Viruses called ‘jumbo’ phages are being considered as a potential weapon against deadly bacterial infections. However, scientists need to understand the unique structure of these mysterious viruses first. Researchers have recently discovered an important aspect of jumbo phage development that helps them combat bacteria. Antibiotics became a popular treatment for bacterial infections in the early 20th century and revolutionized human health. Novel antibiotics were regularly developed during the medication’s golden age in the mid-20th century. However, bacteriaevolve into a new form that is capable of resisting antibiotic treatments, making many of them ineffective. The depletion of new sources of antibiotics has led to a significant increase in bacterial infections, leading to the current global health crisis of antibiotic resistance.
Scientists are now turning to a unique ally, viruses, in an effort to combat this growing threat. In recent years, researchers have turned their attention to bacteriophages, a type of virus, as a new method for treating and disarming antibiotic-resistant bacteria. Researchers are particularly interested in “jumbo” phages, which are viruses with unusually large genomes that have the potential to be used as specialized delivery agents. These phages are not only capable of killing bacteria, but they also have the potential to evolve and target antibiotic-resistant strains.Phages can be designed to transport antibiotics directly to the infection site. However, to use phages for new treatments, researchers need to comprehend their complex biological composition and inner workings. Scientists from the University of California San Diego School of Biological Sciences, in collaboration with the UC Berkeley’s Innovative Genomics Institute and Chulalongkorn University in Bangkok, have made significant progress in understanding various important functions of jumbo phages. These phages have large genomes that could potentially be modified to transport therapeutic payloads.UC San Diego professor Joe Pogliano, along with a team of researchers, has made a breakthrough in finding a way to effectively kill bacteria. The researchers discovered key elements of jumbo Chimalliviridae phages, which are known to replicate inside bacteria by creating a compartment similar to the nucleus found in human cells. This discovery, published in the Proceedings of the National Academy of Sciences, is significant as it sheds light on how these phages can potentially be used to combat bacterial infections. This finding is crucial as the enclosed genome of these phages has made it challenging to access them in the past.The Chimalliviridae’s nucleus-like compartment separates and selectively imports certain proteins that allow it to replicate inside the host bacteria. However, the details of how this process occurs have been a mystery. Using new genetic and cell biology tools, Morgan and his colleagues discovered a key protein, called “protein importer of Chimalliviruses A” (PicA), that selectively allows certain proteins to enter the nucleus while denying access to others. PicA acts as a type of nightclub bouncer, coordinating the transport of cargo proteins.ein trafficking within the phage nucleus. According to Morgan, the ability of this virus to establish such a complex structure and transport system is truly remarkable and unlike anything seen before. Typically, complex biological processes are associated with higher life forms, such as humans with tens of thousands of genes. However, this virus exhibits functionally similar processes within its relatively small genome of roughly 300 genes. This makes it one of the simplest selective transport systems known. The researchers used CRISPRi-ART, a programmable RNA tool, to study genomeThe researchers discovered that PicA plays a crucial role in the nucleus development and replication process of Chimalliviridae.
Co-author Ben Adler, a postdoctoral scholar under CRISPR pioneer Jennifer Doudna, expressed excitement about the potential of RNA-targeting CRISPR technologies in unraveling the mysteries of phage genomes.
Throughout billions of years, bacteria and viruses have been involved in an ongoing arms race, evolving to counter each other’s adaptations.The researchers believe that the advanced PicA transportation system has developed through intense evolutionary competition. This system is highly adaptable and selective, only allowing important beneficial elements into the nucleus. Without the PicA system, the bacteria’s defensive proteins would enter and disrupt the virus’ replication process.
This knowledge is crucial as scientists from the Howard Hughes Medical Institute (HHMI)-funded Emerging Pathogens Initiative and UC San Diego’s Center for Innovative Phage Applications and Therapeutics work towards establishing the foundation for future genetic research.ically program phage to treat a variety of deadly diseases.
“We didn’t have any prior understanding of the protein import system’s functioning or the proteins involved, so this research marks the initial stage in grasping a crucial process for the successful replication of these phage,” said Emily Armbruster, a coauthor of the paper and graduate student at the School of Biological Sciences. “The more we comprehend these vital systems, the more capable we will be in modifying phage for medical purposes.
Future targets for these genetically engineered viruses include Pseudomonas aeruginosa bacteria, which are known to cause severe infections.”Potentially life-threatening infections can be caused by bacteria such as Pseudomonas aeruginosa, which can pose a risk to patients in hospitals. Other bacteria, such as E. coli and Klebsiella, can also cause chronic and recurrent infections that may enter the bloodstream and become life-threatening in some cases.
Journal Reference:
- Chase J. Morgan, Eray Enustun, Emily G. Armbruster, Erica A. Birkholz, Amy Prichard, Taylor Forman, Ann Aindow, Wichanan Wannasrichan, Sela Peters, Koe Inlow, Isabelle L. Shepherd, Alma Razavilar, Vorrapon Chaikeeratisak, Benjamin A. Adler, Brady F. Cress, Jennifer A. Doudna, Kit Pogliano, Elizabeth Villa, Kevin D.Corbett, Joe Pogliano. An important and very specific protein import pathway encoded by nucleus-forming phage. Proceedings of the National Academy of Sciences, 2024; 121 (19) DOI: 10.1073/pnas.2321190121
Viruses called ‘jumbo’ phages are being considered as a potential weapon against deadly bacterial infections. However, scientists need to understand the unique structure of these mysterious viruses first. Researchers have recently discovered an important aspect of jumbo phage development that helps them combat bacteria. Antibiotics became a popular treatment for bacterial infections in the early 20th century and revolutionized human health. Novel antibiotics were regularly developed during the medication’s golden age in the mid-20th century. However, bacteriaevolve into a new form that is capable of resisting antibiotic treatments, making many of them ineffective. The depletion of new sources of antibiotics has led to a significant increase in bacterial infections, leading to the current global health crisis of antibiotic resistance.
Scientists are now turning to a unique ally, viruses, in an effort to combat this growing threat. In recent years, researchers have turned their attention to bacteriophages, a type of virus, as a new method for treating and disarming antibiotic-resistant bacteria. Researchers are particularly interested in “jumbo” phages, which are viruses with unusually large genomes that have the potential to be used as specialized delivery agents. These phages are not only capable of killing bacteria, but they also have the potential to evolve and target antibiotic-resistant strains.Phages can be designed to transport antibiotics directly to the infection site. However, to use phages for new treatments, researchers need to comprehend their complex biological composition and inner workings. Scientists from the University of California San Diego School of Biological Sciences, in collaboration with the UC Berkeley’s Innovative Genomics Institute and Chulalongkorn University in Bangkok, have made significant progress in understanding various important functions of jumbo phages. These phages have large genomes that could potentially be modified to transport therapeutic payloads.UC San Diego professor Joe Pogliano, along with a team of researchers, has made a breakthrough in finding a way to effectively kill bacteria. The researchers discovered key elements of jumbo Chimalliviridae phages, which are known to replicate inside bacteria by creating a compartment similar to the nucleus found in human cells. This discovery, published in the Proceedings of the National Academy of Sciences, is significant as it sheds light on how these phages can potentially be used to combat bacterial infections. This finding is crucial as the enclosed genome of these phages has made it challenging to access them in the past.The Chimalliviridae’s nucleus-like compartment separates and selectively imports certain proteins that allow it to replicate inside the host bacteria. However, the details of how this process occurs have been a mystery. Using new genetic and cell biology tools, Morgan and his colleagues discovered a key protein, called “protein importer of Chimalliviruses A” (PicA), that selectively allows certain proteins to enter the nucleus while denying access to others. PicA acts as a type of nightclub bouncer, coordinating the transport of cargo proteins.ein trafficking within the phage nucleus. According to Morgan, the ability of this virus to establish such a complex structure and transport system is truly remarkable and unlike anything seen before. Typically, complex biological processes are associated with higher life forms, such as humans with tens of thousands of genes. However, this virus exhibits functionally similar processes within its relatively small genome of roughly 300 genes. This makes it one of the simplest selective transport systems known. The researchers used CRISPRi-ART, a programmable RNA tool, to study genomeThe researchers discovered that PicA plays a crucial role in the nucleus development and replication process of Chimalliviridae.
Co-author Ben Adler, a postdoctoral scholar under CRISPR pioneer Jennifer Doudna, expressed excitement about the potential of RNA-targeting CRISPR technologies in unraveling the mysteries of phage genomes.
Throughout billions of years, bacteria and viruses have been involved in an ongoing arms race, evolving to counter each other’s adaptations.The researchers believe that the advanced PicA transportation system has developed through intense evolutionary competition. This system is highly adaptable and selective, only allowing important beneficial elements into the nucleus. Without the PicA system, the bacteria’s defensive proteins would enter and disrupt the virus’ replication process.
This knowledge is crucial as scientists from the Howard Hughes Medical Institute (HHMI)-funded Emerging Pathogens Initiative and UC San Diego’s Center for Innovative Phage Applications and Therapeutics work towards establishing the foundation for future genetic research.ically program phage to treat a variety of deadly diseases.
“We didn’t have any prior understanding of the protein import system’s functioning or the proteins involved, so this research marks the initial stage in grasping a crucial process for the successful replication of these phage,” said Emily Armbruster, a coauthor of the paper and graduate student at the School of Biological Sciences. “The more we comprehend these vital systems, the more capable we will be in modifying phage for medical purposes.
Future targets for these genetically engineered viruses include Pseudomonas aeruginosa bacteria, which are known to cause severe infections.”Potentially life-threatening infections can be caused by bacteria such as Pseudomonas aeruginosa, which can pose a risk to patients in hospitals. Other bacteria, such as E. coli and Klebsiella, can also cause chronic and recurrent infections that may enter the bloodstream and become life-threatening in some cases.
Journal Reference:
- Chase J. Morgan, Eray Enustun, Emily G. Armbruster, Erica A. Birkholz, Amy Prichard, Taylor Forman, Ann Aindow, Wichanan Wannasrichan, Sela Peters, Koe Inlow, Isabelle L. Shepherd, Alma Razavilar, Vorrapon Chaikeeratisak, Benjamin A. Adler, Brady F. Cress, Jennifer A. Doudna, Kit Pogliano, Elizabeth Villa, Kevin D.Corbett, Joe Pogliano. An important and very specific protein import pathway encoded by nucleus-forming phage. Proceedings of the National Academy of Sciences, 2024; 121 (19) DOI: 10.1073/pnas.2321190121