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Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!!

Khan N, Gowthaman U, Pahari S, Agrewala JN - PLoS Pathog. (2012)

Bottom Line: Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells.Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens.We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.

ABSTRACT
Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

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Related in: MedlinePlus

Pathogens modulate the expression of costimulatory molecules for their survival.Sensing of pathogens through PRRs triggers the activation of APCs. (A) Costimulatory molecules, which act as the second signal for T-cell activation, are upregulated on infected cells. Persistence of intracellular pathogens modulates the expression of costimulatory molecules, such as downregulation of CD40/CD80/CD86 and upregulation of PDL-1 on infected APCs. Similarly, retarding the exhibition of CD28/CD40L augments PD-1/CTLA-4 on T cells. (B) Interaction of T cells with the infected APCs impairs the function of T cells by inducing anergy, apoptosis, or exhaustion. (C) Lack of T-cell help impedes the activity of APCs, eventually enhancing the survival of pathogens.
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ppat-1002676-g002: Pathogens modulate the expression of costimulatory molecules for their survival.Sensing of pathogens through PRRs triggers the activation of APCs. (A) Costimulatory molecules, which act as the second signal for T-cell activation, are upregulated on infected cells. Persistence of intracellular pathogens modulates the expression of costimulatory molecules, such as downregulation of CD40/CD80/CD86 and upregulation of PDL-1 on infected APCs. Similarly, retarding the exhibition of CD28/CD40L augments PD-1/CTLA-4 on T cells. (B) Interaction of T cells with the infected APCs impairs the function of T cells by inducing anergy, apoptosis, or exhaustion. (C) Lack of T-cell help impedes the activity of APCs, eventually enhancing the survival of pathogens.

Mentions: Downregulation of CD80/CD86 or upregulation of CTLA-4 by bacteria on APCs may induce anergy/apoptosis of interacting T cells [20], [21]. Defect in this signaling pathway is known to paralyze the release of IL-2, which may compromise the generation of T-cell memory [22]. Impediment in CD28 signaling interferes in IFN-γ production and hence promotes the survival of pathogens. It has been reported that M. leprae obstructs CD28/B7 signaling pathway for rendering antigen-specific T cell unresponsive in lepromatous leprosy patients [21]. Recently, the importance of CD80/CD86 in controlling mycobacterial infection has been demonstrated in CD80/CD86 double knockout mice [23]. The down-modulation of CD80/CD86 in chronic phase of the infection suggests that mycobacteria may actively exploit this pathway to anergize the T cells (Figure 2). Protective CMI is always associated with the release of chemokines and migration of immune cells to the site of infection. Mtb impair chemokines secretion by interfering with the CD28-B7 signaling pathway thereby obstructing the surveillance of immune cells and enhancing the propagation of the bacterium [24], [25]. It has been shown that the most abundant cell wall lipid trehalose 6, 6′-dimycolate (TDM) of Mtb and MTSA-10 inhibit the expression of costimulatory molecules on the surface of the macrophages [26], [27]. Similarly, CD40-CD40L interaction is very important in mediating efficient protection against mycobacteria [28]. Indeed, it has been shown in vitro and in lepromatous patients that CD40 is downregulated by M. leprae[29], [30]. There is indirect evidence indicating the involvement of Mtb manipulating CD40/CD40L expression. In humans, CD40L expression on Th1 cells of tuberculosis (TB) patients has been correlated with the intensity of IFN-γ secretion [31]. However, CD40 but not CD40L knockout mice are susceptible to Mtb infection [32], [33]. It is reported that the heat shock protein 70 (HSP70) of Mtb acts as an alternate ligand for CD40. Corroboratively, over-expression of HSP70 interferes with long-time persistence of Mtb and allows its clearance [34]. Interestingly, in chronic mycobacterial infections, CD40 is suppressed on infected cells [16]. Therefore, it is intriguing to speculate that in the chronic phase of infection, mycobacteria may hamper CD40 expression or manipulate CD40L signaling through binding with HSP70 instead of CD40L in order to evade host defense mechanisms.


Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!!

Khan N, Gowthaman U, Pahari S, Agrewala JN - PLoS Pathog. (2012)

Pathogens modulate the expression of costimulatory molecules for their survival.Sensing of pathogens through PRRs triggers the activation of APCs. (A) Costimulatory molecules, which act as the second signal for T-cell activation, are upregulated on infected cells. Persistence of intracellular pathogens modulates the expression of costimulatory molecules, such as downregulation of CD40/CD80/CD86 and upregulation of PDL-1 on infected APCs. Similarly, retarding the exhibition of CD28/CD40L augments PD-1/CTLA-4 on T cells. (B) Interaction of T cells with the infected APCs impairs the function of T cells by inducing anergy, apoptosis, or exhaustion. (C) Lack of T-cell help impedes the activity of APCs, eventually enhancing the survival of pathogens.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375268&req=5

ppat-1002676-g002: Pathogens modulate the expression of costimulatory molecules for their survival.Sensing of pathogens through PRRs triggers the activation of APCs. (A) Costimulatory molecules, which act as the second signal for T-cell activation, are upregulated on infected cells. Persistence of intracellular pathogens modulates the expression of costimulatory molecules, such as downregulation of CD40/CD80/CD86 and upregulation of PDL-1 on infected APCs. Similarly, retarding the exhibition of CD28/CD40L augments PD-1/CTLA-4 on T cells. (B) Interaction of T cells with the infected APCs impairs the function of T cells by inducing anergy, apoptosis, or exhaustion. (C) Lack of T-cell help impedes the activity of APCs, eventually enhancing the survival of pathogens.
Mentions: Downregulation of CD80/CD86 or upregulation of CTLA-4 by bacteria on APCs may induce anergy/apoptosis of interacting T cells [20], [21]. Defect in this signaling pathway is known to paralyze the release of IL-2, which may compromise the generation of T-cell memory [22]. Impediment in CD28 signaling interferes in IFN-γ production and hence promotes the survival of pathogens. It has been reported that M. leprae obstructs CD28/B7 signaling pathway for rendering antigen-specific T cell unresponsive in lepromatous leprosy patients [21]. Recently, the importance of CD80/CD86 in controlling mycobacterial infection has been demonstrated in CD80/CD86 double knockout mice [23]. The down-modulation of CD80/CD86 in chronic phase of the infection suggests that mycobacteria may actively exploit this pathway to anergize the T cells (Figure 2). Protective CMI is always associated with the release of chemokines and migration of immune cells to the site of infection. Mtb impair chemokines secretion by interfering with the CD28-B7 signaling pathway thereby obstructing the surveillance of immune cells and enhancing the propagation of the bacterium [24], [25]. It has been shown that the most abundant cell wall lipid trehalose 6, 6′-dimycolate (TDM) of Mtb and MTSA-10 inhibit the expression of costimulatory molecules on the surface of the macrophages [26], [27]. Similarly, CD40-CD40L interaction is very important in mediating efficient protection against mycobacteria [28]. Indeed, it has been shown in vitro and in lepromatous patients that CD40 is downregulated by M. leprae[29], [30]. There is indirect evidence indicating the involvement of Mtb manipulating CD40/CD40L expression. In humans, CD40L expression on Th1 cells of tuberculosis (TB) patients has been correlated with the intensity of IFN-γ secretion [31]. However, CD40 but not CD40L knockout mice are susceptible to Mtb infection [32], [33]. It is reported that the heat shock protein 70 (HSP70) of Mtb acts as an alternate ligand for CD40. Corroboratively, over-expression of HSP70 interferes with long-time persistence of Mtb and allows its clearance [34]. Interestingly, in chronic mycobacterial infections, CD40 is suppressed on infected cells [16]. Therefore, it is intriguing to speculate that in the chronic phase of infection, mycobacteria may hamper CD40 expression or manipulate CD40L signaling through binding with HSP70 instead of CD40L in order to evade host defense mechanisms.

Bottom Line: Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells.Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens.We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.

ABSTRACT
Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

Show MeSH
Related in: MedlinePlus