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The endosomal Toll-like receptors 7 and 9 cooperate in detection of MHV68 infection.
Bussey, Kendra A Murthy, Sripriya Reimer, Elisa Chan, Baca Hatesuer, Bastian Schughart, Klaus Glaunsinger, Britt Adler, Heiko Brinkmann, Melanie M
Bussey, Kendra A
Murthy, Sripriya
Reimer, Elisa
Chan, Baca
Hatesuer, Bastian
Schughart, Klaus
Glaunsinger, Britt
Adler, Heiko
Brinkmann, Melanie M
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2018-11-14
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Murine gammaherpesvirus 68 (MHV68) is an amenable small animal model for study of the
human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus. Here,
we have characterized the roles of the endosomal TLR escort protein UNC93B, endosomal
TLR7, 9, and 13, and cell surface TLR2 in MHV68 detection. We found that the interferon α
(IFNα) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9-/-
cells compared to wildtype (WT), but not completely lost. Tlr7-/- pDC responded similarly
to WT. However, we found that in Unc93b-/- pDC, as well as in Tlr7/Tlr9-/- double knockout
pDC, the IFNα response to MHV68 was completely abolished. Thus, the only pattern
recognition receptors contributing to the IFNα response to MHV68 in pDC are TLR7 and
TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role
of UNC93B and TLR for MHV68 infection in vivo, we infected mice with MHV68. Lytic
replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and
liver of UNC93B-deficient mice, in the spleen of TLR9-deficient mice, and in the liver and
spleen of Tlr7/Tlr9-/- mice. The absence of TLR2 or TLR13 did not affect lytic viral titers.
We then compared reactivation of MHV68 from latently infected WT, Unc93b-/-, Tlr7/Tlr9-/-,
Tlr7-/-, and Tlr9-/- splenocytes. We observed enhanced reactivation and latent viral loads,
particularly from Tlr7/Tlr9-/- splenocytes, compared to WT. Our data show that UNC93B-
dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68
infection.
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1098-5514
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Attribution-NonCommercial-ShareAlike 4.0 International