Abstract
Complex interactions between HSV-1 and infiltrating immune cells play important roles in establishing localized, acute virus replication as well as chronic latent infection. The extent and duration of initial virus replication are the key determinants of subsequent pathologic inflammatory responses and therefore, the accumulation of immune cell populations at this time point is a key target for prevention. Therefore, we evaluated the role of various immune cell infiltrates between 1 h and 28 days post-infection (PI) using mice infected with virulent HSV-1 strain McKrae without corneal scarification. The effect of corneal scarification on immune cell infiltrates was also determined. We first determined the activation status and origin of macrophage infiltrates as early as 1 h PI. We found a sharp increase in the total macrophage population after 12 h PI, that was primarily due to infiltration of CCR2+ migratory macrophages, mostly in M1 status (MHC II+). The number of CCR2- resident macrophages, mostly unpolarized (M0), increased gradually over time and peaked at 48 h PI. Interestingly, some of the resident macrophages gained an M2-like phenotype (CD206Low), which peaked at 12 h PI, concurrent with M1 macrophage infiltration. From 1–7 days PI, infiltration of various immune cells correlated strongly with HSV-1 replication, with neutrophils showing the biggest increase, and NKT cells the biggest decrease, after infection. The presence of geographical ulcer did not correlate with increased infiltration, while mice with corneal scarring had significantly more immune cell infiltration than those without corneal scarring. Overall, we showed time-dependent infiltration of various immune cells in the eye of HSV-1 infected mice. Initial infiltration of macrophages followed by infiltration of T cells at later times PI demonstrates the importance of targeting macrophages rather than other immune cells type, for therapeutic treatment of HSV-1.
Highlights
It is well known that herpes stromal keratitis (HSK) mediated by herpes simplex virus type 1 (HSV-1) is an immunopathological disease and that immune cells play important roles in clearing the virus from the eye around days 6–7 post-infection (PI) [1]
We previously reported that HSV-1 infected mice, with macrophages altered toward the M2 phenotype by colony stimulating factor-1 (CSF-1) injection, showed less primary and latent infection than mice with macrophages altered toward the M1 phenotype by IFN-γ injection [26]
C57BL/6 mice were infected with 2 X 105 PFU/eye of wild type HSV-1 strain McKrae without corneal scarification and mock-infected mice were used as controls
Summary
It is well known that herpes stromal keratitis (HSK) mediated by herpes simplex virus type 1 (HSV-1) is an immunopathological disease and that immune cells play important roles in clearing the virus from the eye around days 6–7 post-infection (PI) [1]. The extent and duration of immune cell infiltrates in the eye during both primary HSV-1 infection and reactivation can impact the severity of eye disease and the subsequent HSK, is known as corneal scarring (CS) [3,4,5,6,7,8,9,10,11]. After ocular HSV-1 infection, innate immune cells are thought to play an important role in clearing virus from the eye. Recent studies showed that neutrophils, which start their response around 18 h PI, peak at day 2 PI, and eventually decline [12], along with other innate immune cells including NK cells, γ-delta T cells, macrophages, and dendritic cells (DCs), participate in virus clearance [13, 14]
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