Mechanisms facilitating local herpes simplex virus replication and control in the female reproductive tract
Prof. Dr. Lars Dölken
Genital herpes is a common sexually transmitted disease caused by both Herpes simplex virus 1 and 2
(HSV-1 and HSV-2). Upon primary infection, the virus establishes a life-long latent infection within the sacral ganglia, from which it commonly reactivates several times a year. While HSV-2 used to be the dominant causative agent, HSV-1 has now superseded HSV-2 in genital herpes among US residents. Besides a high level of morbidity due to frequent virus reactivations, the infection may result in life-threatening neonatal infection if undetected. Despite intensive efforts, no vaccine is currently available to prevent primary infection or reduce the frequencies and severity of virus reactivations.
Upon virus reactivation in a sacral neuron, anterograde axonal transport, and release, a burst of productive lytic infection is initiated, which is rapidly controlled by both tissue-resident and immigrating immune cells. Little is known about host factors that define local disease severity and immune control. We will employ human 3D models of the female reproductive tract (FRT) and identify local decision points in this heterogeneous environment that govern efficient control of productive virus replication and loss thereof. We will identify molecular decision points that are targeted by virus-induced host shut-off and study the role of virulence factor-triggered immunity in local virus control in urogenital epithelia. We will pioneer a novel transposon library of HSV-1 mutants to screen for viral gene products and sequence elements that govern infection outcome at unprecedented spatial resolution. We will assess the role of type I and III interferons, NF-kB and PKR activation, as well as cell-cell communication in local virus control. Based on differences in the viral gene products identified in different experimental conditions (e.g., +/- IFN-γ or +/- infiltrating immune cell subsets), we will identify key host determinants of local infection control. A long-term goal is to provide a mechanistic understanding of decision points for spatial and time-resolved immune control of genital herpes and the role of viral countermeasures thereof.