During a natural virus infection small doses of infectious virus are deposited at a peripheral infection site and then a """"""""race"""""""" ensues, in which the replicating virus attempts to """"""""outpace"""""""" the host's immune system. In the early phases of infection, the innate immune system must contain the infection prior to the development of an adaptive response. In Project 1 we will examine the mechanisms that are used by the innate immune system to contain infection with mousepox, a lethal mouse disease caused by ectromelia virus (ECTV), an exclusive mouse pathogen. This system is unique because it allows us to examine the innate response in susceptible and resistant mouse strains. The three Specific Aims will examine the cells that are required to slow the systemic spread of ECTV at the site of infection, the chemoattractants that mediate their migration to the site of infection and the cell biological mechanisms that are used by both the virus and the immune system during virus-cell interaction.
In Aim 1 we will characterize the cellular infiltrate to the site of ECTV infection in resistant or susceptible mice and identify the innate immune effector cell types that are required to slow the systemic spread of ECTV and allow the development of an adaptive response that can clear the infection. In this aim we will also examine the effector functions that are required by innate immune cells to retard ECTV infection.
In Aim 2 we will determine the chemokines and chemokine receptors expressed at the site of ECTV infection in resistant or susceptible mice, and the chemokines that are essential to attract innate effector cells that slow replication and spread of the virus. We will also study the role of immune modifiers of cellular migration encoded by ECTV in the innate response to the virus, and will identify the targets of these genes in vivo.
In Aim 3 we will study the interaction of ECTV and innate immune cells in vitro, focusing primarily upon macropinocytosis, which has recently been described as the mode of infection of orthopoxviruses. Macropinocytosis has an important role in the sampling of extracellular solute for initiation of an adaptive immune response and we will examine its contribution to sampling of the environment for initiation of an innate response. We will also examine the trafficking to macropinosomes of TLR9;,an innate receptor that is required for survival from ECTV challenge. The results from this Project will provide a comprehensive picture of the innate response to a peripheral virus infection.
The insight we gain into the mechanisms that prevent a peripheral virus infection from spreading systemically will aid understanding of the mechanisms deployed against many viruses of importance to human and animal health such as Enterovirus (poljo, cocksackie), Rubivirus (rubella), Flavivirus (Yellow Fever, Dengue, West Nile), Rubulavirus (mumps)* Morbillivirus (measles), Varicelovirus (chickenpox).
|Norbury, Christopher C (2016) Defining cross presentation for a wider audience. Curr Opin Immunol 40:110-6|
|Sei, Janet J; Haskett, Scott; Kaminsky, Lauren W et al. (2015) Peptide-MHC-I from Endogenous Antigen Outnumber Those from Exogenous Antigen, Irrespective of APC Phenotype or Activation. PLoS Pathog 11:e1004941|
|Xu, Ren-Huan; Wong, Eric B; Rubio, Daniel et al. (2015) Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection. Immunity 43:1148-59|
|Fang, Min; Remakus, Sanda; Roscoe, Felicia et al. (2015) CD4+ T cell help is dispensable for protective CD8+ T cell memory against mousepox virus following vaccinia virus immunization. J Virol 89:776-83|
|Kaminsky, Lauren W; Sei, Janet J; Parekh, Nikhil J et al. (2015) Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection. J Virol 89:9974-85|
|Davies, Michael L; Sei, Janet J; Siciliano, Nicholas A et al. (2014) MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2. J Virol 88:3557-67|
|Heipertz, Erica L; Davies, Michael L; Lin, Eugene et al. (2014) Prolonged antigen presentation following an acute virus infection requires direct and then cross-presentation. J Immunol 193:4169-77|
|Hersperger, Adam R; Siciliano, Nicholas A; DeHaven, Brian C et al. (2014) Epithelial immunization induces polyfunctional CD8+ T cells and optimal mousepox protection. J Virol 88:9472-5|
|Ma, Xueying; Xu, Ren-Huan; Roscoe, Felicia et al. (2013) The mature virion of ectromelia virus, a pathogenic poxvirus, is capable of intrahepatic spread and can serve as a target for delayed therapy. J Virol 87:7046-53|
|Remakus, Sanda; Rubio, Daniel; Lev, Avital et al. (2013) Memory CD8âº T cells can outsource IFN-Î³ production but not cytolytic killing for antiviral protection. Cell Host Microbe 13:546-57|
Showing the most recent 10 out of 20 publications