Abstract
Ocular HSV-1 infection is a major cause of eye disease and innate and adaptive immunity both play a role in protection and pathology associated with ocular infection. Previously we have shown that M1-type macrophages are the major and earliest infiltrates into the cornea of infected mice. We also showed that HSV-1 infectivity in the presence and absence of M2-macrophages was similar to wild-type (WT) control mice. However, it is not clear whether the absence of M1 macrophages plays a role in protection and disease in HSV-1 infected mice. To explore the role of M1 macrophages in HSV-1 infection, we used mice lacking M1 activation (M1-/- mice). Our results showed that macrophages from M1-/- mice were more susceptible to HSV-1 infection in vitro than were macrophages from WT mice. M1-/- mice were highly susceptible to ocular infection with virulent HSV-1 strain McKrae, while WT mice were refractory to infection. In addition, M1-/- mice had higher virus titers in the eyes than did WT mice. Adoptive transfer of M1 macrophages from WT mice to M1-/- mice reduced death and rescued virus replication in the eyes of infected mice. Infection of M1-/- mice with avirulent HSV-1 strain KOS also increased ocular virus replication and eye disease but did not affect latency-reactivation seen in WT control mice. Severity of virus replication and eye disease correlated with significantly higher inflammatory responses leading to a cytokine storm in the eyes of M1-/- infected mice that was not seen in WT mice. Thus, for the first time, our study illustrates the importance of M1 macrophages specifically in primary HSV-1 infection, eye disease, and survival but not in latency-reactivation.
Highlights
Herpes simplex virus type 1 (HSV-1) infection impacts global populations with mild to severe health complications
Macrophages circulating in the blood or present in different tissues constitute an important barrier against infection
We previously showed that the absence of M2 macrophages does not impact HSV-1 infectivity in vivo
Summary
HSV-1 infection impacts global populations with mild to severe health complications. The virus establishes lifelong latent infections in neurons, but reactivation can be triggered in response to a variety of stimuli [1,2]. The HSV-1 life cycle involves an initial pre-clinical innate immune response phase that controls the severity of infection and is characterized by neutrophils, macrophages, NK cells, dendritic cells, NKT cells, and their functions [3]. The role of the adaptive immune response in protecting against ocular HSV-1 infection and disease had been extensively studied [4], but little is known about the role of the early host innate immune response in controlling the severity of infection and disease. We previously investigated the time at which various immune cells infiltrated the cornea of infected mice and found that macrophages with M1 phenotype were the dominant corneal infiltrates as early as 1 hour post ocular infection [5]. A proper equilibrium between the M1 and M2 macrophage subtypes must be maintained to avoid detrimental host states leading to various diseases and inflammatory conditions [11]
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