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Mycobacterium tuberculosis PE25/PPE41 protein complex induces necrosis in macrophages: Role in virulence and disease reactivation?

Tundup S, Mohareer K, Hasnain SE - FEBS Open Bio (2014)

Bottom Line: Necrotic cell death during TB infection is an important prerequisite for bacterial dissemination and virulence.The underlying mechanisms and the bacterial factors involved therein are not well understood.The Mycobacterium tuberculosis (M. tuberculosis) co-operonic PE25/PPE41 protein complex, similar to ESAT-6/CFP-10, belonging to the PE/PPE and ESAT-6 families of genes has co-expanded and co-evolved in the genomes of pathogenic mycobacteria.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Chicago, Chicago, IL, 60637, USA.

ABSTRACT
Necrotic cell death during TB infection is an important prerequisite for bacterial dissemination and virulence. The underlying mechanisms and the bacterial factors involved therein are not well understood. The Mycobacterium tuberculosis (M. tuberculosis) co-operonic PE25/PPE41 protein complex, similar to ESAT-6/CFP-10, belonging to the PE/PPE and ESAT-6 families of genes has co-expanded and co-evolved in the genomes of pathogenic mycobacteria. We report a novel role of this highly immunogenic PE25/PPE41 protein complex in inducing necrosis, but not apoptosis, in macrophages. We propose that these protein complexes of M. tuberculosis, secreted by similar/unique transport system (Type VII), have an important role in M. tuberculosis virulence and disease reactivation.

No MeSH data available.


Related in: MedlinePlus

Is the PE25/PPE41 complex involved in quorum sensing of the immune system? A schematic representation of the likely role of the secreted PE25/PPE41 complex on the host immune system. The secretion of the PPE41 or PE25/PPE41 complex is mediated by Type VII secretion system. The PPE41 or the PE25/PPE41 protein complex is secreted outside by the bacterium, which could be recognized by host immune system. But the proteins may help the bacterium by sensing the strength of the host immune system. Weak immune system may induce these proteins to regulate their own expression or signal for multiplication of the bacteria to spread outside the cells by inducing direct lysis of macrophages via necrosis, which in turn helps the bacterium to multiply and spread infection in the surrounding cells resulting into disease reactivation.
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f0030: Is the PE25/PPE41 complex involved in quorum sensing of the immune system? A schematic representation of the likely role of the secreted PE25/PPE41 complex on the host immune system. The secretion of the PPE41 or PE25/PPE41 complex is mediated by Type VII secretion system. The PPE41 or the PE25/PPE41 protein complex is secreted outside by the bacterium, which could be recognized by host immune system. But the proteins may help the bacterium by sensing the strength of the host immune system. Weak immune system may induce these proteins to regulate their own expression or signal for multiplication of the bacteria to spread outside the cells by inducing direct lysis of macrophages via necrosis, which in turn helps the bacterium to multiply and spread infection in the surrounding cells resulting into disease reactivation.

Mentions: The association of PE/PPE and ESAT-6 gene families with virulence is evident from the observations that the duplication and expansion of the PE/PPE and ESAT-6 genes during the course of evolution occurred only in pathogenic mycobacteria [18,19]. These genes are very uniquely organized in the genome with pe and ppe genes in operon with another member of pe/ppe or esat-6 family of genes [19] and evidently both ESAT-6 and PE/PPE family of proteins are secreted by Type VII/ESX secretory apparatus [15]. This also suggests that PE/PPE and ESAT-6 family of genes may have played important role in adaptation and host specificity, as these were earlier shown to be differentially expressed in different species of pathogenic mycobacteria [33–35]. Although exact function of PE/PPE proteins remain unknown, reports suggest that these are surface localized or secreted outside by mycobacteria and may have direct role in virulence and pathogenesis [16,22,36–43]. One of the important virulence mechanisms of pathogenic mycobacteria appears to be their ability to induce necrosis of host immune cells, as not only PE25/PPE41 complex, ESAT-6 protein has also been shown to induce necrosis of immune cells via an unknown mechanism [44]. The fact that the PE/PPE proteins mount both B- and T-cell immune responses [23,24,45] provokes us to also suggest a novel role for these protein families, present exclusively in the genus Mycobacterium, in ‘immune quorum sensing’ (Fig. 6) wherein these proteins are secreted to sense the immune status of the host after which through the possible involvement of cell surface constituents that influence interactions with other cells [38], convey a signal to stay dormant or undergo necrotic cell death. Based on our present and earlier findings, and existing evidences, we believe that the co-evolved and co-expanded PE/PPE and ESAT-6 family of proteins are secreted out, using sophisticated bacterial Type VII secretory systems, interact with host immune cells (Fig. 6), and facilitate mycobacterial dissemination and multiplication, which may ultimately lead to disease reactivation.


Mycobacterium tuberculosis PE25/PPE41 protein complex induces necrosis in macrophages: Role in virulence and disease reactivation?

Tundup S, Mohareer K, Hasnain SE - FEBS Open Bio (2014)

Is the PE25/PPE41 complex involved in quorum sensing of the immune system? A schematic representation of the likely role of the secreted PE25/PPE41 complex on the host immune system. The secretion of the PPE41 or PE25/PPE41 complex is mediated by Type VII secretion system. The PPE41 or the PE25/PPE41 protein complex is secreted outside by the bacterium, which could be recognized by host immune system. But the proteins may help the bacterium by sensing the strength of the host immune system. Weak immune system may induce these proteins to regulate their own expression or signal for multiplication of the bacteria to spread outside the cells by inducing direct lysis of macrophages via necrosis, which in turn helps the bacterium to multiply and spread infection in the surrounding cells resulting into disease reactivation.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219985&req=5

f0030: Is the PE25/PPE41 complex involved in quorum sensing of the immune system? A schematic representation of the likely role of the secreted PE25/PPE41 complex on the host immune system. The secretion of the PPE41 or PE25/PPE41 complex is mediated by Type VII secretion system. The PPE41 or the PE25/PPE41 protein complex is secreted outside by the bacterium, which could be recognized by host immune system. But the proteins may help the bacterium by sensing the strength of the host immune system. Weak immune system may induce these proteins to regulate their own expression or signal for multiplication of the bacteria to spread outside the cells by inducing direct lysis of macrophages via necrosis, which in turn helps the bacterium to multiply and spread infection in the surrounding cells resulting into disease reactivation.
Mentions: The association of PE/PPE and ESAT-6 gene families with virulence is evident from the observations that the duplication and expansion of the PE/PPE and ESAT-6 genes during the course of evolution occurred only in pathogenic mycobacteria [18,19]. These genes are very uniquely organized in the genome with pe and ppe genes in operon with another member of pe/ppe or esat-6 family of genes [19] and evidently both ESAT-6 and PE/PPE family of proteins are secreted by Type VII/ESX secretory apparatus [15]. This also suggests that PE/PPE and ESAT-6 family of genes may have played important role in adaptation and host specificity, as these were earlier shown to be differentially expressed in different species of pathogenic mycobacteria [33–35]. Although exact function of PE/PPE proteins remain unknown, reports suggest that these are surface localized or secreted outside by mycobacteria and may have direct role in virulence and pathogenesis [16,22,36–43]. One of the important virulence mechanisms of pathogenic mycobacteria appears to be their ability to induce necrosis of host immune cells, as not only PE25/PPE41 complex, ESAT-6 protein has also been shown to induce necrosis of immune cells via an unknown mechanism [44]. The fact that the PE/PPE proteins mount both B- and T-cell immune responses [23,24,45] provokes us to also suggest a novel role for these protein families, present exclusively in the genus Mycobacterium, in ‘immune quorum sensing’ (Fig. 6) wherein these proteins are secreted to sense the immune status of the host after which through the possible involvement of cell surface constituents that influence interactions with other cells [38], convey a signal to stay dormant or undergo necrotic cell death. Based on our present and earlier findings, and existing evidences, we believe that the co-evolved and co-expanded PE/PPE and ESAT-6 family of proteins are secreted out, using sophisticated bacterial Type VII secretory systems, interact with host immune cells (Fig. 6), and facilitate mycobacterial dissemination and multiplication, which may ultimately lead to disease reactivation.

Bottom Line: Necrotic cell death during TB infection is an important prerequisite for bacterial dissemination and virulence.The underlying mechanisms and the bacterial factors involved therein are not well understood.The Mycobacterium tuberculosis (M. tuberculosis) co-operonic PE25/PPE41 protein complex, similar to ESAT-6/CFP-10, belonging to the PE/PPE and ESAT-6 families of genes has co-expanded and co-evolved in the genomes of pathogenic mycobacteria.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Chicago, Chicago, IL, 60637, USA.

ABSTRACT
Necrotic cell death during TB infection is an important prerequisite for bacterial dissemination and virulence. The underlying mechanisms and the bacterial factors involved therein are not well understood. The Mycobacterium tuberculosis (M. tuberculosis) co-operonic PE25/PPE41 protein complex, similar to ESAT-6/CFP-10, belonging to the PE/PPE and ESAT-6 families of genes has co-expanded and co-evolved in the genomes of pathogenic mycobacteria. We report a novel role of this highly immunogenic PE25/PPE41 protein complex in inducing necrosis, but not apoptosis, in macrophages. We propose that these protein complexes of M. tuberculosis, secreted by similar/unique transport system (Type VII), have an important role in M. tuberculosis virulence and disease reactivation.

No MeSH data available.


Related in: MedlinePlus