This web page was produced as an assignment for an undergraduate course at Davidson College.
Innate Immune Response to Chicken Pox (Varicella)
The first response to VZV is non-specific. Natural killer cells and Interferons restrict viral replication and spread. IL-2 seems to enhance this innate response. IFN-gamma also inhibits viral replication and can be detected in the serum of infected healthy subjects. Low levels of IFN-gamma correlated with more severe disease.
The pathogenesis of VZV infection during the incubation period is modulated by potent innate immune responses, especially IFN-, mounted by epidermal cells within their differentiated tissue microenvironment in vivo. These observations suggest that viral replication in reticuloendothelial organs, although not excluded, is not necessary to account for the 10–21-day incubation period of varicella. Whereas VZV spreads rapidly from cell to cell and causes cytolysis within 24–48 hours in vitro, our experiments suggest that innate epidermal immune mechanisms may prevent an incapacitating infection of the host that would otherwise limit opportunities for VZV transmission to other susceptible individuals.
The host T cell response is a key component in the hostís recovery from varicella. Although VZV escapes the immune system during the incubation period, however, by 24-72 hours after the appearance of skin lesions, VZV specific T cells can be detected. This indicates that viral replication may be necessary for antigen presentation. The CD4+ T cells are predominantly of the TH1 type and produce IL-2 and IFN-gamma. They recognize VZV glycoproteins gC, gE, gH, and gI as well as IE 62 tegument protein. Because the glycoproteins are expressed on the surfaces on infected cells, they are likely targets of the initial host response. Both CD4+ and CD8+ CTL effector cells are formed to kill infected cells presenting VZV proteins on MHC I or II molecules.
Once infected with VZV, the individual mounts a full immune response and eventually clears the virus. Part of the immune response is the generation of memory B and T cells. Upon re-exposure to VZV, the immune system is primed with cells proven effective against VZV. The secondary immune response is faster and more effective and eliminates the virus before symptoms of VZV occur.
The increased susceptibility of memory T cells to VZV infection may further enhance their role in VZV pathogenesis. During VZV skin infection, viral gene products down-regulated interferon- to permit focal replication, whereas adjacent epidermal cells mounted a potent interferon- response against cell–cell spread. Interleukin-1, although activated in VZV-infected cells, did not trigger expression of endothelial adhesion molecules, thereby avoiding early recruitment of inflammatory cells. The prolonged varicella incubation period appears to represent the time required for VZV to overcome antiviral responses of epidermal cells and generate vesicles at the skin surface. Modulation of VZV replication by cutaneous innate immunity may avoid an incapacitating infection of the host that would limit opportunities for VZV transmission.
IL-1 expression was analyzed in cells expressing VZV proteins as shown within the area outlined in the left panel and in neighboring uninfected epidermal cells in the same section. IL-1 was activated and translocated to the nuclei of VZV infected cells (middle) but showed a diffuse cytoplasmic stain in neighboring uninfected cells (right). http://www.jem.org/content/vol200/issue7/images/large/20040634f2.jpeg
In order for VZV to spread itself throughout the body in the primary viremia, the virus must evade recognition by the immune system during the 10-21 day incubation period. VZV does this by inhibiting increased expression of MHC I molecules on the surfaces of infected cells. The assembled MHC I molecules are not able to leave the Golgi compartment for presentation on the cell surface. VZV also has the ability to evade recognition by the CD4+ CTLs, which recognize peptides presented by MHC II molecules. During a varicella infection, CD4+ T cells release IFN-gamma to stimulate CD8+ CTLs as well as to upregulate the expression of MHC II on cells that do not usually express this molecule. The increase of MHC II in skin cells due to IFN-gamma allows CD4+ CTLs to lyse infected cells of the skin lesions. VZV infected cells do not show this increase of MHC II even in the presence of IFN-gamma. The exact viral genes encoding both of these processes are not yet known.