All humans become infected with multiple herpesviruses during childhood. After clearance of acute infection, herpesviruses enter a dormant state known as latency. Latency persists for the life of the host and is presumed to be parasitic, as it leaves the individual at risk for subsequent viral reactivation and disease. Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host.

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Although pneumonic plague is the deadliest manifestation of disease caused by the bacterium Yersinia pestis, there is surprisingly little information on the cellular and molecular mechanisms responsible for Y. pestis-triggered pathology in the lung. Therefore, to understand the progression of this unique disease, we characterized an intranasal mouse model of primary pneumonic plague. Mice succumbed to a purulent multifocal severe exudative bronchopneumonia that closely resembles the disease observed in humans. Analyses revealed a strikingly biphasic syndrome, in which the infection begins with an antiinflammatory state in the first 24 -36 h that rapidly progresses to a highly proinflammatory state by 48 h and death by 3 days. To assess the adaptation of Y. pestis to a mammalian environment, we used DNA microarray technology to analyze the transcriptional responses of the bacteria during interaction with the mouse lung. Included among the genes up-regulated in vivo are those comprising the yop-ysc type III secretion system and genes contained within the chromosomal pigmentation locus, validating the use of this technology to identify loci essential to the virulence of Y. pestis.inflammation ͉ microarray ͉ Yersinia pestis P neumonic plague is the deadliest manifestation of disease caused by the bacterium Yersinia pestis. Although rare compared with the bubonic form of plague, which is acquired by skin penetration, primary pneumonic plague is highly contagious and almost always fatal. The current worldwide incidence of plague is low by historical standards, but the possible combination of widespread aerosol dissemination and rapid disease progression are of particular concern for defense against bioterrorism (1).In cases of primary pneumonic plague in humans, microscopic examination of lung tissue reveals multiple histological patterns, including acute pneumonia, intraalveolar hemorrhage and edema, and the presence of extracellular bacteria in the alveoli but not the interstitium (2). In addition, extensive neutrophilic infiltrate and fibrin deposition have been observed, and in some cases a complete loss of recognizable alveolar architecture results from the infection (3, 4). Studies of experimental primary pneumonic plague in monkeys, mice, and guinea pigs showed similar pathologic effects, including extensive intraalveolar edema, massive bacterial proliferation in the small airways, and numerous neutrophils in the alveoli (5-8).How Y. pestis triggers pulmonary pathology is largely unexplored, as are the bacterial responses to this dramatically changing host environment. DNA microarray technology has been widely used to assess transcriptional changes in bacterial gene expression in vitro, but analyses of the bacterial transcriptome during host infection have been hampered by two significant problems (9). These include the excess amounts of copurified eukaryotic RNA that may produce nonspecific hybridization signals on the microarray, and the oftenlimiting amounts of bacterial RNA extracted from an animal, which w...

Primary pneumonic plague is transmitted easily, progresses rapidly, and causes high mortality, but the mechanisms by which Yersinia pestis overwhelms the lungs are largely unknown. We show that the plasminogen activator Pla is essential for Y. pestis to cause primary pneumonic plague but is less important for dissemination during pneumonic plague than during bubonic plague. Experiments manipulating its temporal expression showed that Pla allows Y. pestis to replicate rapidly in the airways, causing a lethal fulminant pneumonia; if unexpressed, inflammation is aborted, and lung repair is activated. Inhibition of Pla expression prolonged the survival of animals with the disease, offering a therapeutic option to extend the period during which antibiotics are effective.

Biogenesis of the f lagellum, a motive organelle of many bacterial species, is best understood for members of the Enterobacteriaceae. The f lagellum is a heterooligomeric structure that protrudes from the surface of the cell. Its assembly initially involves the synthesis of a dedicated protein export apparatus that subsequently transports other f lagellar proteins by a type III mechanism from the cytoplasm to the outer surface of the cell, where oligomerization occurs. In this study, the f lagellum export apparatus was shown to function also as a secretion system for the transport of several extracellular proteins in the pathogenic bacterium Yersinia enterocolitica. One of the proteins exported by the f lagellar secretion system was the virulence-associated phospholipase, YplA. These results suggest type III protein secretion by the f lagellar system may be a general mechanism for the transport of proteins that inf luence bacterial-host interactions.