Protein Kinase R's Role in Hantavirus Organ Tropism

Abstract: Old world hantaviruses such as Puumala virus, Seoul virus and Dobrava Belgrade virus infect highly differentiated and specialized microvascular endothelial cells of the kidney, causing hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of ~ 15%. On the other hand, new new-world hantaviruses, such as, Sin Nombre virus and Andes virus infect the microvascular endothelial cells of the heart, causing hantavirus cardiopulmonary syndrome (HCPS) with a mortality rate of ~ 50%. The infection to these organs breaks the endothelial barrier, causing acute kidney injury in HFRS patients and sever pulmonary and cardiac distress in HCPS patients. The molecular mechanism for such organ tropism and disease severity remains unclear. We have strong preliminary data showing that nucleocapsid protein of new-world hantaviruses selectively inhibits the protein kinase R (PKR) in the microvascular endothelial cells of the human heart with the assistance of P58IPK, an endogenous PKR inhibitor from the tetratricopeptide repeat (TPR) family. The detailed molecular mechanism was recently published. The shRNA knockdown of P58IPK triggered a strong PKR antiviral response that dramatically inhibited the replication of new-world hantaviruses in infected endothelial cells. On the other hand, nucleocapsid protein of old-world hantaviruses selectively inhibits the PKR activation by an unknown mechanism in the human glomerular microvascular endothelial cells of the kidney with the assistance of TRBP, a TAR RNA binding protein. We hypothesize that PKR is the anti-hantavirus host restriction factor whose selective inhibition in heart and kidney endothelial cells by mechanistically distinct strategies used by new and old hantaviruses, respectively, defines the organ tropism in hantavirus infected patients. We will use multifaceted experimental approaches to test this hypothesis and delineate the mechanism by which old-world hantavirus inhibit PKR with the assistance of TRBP. These studies will reveal new host targets for therapeutic intervention of hantavirus disease.