Non-Cytolytic Enterovirus May Play a Fundamental Role in ME/CFS Researchers have discovered that in ME/CFS, in addition to normal lytic enteroviruses, there are also non-cytolytic enteroviruses, and the latter may be playing a fundamental role in the pathophysiology of ME/CFS. Whereas lytic enteroviruses are found in the bloodstream and in the space between cells, non-cytolytic viruses live inside human cells on a long-term basis. Non-cytolytic viruses take up residence in your cells as a chronic intracellular infection. Dr John Chia, Prof Nora Chapman, Prof Steven Tracy, and others have pioneered the understanding of non-cytolytic enteroviruses in ME/CFS. When you first catch and enterovirus infection, it begins with the normal lytic form of the virus. However, once inside your body, if this virus is able to enter certain cells types (specifically non-dividing cell types), it can transform into this non-cytolytic enterovirus which take up residence in the cell. These non-cytolytic enteroviruses are associated with ME/CFS,1 as well as a number of other diseases such as type 1 diabetes,1 chronic coxsackievirus B myocarditis,1 cardiomyopathy (in a murine model),1 and chronic inflammatory myopathy.1 Non-cytolytic enteroviruses may be the major casual factor in these diseases. Lytic and Non-Cytolytic Enterovirus: What is the Difference? As its name suggests, in the life cycle of a regular lytic enterovirus, the virus enters a human cell, replicates itself thousands of times inside that cell, and then ruptures and kill the cell by lysis (lysis just means cell rupture) so that these thousands of newly created viruses can escape the cell, and go onto to infect more cells. By contrast, non-cytolytic enteroviruses live within human cells on a long term basis. They do not create any new viral particles, and they do not lyse the cell they live in (they do not rupture and kill the cell). They remain in the cell on a long term basis as a slow "smoldering" infections. Non-cytolytic viruses may nevertheless cause cellular dysfunction due to their presence in the cell, and provoke an immune response, which may lead to disease. So given that non-cytolytic infections do not manufacture any new viral particles (which is the normal way viruses multiply and spread), you might think that a non-cytolytic enterovirus infection would not spread to any new cells. However, a new study uncovers a mechanism by which non-cytolytic enteroviruses may spread from cell-to-cell in the body tissues. How Non-Cytolytic Enteroviruses May Spread To Nearby Cells This study demonstrates how non-cytolytic enteroviruses may be able to spread into adjacent cells. The study found that in infected cells, this virus seems to be able to create tentacle-like cellular protrusions that grow out of the cell, that look like they may set up a bridge to adjacent cells. Cellular protrusions are a normal part of cellular function: they are created by the cell when it wants to gain traction and pull itself along in the tissues. This is basically how cells can move. However, the authors suggest that these tentacle-like protrusions may be co-opted by non-cytolytic CVB infections in order to transmit the infection into adjacent cells. The authors suggest non-cytolytic viruses may induce cellular protrusions to create a bridge to adjacent cells, which they then cross, so as to be able to infect nearby cells. There is a time-lapse video (supplemental file 1) in this study in which shows the cellular protrusions produced by a non-cytolytic CVB infection. In the video, the infected cells shown on the left hand side, and are seen sprouting the cellular protrusions (these look like thin filaments emanating from the cell). The cells shown on the right hand side are uninfected cells, used as a control. Here is a snapshot of this video, showing the cellular protrusions running from cell to cell: Coxsackie B virus infected cells showing cellular protrusions (thin filaments) running from cell to cell. These protrusions may transmit the non-cytolytic Coxsackie B virus to adjacent cells. Normal uninfected cells do not display such protrusions. More Information About Non-Cytolytic Enteroviruses Human Enteroviruses and Chronic Infectious Disease by Prof Steven Tracy and Prof Nora M. Chapman. I believe it was Prof Tracy et al at the University of Nebraska who first discovered non-cytolytic enteroviruses (in the heart muscle in coxsackievirus B myocarditis) Replication Defective Enterovirus Infections: Implications for Type I Diabetes by Prof Nora M. Chapman. Normal lytic enteroviruses are also called: cytolytic enteroviruses cytopathic enteroviruses wild-type viruses Non-cytolytic enteroviruses are also called: non-cytopathic enteroviruses defective enteroviruses terminally-deleted enteroviruses. Non-cytolytic enteroviruses may be detected by sensitive RT-PCR, and by immunohistochemistry (see page 22 of this document). Note that enteroviruses are not the only type of virus that develop into non-cytolytic infections. Google search on the terms: non-cytolytic virus, non-cytopathic virus, defective virus and terminally-deleted virus for more info on non-cytolytic viral infections in general. Non-cytolytic enteroviruses are closely analogous to the herpesvirus abortive infections that Dr Martin Lerner proposed are the cause of herpesvirus-associated ME/CFS.