Interactions between multiple genetic determinants in the 5' UTR and VP1 capsid control pathogenesis of chronic post-viral myopathy caused by coxsackievirus B1.
Mice infected with coxsackievirus B1 Tucson (CVB1(T)) develop chronic, post-viral myopathy (PVM) with clinical manifestations of hind limb muscle weakness and myositis. The objective of the current study was to establish the genetic basis of myopathogenicity in CVB1(T). Using a reverse genetics approach, full attenuation of PVM could only be achieved by simultaneously mutating four sites located at C706U in the 5' untranslated region (5' UTR) and at Y87F, V136A, and T276A in the VP1 capsid. Engineering these four myopathic determinants into an amyopathic CVB1(T) variant restored the ability to cause PVM. Moreover, these same four determinants controlled PVM expression in a second strain of mice, indicating that the underlying mechanism is operational in mice of different genetic backgrounds. Modeling studies predict that C706U alters both local and long range pairing in the 5' UTR, and that VP1 determinants are located on the capsid surface. However, these differences did not affect viral titers, temperature stability, pH stability, or the antibody response to virus. These studies demonstrate that PVM develops from a complex interplay between viral determinants in the 5' UTR and VP1 capsid and have uncovered intriguing similarities between genetic determinants that cause PVM and those involved in pathogenesis of other enteroviruses.
Sandager
Maribeth M
MM
Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN 55455, USA. maribeth@umn.edu
Nugent
Jaime L
JL
Schulz
Wade L
WL
Messner
Ronald P
RP
Tam
Patricia E
PE
D020121:5' Untranslated Regions / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002908:Chronic Disease; D029822:Enterovirus B, Human / Q000235:genetics / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000503:physiopathology* / Q000821:virology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000473:pathology / Q000821:virology; D009154:Mutation; D009220:Myositis / Q000503:physiopathology* / Q000821:virology; D013047:Specific Pathogen-Free Organisms; D014774:Virulence
D020121:5' Untranslated Regions; D036022:Capsid Proteins