A West Nile Virus NS4B P38G mutant strain induces adaptive immunity via TLR7-MyD88-dependent and independent signaling pathways. (P4317)

Abstract

Abstract West Nile virus (WNV)- induced neurological disease has become a public health concern. No vaccines have been approved for human use. We have previously shown that an attenuated WNV, the nonstructural (NS) 4B-P38G mutant, induced stronger innate cytokine and T cell responses than wild-type WNV. Mice immunized with this mutant were all protected from subsequent lethal wild-type WNV infection. Here, we found both Toll-like receptor (TLR7) and MyD88 expression are required for host protection from NS4B P38G mutant infection. Infected MyD88-/- and TLR7-/- mice had lower IL-12 expression, IgM production, and reduced effector T cell functions. MyD88-/- and TLR7-/- dendritic cells (DC)s exhibited impaired antigen-presenting functions compared to wild-type DCs. At the late stage of infection or during secondary challenge with wild-type WNV, MyD88-/- and IL-1R-/- mice displayed reduced memory T cell responses compared to wild-type mice; whereas TLR7-/- mice had normal T cell functions. Moreover, immunization of MyD88-/- and TLR7-/- mice with NS4B P38G mutant strain offer partial or full protection respectively from subsequent lethal wild-type WNV infection. Thus, TLR7-MyD88 signaling is required for initial T cell priming; whereas the TLR7-independent MyD88 signaling is involved in memory T cell development during NS4B P38G mutant infection. Results can be utilized as a paradigm to aid in the rational development of efficacious live attenuated flavivirus vaccines.