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| Immune defense | Role in controlling HSV infection | Immunologic differences in newborns | Comments |
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| Integument | The skin and mucosa provide mechanical and innate antiviral impediments to HSV infection and spread. | Neonates have thin, easily disrupted skin, with differences in pH and sebum production [34]. | Differences in neonatal epithelial anatomy or function have not been formally shown to contribute to susceptibility to HSV infection. Levels of some AMPs appear to be increased during the neonatal period [35–37]. |
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| Autophagy | HSV-mediated suppression of autophagy is central to the pathogenesis of CNS infection [38–40]. | Autophagy is mediated by signaling through TLRs, which have age-dependent responses [41, 42]. | Age-dependent differences in autophagy are plausible but poorly understood. |
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| PRR responses | PRR signaling in HSV-infected cells induces type 1 IFN production that limits initial spread of infection through and attracts and primes protective Th1-type responses [43, 44]. | Neonates have qualitatively different monocyte and DC TLR responses that result in reduced type 1 IFN and IL-12 production, resulting in weaker Th1-type responses [45–48]. | Age-dependent TLR3 responses to HSV are likely important based on the association between CNS HSV infections and defects in TLR signaling. Age-dependent effects of other TLR or PRR responses are unclear but may also be important for the severity of HSV infection in neonates. |
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| NK cells | NK cells are important for control of initial HSV infection prior to development of specific T cell responses [49–51]. | Neonates appear to have impaired NK cell killing of HSV-infected cells [52–54]. | Whether neonatal NK cells have any intrinsic defects or kill less well as a result of impaired activation, for example, decreased IL-12 production by DCs, is unclear [55]. |
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| T cell responses | CD8+ T cell responses appear central to control of HSV replication and prevention of recurrence [56, 57]. | Neonatal T cells respond relatively poorly to HSV [58–60]. | Impaired Th1-type responses against HSV in neonates may be due to differences in innate responses by antigen-presenting cells, intrinsic epigenetic factors (e.g., hypermethylation of the IFN-γ promoter in CD4+ cells), or perhaps active suppression by suppressor cells [2, 61, 62]. |
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| Antibody | HSV neutralizing antibody or ADCC may protect against acquisition of infection [17–21]. | Infants born to women with established HSV infections receive virus-specific transplacental maternal antibody [4]. | Although infants of women with established HSV infection are much less likely to become infected compared to those who acquire primary infection during pregnancy, no definitive proof exists that antibody alone is protective in humans. After infection, antibody responses do not appear to contribute significantly to control of HSV replication. |
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