2022-01-312022-01-312021https://repository.tcu.edu/handle/116099117/49944Ocular 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 eye than did WT mice. Adoptive transfer of M1 macrophages from WT mice to M1(-/-) mice reduced death and rescued virus replication in the eye 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.enhttps://creativecommons.org/licenses/by/4.0/Herpes-Simplex-VirusCentral-Nervous-SystemLatency-Associated TranscriptGreen Fluorescent ProteinAlternative ActivationStromal KeratitisGranzyme-BT-CellsDendritic CellsPeritoneal-MacrophagesArticleCC BY 4.0https://doi.org/10.1371/journal.ppat.1009999