Rhesus monkey rotavirus outer capsid protein VP7 confers on a bovine rotavirus the ability to replicate more efficiently in mice, elevate rotavirus-specific T helper 1-biased antibody responses and accelerate diabetes onset (#103)
Jessica A Pane
1
,
Vi T Dang
1
,
Nicole L Webster
1
,
Barbara S Coulson
1
- Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia
Rotavirus infection of
children at-risk of developing type 1 diabetes correlates with production of
serum islet autoantibodies indicative of disease progression. Oral infection
with Rhesus monkey rotavirus (RRV) accelerates diabetes onset in adult non-obese
diabetic (NOD) mice and T cell-receptor transgenic NOD8.3 mice. Although
independent of pancreatic infection, diabetes acceleration by RRV is associated
with rotavirus spread to mesenteric and pancreatic lymph nodes, development of
a serum T helper (Th)-1 biased anti-rotavirus antibody response and increased proinflammatory
cytokine expression in islets and pancreatic lymph nodes. We examined
the role of RRV outer capsid proteins VP7 and VP4 in accelerated diabetes
onset. NOD8.3 mice infected with wild-type or reassortant rotavirus strains were
monitored for serum anti-rotavirus antibody responses, virus excretion and
diabetes development. In contrast to RRV, infection with bovine UK rotavirus
did not affect diabetes development. RRV infection produced greater virus
excretion in stools and higher serum anti-rotavirus antibody titres than UK infection.
Two reassortant rotaviruses, containing the RRV VP7 gene and
most or all of the other ten gene segments from UK rotavirus, induced diabetes
acceleration. However, a reassortant rotavirus containing RRV VP4 but not VP7 on
a mostly UK rotavirus genetic background did not modulate diabetes onset. The
extent of diabetes acceleration by these RRV VP7 reassortant rotaviruses was greater
in mice with serum anti-rotavirus antibody titres of >1:1600. The presence
of RRV VP7 in the infecting rotavirus was associated with greater rotavirus
excretion and the development of a Th1-biased serum antibody response. These studies demonstrate
the conversion of a rotavirus unable to modulate murine diabetes into a
diabetes-accelerating strain, by the replacement of its VP7 gene with that of
the diabetes-accelerating rotavirus RRV.