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   Immunology and Cell Biology (2015) 93, 839–840; doi:10.1038/icb.2015.73;   
   published online 11 August 2015   
      
   Limiting Herpes Simplex Encephalitis   
      
   Battling the spread: Herpes simplex virus and encephalitis   
      
   Christina M Slifer1 and Stephen R Jennings1   
      
   1Department of Microbiology and Immunology, Drexel University College of   
   Medicine, Philadelphia, PA, USA   
      
   Correspondence: CM Slifer SR Jennings, E-mail: Christina.Slifer@DrexelMed.edu   
   or Stephen.Jennings@DrexelMed.edu   
      
   Herpes simplex virus type 1 (HSV-1) is a ubiquitous human viral pathogen   
   commonly associated with oral vesicular lesions, so called ‘cold sores’.   
   HSV-1 is a highly successful pathogen, as it generally does not impair the   
   health of the infected host.    
   The virus has the ability to enter into the endings of sensory nerves   
   innervating the primary site of infection, and subsequently enters into a   
   non-infectious, latent state within the peripheral nervous system. From this   
   latent state, the virus can    
   periodically reactivate and be shed as infectious virus, even in the absence   
   of a clinical lesion, with the potential to infect other hosts. However, in   
   very rare instances, estimated to be on the order of two to four cases per   
   million per year,1 HSV-1    
   can gain access to the central nervous system, and may enter the frontal   
   cortex, causing a devastating disease known as herpes simplex encephalitis   
   (HSE). In this issue, Kastrukoff et al.2 have used a well-established lip   
   scarification infection model of    
   orofacial HSV-1 infection in mice to understand the underlying immunogenetics   
   of the infected host that help control the spread of HSV-1 in the central   
   nervous system and brain once it has gained access from the peripheral site of   
   infection.   
      
   The group used classic interbreeding between the mouse strains C57BL/6, which   
   is resistant to HSE, and BALB/c, which is susceptible to HSE. Through   
   subsequent backcrossing, they were able to determine that resistance was due   
   to a single locus. Further    
   analysis, using recombinant intragenic mice,3 determined that the locus mapped   
   to the distal arm of chromosome 6, and was found within the region delineated   
   between Cd69 and D6Wum34 of the Natural Killer Complex (NKC). Finally, through   
   in vivo antibody    
   depletion studies, it was found that Natural Killer (NK) cells expressing   
   NK1.1 were the principal effector cell responsible for restricting HSV-1   
   spread from the brainstem into the cerebellum and cerebral hemispheres in   
   resistant mice.   
      
   The newly identified locus, termed Herpes Resistance Locus 2 (hrl2), is likely   
   distinct from previously identified resistance loci, rhs1 and hrl. Using the   
   cutaneous flank abrasion model, Simmons and LaVista4 found that the spread of   
   HSV-1 within the    
   peripheral nervous system was under complex genetic control, possibly   
   involving up to four separate loci, including the class I major    
   istocompatibility complex allele. Using this flank abrasion model, Pereira et   
   al.5 identified a dominant locus, mapping    
   to the NKC, which contributed to the control of acute, primary cutaneous HSV-1   
   infection and designated it as rhs1, for ‘resistance to herpes simplex 1’.   
   In a model of lethal HSE following corneal infection, Lundberg et al.6   
   identified a single locus,   
    designated the ‘herpes resistance locus’ (hrl), which conveyed protection   
   in resistant C57BL/6 mice, although this locus was found to be important only   
   in the absence of a functional tumor necrosis factor receptor. The role of the   
   distinct loci in    
   the resistance to HSE may reflect the route by which the virus gains entry   
   into the peripheral nervous system, and certain loci may be particularly   
   relevant for the entry of HSV-1 into the central nervous system. The nature of   
   the gene product encoded    
   within the hrl2 locus is not known. It is likely expressed by NK1.1   
   (Ly55)-expressing NK cells, as depletion of this population of immune cells   
   ablates the restriction of HSV-1 spread in the brain. Perhaps the gene product   
   is associated with the    
   activation process of NK cells during primary infection, or their mobilization   
   to the site before HSV-1 spread from the brainstem. This is an area for future   
   research.   
      
   The precise series of events that leads to the development of HSE is not   
   known; however, a model is suggested (Figure 1). In the mouse model of   
   orofacial HSV-1 infection used in this study, HSV-1 replicating at the primary   
   site of infection gains access    
   to the local sensory neurons, and is then transported by retrograde transport   
   mechanisms to the trigeminal ganglion (TG), where latent infection is   
   established.7 In susceptible strains of mice, the development of HSE is   
   therefore a consequence of the    
   unrestricted spread of the virus from the TG into the brainstem, and   
   subsequently into the cerebellum and the cerebral hemispheres, where the   
   neuropathological changes associated with the encephalitis are manifested.   
   However, this may not be the only    
   sequence of events involved in HSE development in humans. Human HSE is   
   characterized by lesion formation in the orbitofrontal and temporal lobes.8 It   
   has been argued that this may reflect access of HSV-1 to the brain via the   
   olfactory route, which would    
   then be able to spread directly to the frontal and temporal regions.9 Indeed,   
   HSE may not be related to the initial HSV-1 infection, which has established   
   latency, but instead to a second HSV-1 infection that gains access to the   
   olfactory epithelium    
   through inhalation.8 Intranasal infection of mice with HSV-1 results in   
   neuropathology that is very similar to HSE in humans, as assessed by magnetic   
   resonance imaging.10 In mouse studies comparing intranasal and oral   
   inoculation of HSV-1, Shivkumar et    
   al.11 demonstrated that intranasal infection was 100-fold more effective in   
   delivering HSV-1 to the TG than instillation of HSV-1 into the oral cavity,   
   where it would have access to the oral mucoepithelium. Overall, the   
   development of HSE may result from    
   multiple routes of infection, resulting in different types of neuropathology.   
   It will be interesting to determine whether hrl2, or other identified   
   resistance loci, also contribute to resistance if HSV-1 is introduced via the   
   intranasal route.   
      
   Figure 1.   
   Figure 1 - Unfortunately we are unable to provide accessible alternative text   
   for this. If you require assistance to access this image, please contact   
   help@nature.com or the author   
      
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