Disruption of immune regulation by microbial pathogens and resulting chronic inflammation

Abstract

Activation of the immune response is a tightly regulated, coordinated effort that functions to control and eradicate exogenous microorganisms, while also responding to endogenous ligands. Determining the proper balance of inflammation is essential, as chronic inflammation leads to a wide array of host pathologies. Bacterial pathogens can instigate chronic inflammation via an extensive repertoire of evolved evasion strategies that perturb immune regulation. In this review, we discuss two model pathogens, Mycobacterium tuberculosis and Porphyromonas gingivalis, which efficiently escape various aspects of the immune system within professional and non-professional immune cell types to establish chronic inflammation.

Fig. 1

Evasion strategies utilized by Mycobacterium tuberculosis disrupts immune regulation to promote bacterial transmission.M. tuberculosis is considered a pathogen capable of persistence within the human host. There are, however, differences in the extent to which the immune system is able to limit transmission to new hosts. A: Within 90% of Mtb infected individuals, infection is insufficiently controlled by the innate immune system, thus requiring adaptive responses. The coordination of both arms of immunity results in granuloma formation and containment of the organism. Eradication is not achieved, yet transmission is limiting. A number of interactions involving several cell types are critical for host containment of Mtb. APC actively prime T cells as Th1 effector cells, specialized to activate macrophages via TNFα and IFNg secretion, allowing for phagocyte-dependent clearance of bacteria. Macrophage-derived cytokines importantly activate other macrophages (TNFα) and actively promote Th1 differentiation (IL-12). Internalized bacteria become sensitive to phagocytic killing mechanisms (ROS/RNS), provided vascular sorting remains unaltered, allowing for maturation and fusion of lysosomes, both key steps in generating bactericidal activity of these cells. Inflammasome activation may ensue with detection of DAMP or PAMP, inducing the expression of IL-1b, involved inmacrophage and T cell activation. Lastly, Mtb infected cells can undergo apoptosis. B: Approximately 10% of infected individuals fail to contain the infection, which offers potential opportunities for pathogen transmission. The lack of containment can be partly attributed to Mtb subversion of both innate and adaptive immune responses. Infection of APC in concert with inhibition of antigen processing/presentation greatly subverts APC function in T cell priming. Direct Mtb binding to C-type lectins induces anti-inflammatory cytokines (IL-4, IL-13), diminishes Th1 development via IL-10 induction and prevents IL-12 expression, a powerful mediator for Th1 responses. Failure to generate appropriate Th1 responses leads to decreased TNFα and IFNg, cytokines known to be protective against Mtb infection with critical functions in cellular activation and granuloma formation. Bacterial secretion of immunological decoys skew CD4⁺ T cell responses to non-expressed antigens. Mtb prevents phagosomal maturation and arrests lysosomal fusion. For those bacteria that encounter ROS/RNS killing mechanisms, three distinct evasion strategies provide assistance. Inhibition of species generation, detoxification of reactive species and repair of damaged macromolecules affords protection for the pathogen. Mtb actively inhibits Inflammasome activation, preventing IL-1bexpression,which impairs the ability of host cells to overcome phagosome arrest. Lastly, Mtb postpones host cell death during the initial phases of intracellular replication, instead promoting necrosis that allows phagosome exit by the bacterium, thus increasing the potential for infection of other cell populations.

Fig. 2

Model of P. gingivalis evasion strategies preferentially targeting innate immunity to promote pathogen persistence. One of the major virulence factors expressed by P. gingivalis are gingipains, which proteolytically degrade (denoted by scissors) a wide range of substrates critically involved within host immunity (A). Since gingipains are both membrane anchored and secreted in OMV, alternative opportunities exist for immune interference at sites proximal and distant to infection, as denoted by the gradient encircling the bacterium. Targets include complement components (C3 and C5), pro-inflammatory cytokines/chemokines generated from both immune and nonimmune cells (IL-1b, IL-6, IL-8, and TNFα), immunoglobulins (IgA, IgM, and IgG), in addition to PRR coreceptors (CD14). A variety of subversion techniques exploit host cell receptors within the macrophage, providing disruption of its cell activation, expression of inflammatory mediators and microbicidal potential (B). P. gingivalis modifies its lipid A structure to express LPS with unique characteristics. It is not only immunologically silent, but harbors the ability to antagonize TLR4 signaling, leading to increased bacterial survival within macrophages. Following gingipain cleavage of complement factor C5 and C5aR is activated in concert with fimbriae-dependent activation of CXCR4. Receptor engagement activates protein kinase A (PKA), impairing iNOS-dependent killing of the pathogen. Major fimbriae-dependent binding to CR3 induces ERK1/2 signaling, repressing IL-12 expression, impairing immune clearance in vivo. P. gingivalis also expresses minor fimbriae that binds DC-SIGN to promote bacterial internalization that affects DC function (C). DC maturation is uncoupled from the cytokine response resulting in decreased expression of IL-1b, IL-6, IL-8, IL-12, and TNFα. The other important cell type involved in chronic inflammatory diseases of the vascular system is the endothelial cell. A number of reports have proposed P. gingivalis strategies that attempt to create an intracellular niche for the organism within the cells of the endothelium (D). Autophagy is initiated following attachment and invasion of endothelial cells, causing sorting to vacuoles that fail to mature into autolysosomes, thus establishmentofa“replicatingvacuole.”Furthermore, intracellular PRR signaling pathways involved in endothelial cell activation(TNF-R/RIPK1) and intracellular recognition of pathogens (NOD/RIPK2) is targeted by gingipain-dependent activity. We propose degradation of RIPK allows for intracellular survival of the pathogen within endothelial cells. The majority of these evasion strategies have only been tested within specific cell types, as described within the text, and future studies will likely increase the breadth of cell types sensitive to the specific examples of immune intervention. Consequently, P. gingivalis utilizes its own protein factors or exploits host pathways to subvert immune responses. These strategies act to repress cellular function (endothelial, macrophage, dendritic, T cell, etc.) and disrupt communication of the immune system, effectively offering an opportunity for persistence and chronic immune stimulation.