While investigating the mechanisms of reactivation of murine gammaherpesvirus 68, Barton et al. noted that peritoneal macrophages from latently infected mice were uniformly activated. Macrophage activation was not a consequence of direct infection and was associated with efficient in vitro killing of the intracellular bacterial pathogen Listeria monocytogenes, which is known to be controlled by activated macrophages. This observation led the authors to test whether herpesvirus latency might provide protection from infection with this bacterial pathogen and others. Indeed, mice latently infected with herpesvirus were shown to be highly resistant to infection with L. monocytogenes or Yersinia pestis (the causative agent of bubonic plague), whereas acute herpesvirus infection did not affect susceptibility to these pathogens. Moreover, a mutant herpesvirus that is unable to establish latency failed to protect mice from L. monocytogenes infection and did not stimulate macrophage activation, which confirms the importance of latency in this protection. Similar latency-associated protection against bacterial pathogens was also observed in mice infected with the betaherpesvirus murine cytomegalovirus but not in mice infected with Sindbis virus (which does not establish latent infection).
To explore the mechanism of viral latency-associated protection from bacterial infection, the authors measured cytokine levels in the serum of mice latently infected with herpesviruses. The levels of interferon-γ (IFNγ) and tumour-necrosis factor (TNF), probably produced mainly by the activated macrophages, were found to be significantly increased in latently infected mice compared with acutely infected mice or mice infected with a latency-defective virus. This innate immune activation was sufficient to mediate protection, as in vivo depletion of CD4+ and CD8+ T cells prior to challenge with L. monocytogenes had no effect.
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