Developmental Biology - Heart Viruses|
'Cold' Virus Upsets the Electrical System of Our Heart
The Adenovirus, which typically causes the "common cold", is far more dangerous if it reaches our heart...
Scientists at the Fralin Biomedical Research Institute Center for Heart and Reparative Medicine, at Virginia Polytechnic Institute and State University, can now define how the adenovirus disrupts electrical signals in the heart.
The Adenovirus typically causes our common cold. But if it settles in our heart, it can be far more dangerous. It can then commandeer gap junctions which exist in the membranes uniting each heart muscle cell. It can also slow the production of connexin 43 - a protein regulating cell death, proliferation, and differentiation.
Patrick J. Calhoun is a PhD candidate conducting experiments to confirm how the adenovirus is in effect hijacking cell signals. Similar research has been done using mice as the model system, but not using adenovirus in human heart cells. Calhoun innovated a diagnostic technique using induced pluripotent stem cells he made from cardiomyocytes (which are human skin cells converted into heart cells). Applying adenovirus to the cardiomyocyte cells in culture, he watched as the virus took over the gap junctions between cells in order to replicate itself. But, he also saw something he hadn't expect.
Calhoun: "I realized there were two distinct processes going on here, with the virus giving a double hit to the cell's ability to communicate with its neighbors. First, it rapidly closed existing channels. Second, it shut down the cells' ability to make new cells."
Rachel Padget, also working in the lab of James Smyth, recently was awarded a National Institutes of Health fellowship to develop the first mouse model for investigating how adenovirus attacks the heart.
The research is published in the journal of the American Heart Association FASEB.
The adenovirus switched a protein pathway from make new connexin - into suppress connexin.
"We might learn something very new here about the molecular biology causing this switch. We're essentially learning from adenovirus the most efficient way to stop, rather than cause, arrhythmias."
James W. Smyth PhD, Associate Professor, Fralin Biomedical Research Institute, Department of Biological Sciences, Roanoke, Virginia Tech, Blacksburg, VA; Virginia Tech Carilion School of Medicine, Roanoke, VA, USA.
Adenoviruses are responsible for a spectrum of pathogenesis including viral myocarditis. The gap junction protein connexin43 (Cx43, gene name GJA1 ) facilitates rapid propagation of action potentials necessary for each heartbeat. Gap junctions also propagate innate and adaptive antiviral immune responses, but how viruses may target these structures is not understood. Given this immunological role of Cx43, we hypothesized that gap junctions would be targeted during adenovirus type 5 (Ad5) infection. We find reduced Cx43 protein levels due to decreased GJA1 mRNA transcripts dependent upon ß-catenin transcriptional activity during Ad5 infection, with early viral protein E4orf1 sufficient to induce ?-catenin phosphorylation. Loss of gap junction function occurs prior to reduced Cx43 protein levels with Ad5 infection rapidly inducing Cx43 phosphorylation events consistent with altered gap junction conductance. Direct Cx43 interaction with ZO-1 plays a critical role in gap junction regulation. We find loss of Cx43/ZO-1 complexing during Ad5 infection by co-immunoprecipitation and complementary studies in human induced pluripotent stem cell derived-cardiomyocytes reveal Cx43 gap junction remodeling by reduced ZO-1 complexing. These findings reveal specific targeting of gap junction function by Ad5 leading to loss of intercellular communication which would contribute to dangerous pathological states including arrhythmias in infected hearts.
Patrick J. Calhoun, Allen V. Phan, Jordan D. Taylor, Carissa C. James, Rachel L. Padget, Michael J. Zeitz and James W. Smyth.
The authors thank Dr David Ornelles (Wake Forest School of Medicine, Microbiology and Immunology) for providing adenovirus reagents and helpful discussion. Dr Allison N. Tegge (Fralin Biomedical Research Institute, Department of Statistics, Virginia Tech) for consultation on statistical methods used and Dr Samy Lamouille for critical review of this manuscript (Fralin Biomedical Research Institute, Department of Biological Sciences, Virginia Tech). This work was supported by a NIH NHLBI R01 grant (HL132236 to JWS), an American Heart Association Predoctoral Fellowship (18PRE33960573 to PJC), a NHLBI F31 grant (HL140909 to CCJ), and a NHLBI F31 grant (HL152649 to RLP).
The authors declare no competing interests.
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