Increased phagocytosis in the presence of enhanced M2-like macrophage responses correlates with increased primary and latent HSV-1 infection
Authors: Jaggi, Ujjaldeep; Yang, Mingjie; Matundan, Harry H.; Hirose, Satoshi; Shah, Prediman K.; Sharifi, Behrooz G.; Ghiasi, Homayon
After HSV-1 infection, macrophages infiltrate early into the cornea, where they play an important role in HSV-1 infection. Macrophages are divided into M1 or M2 groups based on their activation. M1 macrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory. Macrophage phenotypes can shift between M1 or M2in vitroandin vivofollowing treatment with specific cytokines. In this study we looked at the effect of M2 macrophages on HSV-1 infectivity using mice either lacking M2 (M2(-/-)) or overexpressing M2 (M2-OE) macrophages. While presence or absence of M2 macrophages had no effect on eye disease, we found that over expression of M2 macrophages was associated with increased phagocytosis, increased primary virus replication, increased latency, and increased expression of pro- and anti-inflammatory cytokines. In contrast, in mice lacking M2 macrophages following infection phagocytosis, replication, latency, and cytokine expression were similar to wild type mice. Our results suggest that enhanced M2 responses lead to higher phagocytosis, which affected both primary and latent infection but not reactivation.
Termination of Transcription of LAT Increases the Amounts of ICP0 mRNA but Does Not Alter the Course of HSV-1 Infection in Latently Infected Murine Ganglia
Authors: Jiang, Haifang; Wu, Jiaming; Liu, Xianjie; Lu, Ruitao; Zhou, Manling; Chen, Meiling; Liu, Yonghong; Zhou, Grace Guoying; Fu, Wenmin
On entering sensory ganglia, herpes simplex viruses 1 (HSV-1) establishes a latent infection with the synthesis of a latency associated transcript (LAT) or initiates productive infection with expression of a set of immediate early viral proteins. The precise mechanisms how expression of alpha genes is suppressed during the latency are unknown. One mechanism that has been proposed is illustrated in the case of ICP0, a key immediate early viral regulatory protein. Specifically, the 2 kb LAT intron is complementary to the 3 ' terminal portion of ICP0 mRNA. To test the hypothesis that accumulation of LAT negatively affects the accumulation of ICP0 mRNA, we inserted a DNA fragment encoding two poly(A) sequences into LAT to early terminate LAT transcript without interrupting the complementary sequence of ICP0 transcript (named as SR1603). Comparisons of the parent (SR1601) and mutant (SR1603) HSV-1 viruses showed the following: Neurons harboring latent SR1603 virus accumulated equivalent amounts of viral DNA but higher amounts of ICP0 mRNA and lower amounts of LAT, when compared to neurons harboring the SR1601 virus. One notable difference between the two viruses is that viral RNA accumulation in explanted ganglia harboring SR1603 virus initiated significantly sooner than that in neurons harboring SR1601 virus, suggesting that ICP0 may act as an activator of viral gene expression in permissive cells. Collectively, these data suggest that increased ICP0 mRNA by suppressed LAT did not affect the establishment of latency in latently infected murine ganglia.