Viruses may monitor their hosts' environment to spread more effectively

A team of international researchers has revealed that viruses take cues from their surroundings to perform different actions. This implies that they have the ability to sense their and their host's environment and decide whether or not it is suitable to spread infection, attack the host cells, multiply in number, or suspend activity at any given time.

The researchers believe that this discovery could further disclose various unknown aspects of the virus-host interaction and lead to the development of a new generation of antiviral drugs. During their study, they studied bacteriophages, also called "phages," viruses that infect and harm bacteria, and discovered that the DNA of such viruses contains binding sites for a protein called CtrA.

Interestingly, a phage never produces CtrA, so why does its DNA have a binding site for the protein? While looking for an answer to this question, the researchers discovered an unheard power of the phages.

Viruses are smarter than you think

CtrA is actually associated with the formation of special outgrowths in bacterial cells. These outgrowths called flagella allow the microorganism to move and perform other actions such as adhesion, reproduction, and infecting a host. The researchers suggest that the binding site in a phage DNA is actually meant for the CtrA protein that controls flagella formation in their host bacteria.

Moreover, the occurrence of CtrA binding sites is not limited to a particular phage species. They are found in numerous types of flagellotropic phages. The findings explain why and how phages decide to attack only the bacteria that have developed flagella.

During the study, the researchers studied a phage that infects caulobacterales, an order that incorporates many gram-negative bacteria species. The special characteristic of caulobacter bacteria cells is that when plenty of food is available, they produce non-motile stalked cells. However, when there is a scarcity of food, the cells develop flagella and give rise to swarmers — bacteria that can freely move.

The phage only infects the swarmer bacteria, but how is it able to distinguish between the different members of caulobacterales? Interestingly, the researchers found that CtrA protein decided whether the bacterial cell would divide to form stalkers or swarmers. They suggest that CtrA levels in a caulobacter enable the phage to choose the right host.

"We hypothesize the phages are monitoring CtrA levels, which go up and down during the life cycle of the cells, to figure out when the swarmer cell is becoming a stalk cell and becoming a factory of swarmers, and at that point, they burst the cell, because there are going to be many swarmers nearby to infect," one of the authors and computational biologist at University of Maryland Baltimore County, Ivan Erill told PhysX.

A phage can do much more than just spot flagella

The presence of CtrA binder sites in phages gives them the ability to monitor the environment around them and make decisions that better suit their biology. Interestingly, this could be just one of the many talents, the researchers believe that phages might also have receptors that allow them to listen to the activities taking place inside host cells. However, this is just a hypothesis, and further research is required to prove this and many other possibilities.

The knowledge of more such binding sites and receptors could allow us to create better and more effective antiviral drugs. For instance, the current study highlights that the CtrA binder is responsible for a flagellotropic phage's ability to monitor its environment. Now using this information scientists can create a drug that could trigger false CtrA monitoring and fool the virus.

The most fascinating finding of this research work is that "the virus is using cellular intel to make decisions, and if it's happening in bacteria, it's almost certainly happening in plants and animals because if it's an evolutionary strategy that makes sense, evolution will discover it and exploit it," said Professor Erill.

The study is published in the journal Frontiers in Microbiology.

Abstract:

Pilitropic and flagellotropic phages adsorb to bacterial pili and flagella. These phages have long been used to investigate multiple aspects of bacterial physiology, such as the cell cycle control in the Caulobacterales. Targeting cellular appendages for adsorption effectively constrains the population of infectable hosts, suggesting that phages may have developed strategies to maximize their infective yield. Brevundimonas phage vB_BsubS-Delta is a recently characterized pilitropic phage infecting the Alphaproteobacterium Brevundimonas subvibrioides. Like other Caulobacterales, B. subvibrioides divides asymmetrically and its cell cycle is governed by multiple transcriptional regulators, including the master regulator CtrA. Genomic characterization of phage vB_BsubS-Delta identified the presence of a large intergenic region with an unusually high density of putative CtrA-binding sites. A systematic analysis of the positional distribution of predicted CtrA-binding sites in complete phage genomes reveals that the highly skewed distribution of CtrA-binding sites observed in vB_BsubS-Delta is an unequivocal genomic signature that extends to other pilli- and flagellotropic phages infecting the Alphaproteobacteria. Moreover, putative CtrA-binding sites in these phage genomes localize preferentially to promoter regions and have higher scores than those detected in other phage genomes. Phylogenetic and comparative genomics analyses show that this genomic signature has evolved independently in several phage lineages, suggesting that it provides an adaptive advantage to pili/flagellotropic phages infecting the Alphaproteobacteria. Experimental results demonstrate that CtrA binds to predicted CtrA-binding sites in promoter regions and that it regulates transcription of phage genes in unrelated Alphaproteobacteria-infecting phages. We propose that this focused distribution of CtrA-binding sites reflects a fundamental new aspect of phage infection, which we term lytic deferment. Under this novel paradigm, pili- and flagellotropic phages exploit the CtrA transduction pathway to monitor the host cell cycle state and synchronize lysis with the presence of infectable cells.