In Defense of Viruses

Viruses have a long and glorious past, probably having evolved from the earliest cellular creatures on Earth to become the most abundant and diverse group of microbes on the planet. Most spend their time shuttling genes around and driving evolution, some have developed mutually beneficial relationships with animals and plants, and only a very few viruses cause disease. Unfortunately, most virus research is focused on a relatively small group of pathogens. A similar situation confronted bacteria when only the diseasecausing among them were studied. However, just as most bacteria have been absolved of wrongdoing, scientists are now revealing a viral world in which the majority of these enterprising microbes are doing more good than harm. Viruses could not get any more helpful than the tiny bacteria-hunting phages that partner with our mucus to fend off potential predators. In a recently described model called bacteriophage adhering to mucus (BAM), Jeremy J. Barr, at San Diego State University (SDSU), and his colleagues recently reported that this novel relationship constitutes “a non-host-derived, phagemediated immune defense that actively protects mucosal surfaces; the main site of pathogen entry into metazoans” (doi:10.1073/pnas.1307782110). So far, every metazoan that these researchers have studied—including sea anemones and fish, as well as humans—secretes phage-attracting mucus to help defend against incoming bacteria. “It seems a very well-conserved immune defense,” Barr notes. This model works like “Velcro,” explains Justin R. Meyer, from Harvard Medical School. The underlying epithelial cells constantly secrete negatively charged mucin glycoproteins that drive the mucus outward. Incoming phages stick to the glycans with one or another of a large variety of immunoglobulin (Ig)–like proteins on their surfaces, anchoring their heads in the mucus matrix with their tail-like spikes sticking up. This stance enables them to stab through bacterial cell envelopes and discharge viral DNA and proteins inside, where they replicate at the expense of their victims. Like the antibodies they resemble, phage Ig proteins come in thousands of different versions, and each can lock on to a different target. “Notably, metazoan mucus and the sticky phage proteins appear to have coevolved into a very successful relationship,” says principal investigator Forest Rohwer at SDSU. “It’s a dynamic system, and the mucin at any location can be altered by the host in response to events like infection or inflammation. “The recent worldwide rise of pathogens with multidrug resistance has spurred a renewed and urgent interest in phage therapy,” according to Rohwer. A novel approach is being researched by ContraFect in concert with The Rockefeller University. Together, they are developing bacteriophage-derived enzymes called lysins for clinical use. In nature, phages use lysins to liberate their progeny from inside infected Gram-positive bacteria, such as Staphylococcus aureus, by degrading their tough bacterial peptidoglycan coats. “Our first therapeutic lysin attacks peptidoglycan from the outside and has proved synergistic with a number of antibiotics currently used against S. aureus, even the very resistant kinds,” says ContraFect’s lead scientist Raymond Schuch. “The beauty of lysins is that antibiotic resistance doesn’t affect them; they eradicate biofilms and are highly specific, rarely killing nontarget organisms [and] thereby sparing our commensal bacteria, like those in the gut,” adds laboratory chief Vincent Fischetti of Rockefeller. Giant viruses are also prey to phages, and Matthias Fischer, of the Max Planck Institute for Medical Research, in Heidelberg, speculates that the Mavirus virophage discovered parasitizing the giant Cafeteria roenbergenis virus, or CroV, are allies of the flagellate marine predator that they protect and after which CroV is named. “Maviruses resemble mobile genes called, transposons, [which are] found in many eukaryotes,” he says. “It appears that they integrate themselves into the host’s genome and are reactivated when the host is infected with CroV. Experimental data are in the making.” Even endogenous retroviruses (ERVs), with their deservedly bad reputation, are sometimes beneficial. For example, “expression of human salivary amylase is controlled by an ERV insertion that may have helped our forebears switch from a mainly fruitbased diet to one containing starch,” say Robin Weiss and Jonathan Stoye, respectively of University College London and the Medical Research Council National Institute of Medical Research. Furthermore, ERV genes are essential for proper placenta formation in mammals and for the immune suppression that allows a mother to tolerate her fetus. “Viruses are generally good— particularly bacteriophages—and we would not be here without them. They are doing more for our survival than we understand, but we soon will [understand more],” comments Fischetti. Notably, 2015 is the year of the phage, so whether you love traditional bacteriophages or the newly discovered virophages, get ready to celebrate. For details, check the Rohwer Lab blog at http://coralandphage.org.