Efecto de la proteína presentadora de antígenos Tap en la infección IN VIVO del virus Herpes Simplex tipo 1 y generación de modelos transgénicos para su estudio

Abstract

The vast majority of Alzheimer’s disease (AD) cases have a complex etiology, with multiple genetic and environmental factors influencing its pathogenesis. Recently, herpes simplex virus type 1 (HSV-1) has been related with this dementia in conjunction with several host factors as the allele ε4 of the apolipoprotein E. HSV-1 may reach the central nervous system (CNS) via either the neural or the hematogenous route. Although the main route for HSV-1 infection in humans is certainly neural, hematogenous infection could be important in some contexts, especially when immune system is affected. In fact, if HSV-1 plays a true role in this dementia, the mechanisms of the immune system should be also compromised. HSV-1 expresses an immediate-early protein (ICP47) that blocks the major histocompatibility complex class I presentation pathway, by binding to the transporter associated with antigen presentation (TAP). Human TAP forms a heterodimer consisting of TAP1 and TAP2 subunits, where the TAP2B variant (but not TAP2A), has been associated to AD. In the present work, several infection parameters were analysed in order to characterise the HSV-1 challenge to the CNS. In this sense, the neural and hematogenous routes of infection were studied. For the neural route, intranasal and snout abrasion inoculations were employed; for the hematogenous route, intraperitoneal and intravenous vias were used. Additionally, the virulence and invasiveness of two viral strains (KOS and F) were analysed. Then, the influence of the ICP47 viral protein in the infection (in conjunction with murine TAP protein) was studied. Finally, three transgenic mouse lines with the main human TAP variants were generated: TAP1A, TAP2A and TAP2B. Furthermore, the analysis of the transgenic mice has proven that the pattern of expression of the transgenes in the nervous system. The results here obtained indicates that: (i) hematogenous route is more efficient than neural route for the HSV-1 infection; (ii) hematogenous and neural routes describe two different pathways to colonise the brain by the HSV-1; (iii) ICP47 viral protein influences general invasiveness; (iv) murine TAP is irrelevant for the viral infection; (v) the neuroinvasiveness of the ICP47 defective virus is recovered in TAP deficient mice; (vi) three transgenic mouse lines containing the main human TAP variants (TAP1A, TAP2A and TAP2B) were constructed. Here, the HSV-1 infection to the CNS has been characterised, and several host and viral factors influencing the brain infection were analysed, especially the ICP47 and the TAP protein. Moreover, three transgenic mouse lines containing the several human variants of TAP have been generated. These animals could be used as tools for the investigation of several human diseases, where the involvement of HSV-1 in the Alzheimer disease will be a priority