Granuloma Formation and Host Defense in Chronic Mycobacterium tuberculosis Infection Requires PYCARD/ASC but Not NLRP3 or Caspase-1

Erin Mcelvania Tekippe,Paul D Hulseberg,Matyas Sandor,Irving C Allen,Jenny P.-Y Ting,Miriam Braunstein,Jonathan T Sullivan,Jessica R Mccann

doi:10.1371/journal.pone.0012320

Abstract

The NLR gene family mediates host immunity to various acute pathogenic stimuli, but its role in chronic infection is not known. This paper addressed the role of NLRP3 (NALP3), its adaptor protein PYCARD (ASC), and caspase-1 during infection with Mycobacterium tuberculosis (Mtb). Mtb infection of macrophages in culture induced IL-1β secretion, and this requires the inflammasome components PYCARD, caspase-1, and NLRP3. However, in vivo Mtb aerosol infection of Nlrp3−/−, Casp-1−/−, and WT mice showed no differences in pulmonary IL-1β production, bacterial burden, or long-term survival. In contrast, a significant role was observed for Pycard in host protection during chronic Mtb infection, as shown by an abrupt decrease in survival of Pycard−/− mice. Decreased survival of Pycard−/− animals was associated with defective granuloma formation. These data demonstrate that PYCARD exerts a novel inflammasome-independent role during chronic Mtb infection by containing the bacteria in granulomas.

Highlights

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease affecting one-third of the world’s population and killing 1.7 million people each year [1]
IL-18 secretion from Mtb-infected THP-1 cells was dependent on PYCARD and NLRP3 (Figure 1B)
We focus on the ability of virulent Mtb to stimulate inflammasome activation and the role of the inflammasome in host defense against Mtb

Summary

Introduction

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease affecting one-third of the world’s population and killing 1.7 million people each year [1]. Mtb is spread by aerosol droplets from persons with active infection. Mtb travels to the lung where it infects resident alveolar macrophages [2]. This initial infection leads to an innate immune response, which includes stimulation of Toll-like receptors (TLRs) that recognize pathogens and are located on the plasma membrane and within endosomes of host cells. Mtb is recognized by TLRs 2, 4, and 9 [3]. TLR activation upregulates transcription of proinflammatory cytokines interleukin-1b (IL-1b), tumor necrosis factor alpha (TNFa), and interleukin-6 (IL-6), which are essential for the recruitment of immune cells to the site of infection and controlling Mtb infection [4,5,6]

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Results

Conclusion