**5. Role of miRNAs in the immunological events of HSV infection**

Ocular infection by HSV-1 may lead to chronic inflammation resulting in lesions of stromal keratitis (SK). The immunological events underlying the development of SK involve organized T-helper 1 (Th1) and T-helper-17 (Th17) cells, which produce IFN-γ and IL-17, respectively [43, 44]. Also, the involvement of the regulatory T cells (Treg) guides the exacerbation or abatement of the keratitis [45, 46] miRNAs also regulate the development, activation, function and recruitment of the Th and

#### *Herpesviridae and microRNAs DOI: http://dx.doi.org/10.5772/intechopen.100370*

the Treg cells [47]. A pro-inflammatory miRNA, miR-155 is known to be upregulated during SK and leads to the enhancement of the Th1 and Th17 responses and helps promoting the keratitis. Antagomir nanoparticles containing the anti-miR-155 sequences have been shown to downregulate miR-155 expression and suppress SK [48]. Also, miR-132 was found to be upregulated during SK, which helps in the advancement of angiogenesis via upregulation of the vascular endothelial growth factor (VEGF) by directly targeting a negative regulator of VEGF, a Ras-GTP inhibitor [49]. The Toll-like receptor (TLR) pathway is an integral innate immune response pathway that is altered in almost all infection scenarios. Similarly, the genes associated with the TLR pathway are modulated post-HSV-2 infection by the miRNAs, miR-124, miR-150, miR-342-5p, miR-1245b-5p, miR-1245b-3p, and miR-592 [50]. Speaking of the innate immune responses, type I Interferon (IFN) signal transduction plays a crucial role in curbing viral replication. Thus, for the virus to establish a progressive infection, it must manipulate the host machinery to overcome the IFN combat. So far, in case of HSV-1, miR-221 is manipulated by HSV-1 to suppress the IFN-β production and effector functions [51]. The major innate immune response involved immediately after the HSV infection is the series of events resulting in acute inflammation, which is essential for virus clearance. This also implies that the infiltrates need to be resolved and the cell debris need to be cleared off so as to maintain the immunological homeostasis of the host, preventing a chronic inflammation that could be lethal [52]. Certain pro-resolving mediators (SPMs) function to resolve the acute inflammatory state and may engage a few miRNAs to do so. The binding of Resolvin (RvD1), a SPM, to its receptor upregulates the miRNAs miR-21, miR-146b, miR-219, and downregulates miR-208a [53, 54]. The target mRNA of miR-219 is the transcript of the gene encoding the 5-lipoxygenase enzyme that leads to the decreased production of leukotriene B4 and increased production of the SPMs. miR-146b suppresses the expressions of IL-8 and RANTES, which are the leucocyte-recruiting chemokines at the inflamed regions [54]. miR-146a is also pro-inflammatory in nature and have been shown to trigger the arachidonic acid-mediated, overproduction of IL-1β, to induce an Alzheimer's-like neuropathological condition in the brain. Since it can directly suppress the complement factor H, it is considered as one of the mechanisms of complement evasion by HSV-1 [55]. Another miRNA upregulated as a result of RvD1 binding is miR-21 which contributes to the establishment of an anti-inflammatory milieu by increasing the production of IL-10 when the resolution of inflammation is vital [56, 57]. Contradictorily, miR-208a, which decreases the IL-10 production and enhances the NFκB activation to prolong the inflammatory events, was itself constrained [54]. It has also been noted that miRNAs can function in a cell/tissuespecific manner. miR-4661 is one such miRNA that promotes acute inflammation in the neutrophils, whereas mediates the cessation of the inflammatory responses in the monocytes and the macrophages via the augmented production of SPMs. It also polarizes the macrophages towards the resolution of inflammation [58]. HSV-1 miR-H8 reduces natural killer (NK) cell- dependent killing of the virus-infected cells by the suppression of the glycosylphosphatidylinositol gene expression [59]. HSV-1 viral miR-H28 induces the production of IFN-γ also to restrict the spread of HSV-1 between cells while not affecting the viral replication, so that optimal transmission between individuals take place [60].
