Critical Role of MicroRNA-155 in Herpes Simplex Encephalitis

Abstract

Herpes simplex virus (HSV) infection of adult humans occasionally results in life-threatening herpes simplex encephalitis (HSE) for reasons that remain to be defined. An animal system that could prove useful to model HSE could be miR-155 knockout mice (miR-155KO). Thus we observe that mice with a deficiency of miR-155 are highly susceptible to HSE with a majority of animals (75–80%) developing HSE after ocular infection with HSV-1. The lesions appeared to primarily represent the destructive consequences of viral replication and animals could be protected from HSE by acyclovir treatment provided 4 days after ocular infection. The miR-155KO animals were also more susceptible to develop zosteriform lesions, a reflection of viral replication and dissemination within the nervous system. One explanation for the heightened susceptibility to HSE and zosteriform lesions could be because miR-155KO animals develop diminished CD8 T cell responses when the numbers, functionality and homing capacity of effector CD8 T cell responses were compared. Indeed, adoptive transfer of HSV-immune CD8 T cells to infected miR-155KO mice at 24 hours post infection provided protection from HSE. Deficiencies in CD8 T cell numbers and function also explained the observation that miR-155KO animals were less able than control animals to maintain HSV latency. Our observations may be the first to link miR-155 expression with increased susceptibility of the nervous system to virus infection.

microRNAs function in CD8+T cell biology

“…However, it has been shown in CD8 + T cells from patients with chronic hepatitis B that it specifically regulates effector functions by targeting STAT1 [84]. In contrast, miR-155 substantially enhances effector functions through repression of Ship1, a potent, negative regulator of expression of T-bet and its transcriptional target, IFN-g [85][86][87]. As a result, miR-146a-deficient mice restrict tumor growth, whereas miR-155-deficient mice permit enhanced tumor activity.…”

“…Dysregulation of these proteins has been linked to CD8 + T cell-related immunologic diseases, in which the miRNAs are found to be mutated, or their expression levels are dysregulated. Recent work in animals lacking or overexpressing individual miRNAs has allowed investigators to explore the role of miRNAs, including miR-155 [38-40, 42, 73, 85, 87, 88], miR-17 ;92 [37,49], miR-150 [28,67], miR-21 [28], miR-146a [87], miR-29 [83], miR-15b [72], miR-139/342 [67], and miR-US4-1 [85] in these diseases. Unsurprisingly, severe physiologic consequences, such as viral or malignant attacks, were observed frequently in such experimental models, accompanied by damaged development and function of the CD8 + T cells.…”

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

“…Many host cell factors have been reported to regulate HSV-1 replication and/or pathogenicity in the CNS, as determined using experiments performed in genetically modified mice (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Notably, most of the host cell factors identified were regulators of innate and/or acquired immunity (33)(34)(35)(36)(37)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”

Induction of Multiple miR-200/182 Members in the Brains of Mice Are Associated with Acute Herpes Simplex Virus 1 Encephalitis

“…MiRNAs can also have an indirect effect on HSV-1 pathogenicity. MiR-155 deficient mice are highly susceptible to HSV-1 replication, resulting in enhanced mortality [30]. These data highlight the critical roles miRNAs play during viral pathogenicity.…”