TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules.
In the wake of RNA virus infections, dsRNA intermediates are often generated. These viral pathogen-associated molecular patterns can be sensed by a growing number of host cell cytosolic proteins and TLR3, which contribute to the induction of antiviral defenses. Recent evidence indicates that melanoma differentiation-associated gene-5 is the prominent host component mediating IFN production after exposure to the dsRNA analog, poly(I:C). We have previously reported that Punta Toro virus (PTV) infection in mice is exquisitely sensitive to treatment with poly(I:C(12)U), a dsRNA analog that has a superior safety profile while maintaining the beneficial activity of the parental poly(I:C) in the induction of innate immune responses. The precise host factor(s) mediating protective immunity following its administration remain to be elucidated. To assess the role of TLR3 in this process, mice lacking the receptor were used to investigate the induction of protective immunity, type I IFNs, and IL-6 following treatment. Unlike wild-type mice, those lacking TLR3 were not protected against PTV infection following poly(I:C(12)U) therapy and failed to produce IFN-alpha, IFN-beta, and IL-6. In contrast, poly(I:C) treatment significantly protected TLR3(-/-) mice from lethal challenge despite some deficiencies in cytokine induction. There was no indication that the lack of protection was due to the fact that TLR3-deficient mice had a reduced capacity to fight infection because they were not found to be more susceptible to PTV. We conclude that TLR3 is essential to the induction of antiviral activity elicited by poly(I:C(12)U), which does not appear to be recognized by the cytosolic sensor of poly(I:C), melanoma differentiation-associated gene-5.
Gowen
Brian B
BB
Institute for Antiviral Research, Utah State University, Logan, Utah 84341, USA. bgowen@cc.usu.edu
Wong
Min-Hui
MH
Jung
Kie-Hoon
KH
Sanders
Andrew B
AB
Mitchell
William M
WM
Alexopoulou
Lena
L
Flavell
Richard A
RA
Sidwell
Robert W
RW
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D002044:Bunyaviridae Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D016899:Interferon-beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016856:Phlebovirus; D011070:Poly I-C / Q000627:therapeutic use*; D011072:Poly U / Q000627:therapeutic use*; D012330:RNA, Double-Stranded / Q000627:therapeutic use*; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D019562:Viral Load
D000998:Antiviral Agents; D015850:Interleukin-6; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3; D011072:Poly U; D016899:Interferon-beta; C047490:poly(I).poly(c12,U); D000410:Alanine Transaminase; D011070:Poly I-C