Editorial: Yersinia pestis survives in neutrophils and sends a PS to macrophages: bon appetit!

The Gram-negative bacteria Yersinia pestis is the causative agent of plague, a fatal disease that has killed millions of people in three major pandemics. During the third pandemic, Y. pestis spread worldwide and became established as an important zoonosis in new locations, including North America [1]. The most common type of plague in humans is the bubonic form, in which bacteria are transmitted through bites of pathogen-infected fleas. The bacteria also can be transmitted from human to human by inhalation of respiratory droplets, causing pneumonic plague [1]. Pathogenesis of Y. pestis has a characteristic biphasic pattern that has been best characterized in the murine pneumonic model of plague. At the initial stages of infection, bacteria replicate at the site of infection with little inflammation. By 48 h postinfection, however, the host innate-immune response results in a highly inflammatory state associated with cytokine production and tissue damage [2]. Y. pestis produces an array of virulence factors to counteract the host immune response. For example, a 70-kb virulence plasmid (pCD1) encodes a type III secretion system and its effector proteins (termed Yops) that can inhibit phagocytosis and suppress proinflammatory cytokine production [3]. Y. pestis also produces a capsule composed of a F1 protein that helps to inhibit phagocytosis [1]. Likely as a result of these factors, bacteria are more often found extracellularly within the tissues of an infected host at the later, highly inflammatory stages of infection. However, these virulence factors are maximally expressed only after cultivation at 37°C and not at an ambient temperature (e.g., 26°C) [1]. Therefore, the challenge for Y. pestis is to survive and suppress the host immune response during the initial phase of the infection when the bacteria have not been acclimated to the mammalian host temperature of 37°C. Y. pestis is considered to be a facultative intracellular bacterium, as various in vitro studies have demonstrated that Y. pestis can survive and replicate within macrophage phagosomes [2]. Detection of Y. pestis in the in vivo host environment at the early stages of infection has proven to be technically challenging. Nevertheless, several in vivo studies have observed Y. pestis inside macrophages and polymorphonuclear leukocytes (or neutrophils) [2]. Most recently, Shannon et al. [4] revealed that neutrophils are recruited to the site of infection soon after the initial intradermal inoculation of mice and that Y. pestis mainly associates with neutrophils, as well as macrophages. In a murine intranasal infection model, the Y. pestis type III secretion system was found to target alveolar macrophages and neutrophils for Yop injection, suggesting close association of Y. pestis and these host immune cells [5]. These observations have led to the hypothesis that Y. pestis escapes the initial encounter with the components of innate-immune response by surviving within host macrophages, before the bacteria replicate more robustly in the extracellular environment [2]. Although past in vivo studies have consistently indicated that neutrophils are recruited to the initial site of infection and that Y. pestis associates with neutrophils and macrophages, the current model [2] has focused on macrophages as a permissive site for bacterial replication during the early stages of infection. This is because previous in vitro studies have suggested that the majority of Y. pestis bacteria engulfed by neutrophils is killed, whereas Y. pestis can survive and replicate within macrophage phagosomes [2, 6]. However, most of the previous studies examined the survival of Y. pestis inside neutrophils only for a short period of time (up to 6 h) postinfection. Therefore, it has remained unclear whether any of the bacteria ingested by neutrophils can survive and replicate intracellularly for the long term. In the study published in the current Journal of Leukocyte Biology, Spinner et al. [7] show that a small portion of Y. pestis engulfed by human neutrophils survives and replicates, raising the possibility that neutrophils could be used as a temporary niche or transport vehicle for Y. pestis.