Presentation Title

DEC-205+ DCs Within the CNS Critically Modulate CD8+ T Cell-Mediated Immunity Against WNV Encephalitis

Faculty Mentor

Douglas M. Durrant, PhD

Start Date

23-11-2019 10:45 AM

End Date

23-11-2019 11:30 AM

Location

62

Session

poster 4

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

West Nile Virus (WNV), a neurotropic flavivirus, is the leading cause of mosquito-borne neuroinvasive disease in the United States. After peripheral infection, WNV is able to enter the central nervous system (CNS) and infect neurons causing neuronal injury and inflammation that may result in long-term sequalae and death. In order to restrict viral replication and pathogenesis within the CNS during WNV encephalitis, infiltrating virus-specific CD8+ T cells are critically dependent on dendritic cell (DC) mediated reactivation at this site. However, while previous reports have shown that DCs rapidly accumulate within the CNS during neuroinflammation, the subset necessary to induce T-cell mediated protection against a neurotropic virus has not been clarified. Previously, we detected the presence of DEC-205+ DCs within the perivascular spaces of the CNS during WNV encephalitis. DEC-205 is an endocytic receptor expressed on a subset of DCs that effectively promote cross-presentation and induction of anti-viral immunity. However, the specific role of DEC-205+ DCs in establishing immunity against WNV encephalitis has not been shown. We hypothesize that DEC-205+ DCs restrict WNV pathogenesis via the activation of anti-viral T cell immunity. Using a well-established mouse model of WNV encephalitis, we show that DEC-205-/- mice demonstrated increased symptomatic disease and mortality compared to wild-type (WT) controls. The enhanced susceptibility of the DEC-205-/- mice arose from increased viral burden and neuronal death, however, this was associated with increased neuronal chemokine expression and increased numbers of infiltrating T cells and inflammatory myeloid cells. These results suggest that DEC-205+ DCs promote protective immune responses to CNS viral infection that limits immunopathology. To begin to decipher the mechanisms by which these cells provide protection, we plan to investigate the number and activation status of the WNV-specific lymphocytes as well as their ability to penetrate the parenchyma of the WNV-infected CNS through invitro and exvivo techniques. In addition, we hope to perform an adoptive transfer of DEC-205+ DCs to determine whether these cells are capable of restoring T cell functions and/or parenchymal penetration. These findings will uncover the mechanism by which specific subsets of DCs critically modulate protective immune responses within the CNS in order to restrict a neurotropic viral infection which is critical for the development of targeted treatments, none of which currently exist

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Nov 23rd, 10:45 AM Nov 23rd, 11:30 AM

DEC-205+ DCs Within the CNS Critically Modulate CD8+ T Cell-Mediated Immunity Against WNV Encephalitis

62

West Nile Virus (WNV), a neurotropic flavivirus, is the leading cause of mosquito-borne neuroinvasive disease in the United States. After peripheral infection, WNV is able to enter the central nervous system (CNS) and infect neurons causing neuronal injury and inflammation that may result in long-term sequalae and death. In order to restrict viral replication and pathogenesis within the CNS during WNV encephalitis, infiltrating virus-specific CD8+ T cells are critically dependent on dendritic cell (DC) mediated reactivation at this site. However, while previous reports have shown that DCs rapidly accumulate within the CNS during neuroinflammation, the subset necessary to induce T-cell mediated protection against a neurotropic virus has not been clarified. Previously, we detected the presence of DEC-205+ DCs within the perivascular spaces of the CNS during WNV encephalitis. DEC-205 is an endocytic receptor expressed on a subset of DCs that effectively promote cross-presentation and induction of anti-viral immunity. However, the specific role of DEC-205+ DCs in establishing immunity against WNV encephalitis has not been shown. We hypothesize that DEC-205+ DCs restrict WNV pathogenesis via the activation of anti-viral T cell immunity. Using a well-established mouse model of WNV encephalitis, we show that DEC-205-/- mice demonstrated increased symptomatic disease and mortality compared to wild-type (WT) controls. The enhanced susceptibility of the DEC-205-/- mice arose from increased viral burden and neuronal death, however, this was associated with increased neuronal chemokine expression and increased numbers of infiltrating T cells and inflammatory myeloid cells. These results suggest that DEC-205+ DCs promote protective immune responses to CNS viral infection that limits immunopathology. To begin to decipher the mechanisms by which these cells provide protection, we plan to investigate the number and activation status of the WNV-specific lymphocytes as well as their ability to penetrate the parenchyma of the WNV-infected CNS through invitro and exvivo techniques. In addition, we hope to perform an adoptive transfer of DEC-205+ DCs to determine whether these cells are capable of restoring T cell functions and/or parenchymal penetration. These findings will uncover the mechanism by which specific subsets of DCs critically modulate protective immune responses within the CNS in order to restrict a neurotropic viral infection which is critical for the development of targeted treatments, none of which currently exist