Research Article: Inflammasome-Independent NLRP3 Restriction of a Protective Early Neutrophil Response to Pulmonary Tularemia

Date Published: December 7, 2016

Publisher: Public Library of Science

Author(s): Sivakumar Periasamy, Hongnga T. Le, Ellen B. Duffy, Heather Chin, Jonathan A. Harton, David Weiss.

http://doi.org/10.1371/journal.ppat.1006059

Abstract

Francisella tularensis (Ft) causes a frequently fatal, acute necrotic pneumonia in humans and animals. Following lethal Ft infection in mice, infiltration of the lungs by predominantly immature myeloid cells and subsequent myeloid cell death drive pathogenesis and host mortality. However, following sub-lethal Ft challenge, more mature myeloid cells are elicited and are protective. In addition, inflammasome-dependent IL-1β and IL-18 are important for protection. As Nlrp3 appears dispensable for resistance to infection with Francisella novicida, we considered its role during infection with the virulent Type A strain SchuS4 and the attenuated Type B live vaccine strain LVS. Here we show that both in vitro macrophage and in vivo IL-1β and IL-18 responses to Ft LVS and SchuS4 involve both the Aim2 and Nlrp3 inflammasomes. However, following lethal infection with Francisella, IL-1r-, Caspase-1/11-, Asc- and Aim2-deficient mice exhibited increased susceptibility as expected, while Nlrp3-deficient mice were more resistant. Despite reduced levels of IL-1β and IL-18, in the absence of Nlrp3, Ft infected mice have dramatically reduced lung pathology, diminished recruitment and death of immature myeloid cells, and reduced bacterial burden in comparison to wildtype and inflammasome-deficient mice. Further, increased numbers of mature neutrophil appear in the lung early during lethal Ft infection in Nlrp3-deficient mice. Finally, Ft infection induces myeloid and lung stromal cell death that in part requires Nlrp3, is necrotic/necroptotic in nature, and drives host mortality. Thus, Nlrp3 mediates an inflammasome-independent process that restricts the appearance of protective mature neutrophils and promotes lethal necrotic lung pathology.

Partial Text

Pulmonary tularemia is an acute, necrotizing, and highly lethal pneumonia caused by the highly pathogenic zoonotic bacterium Francisella tularensis (Ft) [1]. The Type A (F. tularensis tularensis) and Type B (F. tularensis holarctica) strains cause disease in both animals and humans [2]. Type A strains (e.g. SchuS4) are highly pathogenic to humans and animals and inhalation of as few as 10 cfu of SchuS4 causes lethal disease in humans and mice [1]. Thus, Type A strains are classified as category ‘A’ biothreat agents by the CDC [3]). Although used to model pulmonary tularemia in mice, the attenuated Type B live vaccine strain (Ft LVS) is not pathogenic to humans. Another strain, Francisella novicida (Fn) is closely related to Ft and highly pathogenic in rodents, but nonpathogenic in humans [3].

Pulmonary tularemia is a frequently fatal, acute necrotic pneumonia in humans and animals caused by various sub-species of the environmental bacterium Francisella tularensis (Ft). Most human cases of pulmonary tularemia result from infection with F. tularensis holarctica (the parent strain of the live vaccine strain; LVS) or F. tularensis tularensis (e.g. SchuS4), while and Francisella novicida (Fn) cause disease in rodents. As a vaccine strain, Ft LVS is non-pathogenic to humans and Fn rarely causes human disease [1–3]. Despite intensive research efforts, the mechanism by which Ft elicits fatal disease is poorly understood. Many studies have reported that the Asc/Caspase-1 axis and, in particular, the Aim2, inflammasome which generates IL-1β and IL-18 is critical for resistance to Fn [14–19]. Owing to the emphasis on IL-1β and the still unexplained inability of Fn to elicit an Nlrp3 inflammasome response in mouse macrophages, the role of Nlrp3 during Ft infection has not been explored further. In addition, with the exception of a few studies [13, 28], the roles played by Nlrp3, Aim2 or other inflammasomes during infection with Ft LVS and SchuS4 have not been investigated.

 

Source:

http://doi.org/10.1371/journal.ppat.1006059

 

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