomes difficult for a phage to find its specific host,鈥� Barr said. 鈥淯nder these conditions it鈥檚 more advantageous to move subdiffusively, to keep yourself in a location longer and seek out your prey more slowly.鈥�

This makes bacteriophages unique among predators on earth, he added. It鈥檚 the first time an organism has been shown to use subdiffusion as a hunting strategy.

Researchers looking at phage therapy might one day be able to genetically modify bacteriophages to tweak their hunting strategies in order to maximize the chances they鈥檒l encounter harmful bacteria, thereby reducing infection and disease. To that end, he and his colleagues have worked with 黑料吃瓜鈥檚 technology incubator, the Zahn Innovation Center, to submit several provisional patents on this technique.

鈥淭here鈥檚 a huge amount of potential for ways you can engineer and optimize the system,鈥� Barr said.

This research was supported by grants from the National Institutes of Health, the Gordon and Betty Moore Foundation, and internal funding from 黑料吃瓜.