Hypervirulent mutant ofMycobacterium tuberculosisresulting from disruption of themce1operon

Abstract

An estimated one-third of the world's population is latently infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. Here, we demonstrate that, unlike wild-type M. tuberculosis, a strain of M. tuberculosis disrupted in the mce1 operon was unable to enter a stable persistent state of infection in mouse lungs. Instead, the mutant continued to replicate and killed the mice more rapidly than did the wild-type strain. Histological examination of mouse lungs infected with the mutant strain revealed diffusely organized granulomas with aberrant inflammatory cell migration. Murine macrophages infected ex vivo with the mutant strain were reduced in their ability to produce tumor necrosis factor ␣, IL-6, monocyte chemoattractant protein 1, and nitric oxide (NO), but not IL-4. The mce1 mutant strain complemented with the mce1 genes stimulated tumor necrosis factor ␣ and NO production by murine macrophages at levels stimulated by the wild-type strain. These observations indicate that the mce1 operon mutant is unable to stimulate T helper 1-type immunity in mice. The hypervirulence of the mutant strain may have resulted from its inability to stimulate a proinflammatory response that would otherwise induce organized granuloma formation and control the infection without killing the organism. The mce1 operon of M. tuberculosis may be involved in modulating the host inflammatory response in such a way that the bacterium can enter a persistent state without being eliminated or causing disease in the host. Approximately 60% of people who become infected with Mycobacterium tuberculosis develop asymptomatic latent infection (1). This reservoir of latently infected individuals has a 2-23% lifetime risk of developing active disease, referred to as reactivation tuberculosis (1). How M. tuberculosis establishes and maintains latent infection in an animal host is poorly understood. Several candidate M. tuberculosis genes have been recently reported to be important for persistence in the mouse model of tuberculosis. They include the isocitrate lyase gene (icl), mycolic acid cyclopropane synthase gene (pca), and a two-component response regulator called mprA (2)(3)(4). In each case, the disruption of the gene led to attenuation of the mutant strains in the mouse model of infection, whereas their in vitro growth kinetics remained similar to that of the respective wild-type strain (2-4).We reported previously the identification of a M. tuberculosis gene mce1A (Rv0169, Sanger Centre genome sequence designation) that conferred on a nonpathogenic Escherichia coli strain an ability to enter nonphagocytic cells (5). The encoded product facilitated uptake of synthetic microspheres into nonphagocytic cells, and an active domain of the protein was recently shown to cause cytoskeletal rearrangement in HeLa cells that was both microfilament-and microtubule-dependent (6, 7). The gene mce1A is located in a putative operon called mce1 containing 12 genes in the M. tuberculosis H37Rv genome (8) (Fig. 1A). The genome of M. tuberculosi...

A sulfated metabolite produced bystf3negatively regulates the virulence ofMycobacteriumtuberculosis

“…Previous studies have implicated the mce operon (53) and several two-component signaling modules (54) as additional negative regulators of M. tuberculosis virulence. In these studies, however, the pleiotropic nature of the mutants may complicate efforts to define the molecular underpinnings of the phenotype.…”

Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response

“…Both groups suggested that the operon might encode an importer system involved in recycling of MA. Also, disruption of the mce1operon renders the cells hypervirulent in mice 40,41 . The mutant is unable to induce a strong T-helper 1 (Th1) type T cell immune response and organized granuloma formation in lungs 41 .…”

Extracellular Mycobacterial DNA-binding Protein 1 Participates in Mycobacterium-Lung Epithelial Cell Interaction through Hyaluronic Acid

“…Thus interaction with epithelia is thought to be crucial for dissemination and to dominate the disease outcome. Besides HBHA, M. tuberculosis has another possible adhesin, designated mycobacterial cell entry protein 1 (Mcep1), of which DNA fragmentation confers on Escherichia coli an ability to invade into nonphagocytic HeLa cells (9), although its precise role as an adhesin remains unclear (10). It is likely that myco-bacteria utilize multiple adhesins to promote attachment to nonprofessional phagocytes.…”