Targeting of Mammalian Glycans Enhances Phage Predation in the Gastrointestinal Tract
Authors: Anthony W Maresso
Robert F Ramig
Sabrina I Green
Shelley Gibson
Anubama Rajan
Xuezheng Song
Wilhem Salmen
Heidi B Kaplan
Barbara W Trautner
Xue Yu
Justin R Clark
Hannah E Carter
Carmen Gu Liu
Journal: mBio (2021)
Discipline: MICROBIOLOGY
Keywords: E. coli; bacteriophage therapy; bacteriophages; multidrug resistance; pathobiont
Affiliations: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA., Department of Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Department of Biochemistry, Emory Comprehensive Glycomics Core, Emory University School of Medicine, Atlanta, Georgia, USA., Michael E. Debakey Veterans Affairs Medical Center, Houston, Texas, USA., Department of Medicine, Baylor College of Medicine, Houston, Texas, USA., Department of Microbiology and Molecular Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA., Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA .

Abstract:  The human gastrointestinal mucosal surface consists of a eukaryotic epithelium, a prokaryotic microbiota, and a carbohydrate-rich interface that separates them. In the gastrointestinal tract, the interaction of bacteriophages (phages) and their prokaryotic hosts influences the health of the mammalian host, especially colonization with invasive pathobionts. Antibiotics may be used, but they also kill protective commensals. Here, we report a novel phage whose lytic cycle is enhanced in intestinal environments. The tail fiber gene, whose protein product binds human heparan sulfated proteoglycans and localizes the phage to the epithelial cell surface, positions it near its bacterial host, a type of locational targeting mechanism. This finding offers the prospect of developing mucosal targeting phage to selectively remove invasive pathobiont species from mucosal surfaces.IMPORTANCE Invasive pathobionts or microbes capable of causing disease can reside deep within the mucosal epithelium of our gastrointestinal tract. Targeted effective antibacterial therapies are needed to combat these disease-causing organisms, many of which may be multidrug resistant. Here, we isolated a lytic bacteriophage (phage) that can localize to the epithelial surface by binding heparan sulfated glycans, positioning it near its host, Escherichia coli This targeted therapy can be used to selectively remove invasive pathobionts from the gastrointestinal tract, preventing the development of disease. 

Retracted: No

PubPeer comments:
 1 Figure 6 summarize the conclusions. Fig6-1 states that most phages are inhibited by intestinal glycans. But is not the intestine the largest reservoir of phages in a body? It makes no sense to state that most phages are inhibited and the data do not support this. The literature show otherwise. 2 Figure 6 summarize the conclusions. Fig6-2 states that some phages bind to intestinal glycans as receptors on bacteria embedded in mucus. From a virological perspective it makes no sense, otherwise the virus would be able to infect any cell covered with glycans. It is not discussed in the manuscript and the concept of a receptor for a virus was misunderstood. , 
 #1 Hi. Thank you for the questions, which are good ones. I am happy to respond to them shortly. Today is very bad for me with things piling up. AM , 
 #1 I mostly agree with your point. In the paper, we demonstrate that mucus (mostly mucins) are inhibitory to a key phage, HP3, that has traditionally been effective at killing its targets in various environments. Hypothesizing that there were phage that were not inhibited by mucins (to your point), we screened many of our phage for activity when faced with mucins. This led to the discovery of ES17 which seemed to work despite mucins. When we investigated why it worked well, we found that it contains tail fibers that bind the sugars in mucins. Thus, it seems that some phage which are found at mucosal surfaces like the intestine may have evolved the ability to bind to human sugars to position themselves in the exact environment where their host will be. Regarding your second point, there are many steps that lead to productive infection by a virus of a host cell, not only the binding step. Just because this phage sticks to human cells or human mucins does not mean it will have the machinery to mount a productive infection of human cells. The downstream steps that lead to infectious virions is also specified in the host cell. Phage to my knowledge cannot mount a productive infection of mammalian cells because they lack downstream machinery to do so. Our data does show that the phage stays on the surface of the mammalian cell and does not get in which supports this comment. ,