Serum Amyloid P and IgG Exhibit Differential Capabilities in the Activation of the Innate Immune System in Response to Bacillus anthracis Peptidoglycan

Girton, Alanson; Popescu, Narcis I.; Keshari, Ravi S.; Burgett, Tarea; Lupu, Florea; Coggeshall, K. Mark

doi:10.1128/iai.00076-18

Cited by 10 publications

(24 citation statements)

References 29 publications

(48 reference statements)

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“…25 Digested PGN fragments but not the polymeric structures activate NOD sensors. 28 Alternatively, immunoglobulin G (IgG) or serum amyloid P opsonized PGN can activate cellular FcgR receptors 27,33 and this mechanism is partially responsible for the platelet activation we reported. 34 PGNactivated platelets exhibit procoagulant responses including aggregation and exposure of anionic phospholipids.…”

Section: Introductionmentioning

confidence: 82%

“…29 Anthrax PGN is not a Toll-like receptor (TLR) ligand 30 but rather signals through intracellular pattern recognition nucleotide-binding oligomerization receptors 1 and 2 (NOD1 and NOD2). 31,32 PGN signaling requires recognition of opsonized PGN particles, 27,33 internalization, and lysosomal processing. 25 Digested PGN fragments but not the polymeric structures activate NOD sensors.…”

Section: Introductionmentioning

confidence: 99%

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Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways

Popescu¹,

Silasi‐Mansat

Keshari

et al. 2018

Blood

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Anthrax infections exhibit progressive coagulopathies that may contribute to the sepsis pathophysiology observed in fulminant disease. The hemostatic imbalance is recapitulated in primate models of late-stage disease but is uncommon in toxemic models, suggesting contribution of other bacterial pathogen-associated molecular patterns (PAMPs). Peptidoglycan (PGN) is a bacterial PAMP that engages cellular components at the cross talk between innate immunity and hemostasis. We hypothesized that PGN is critical for anthrax-induced coagulopathies and investigated the activation of blood coagulation in response to a sterile PGN infusion in primates. The PGN challenge, like the vegetative bacteria, induced a sepsis-like pathophysiology characterized by systemic inflammation, disseminated intravascular coagulation (DIC), organ dysfunction, and impaired survival. Importantly, the hemostatic impairment occurred early and in parallel with the inflammatory response, suggesting direct engagement of coagulation pathways. PGN infusion in baboons promoted early activation of contact factors evidenced by elevated protease-serpin complexes. Despite binding to contact factors, PGN did not directly activate either factor XII (FXII) or prekallikrein. PGN supported contact coagulation by enhancing enzymatic function of active FXII (FXIIa) and depressing its inhibition by antithrombin. In parallel, PGN induced de novo monocyte tissue factor expression in vitro and in vivo, promoting extrinsic clotting reactions at later stages. Activation of platelets further amplified the procoagulant state during PGN challenge, leading to DIC and subsequent ischemic damage of peripheral tissues. These data indicate that PGN may be a major cause for the pathophysiologic progression of sepsis and is the primary PAMP behind the pathogen-induced coagulopathy in late-stage anthrax.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways

Popescu¹,

Silasi‐Mansat

Keshari

et al. 2018

Blood

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“…Amongst those, FcγRIIA [ 48 ] and complement receptors CR1 and CR3 [ 49 ] are considered the primary phagocytic receptors on neutrophils, a process modulated by FcγRIIIb engagement [ 48 , 50 ] and/or TLRs [ 51 ]. While anthrax bacterium could potentially interact with all the above receptors, anthrax PGN does not bind surface TLR receptors [ 37 ], and primarily uses Fc and complement receptors for interaction with myeloid cells [ 35 , 39 , 42 , 52 ]. Our current study identifies C3b recognition as a central mediator in neutrophil interaction with anthrax particles, either bacteria or PGN sacculi, at subphysiologic temperatures.…”

Section: Discussionmentioning

confidence: 99%

“…PGN was purified from parental bacteria (Sterne Strain BA781) as reported [ 36 , 37 ]. Quality control analysis is described in detail elsewhere [ 37 , 38 ]; purified PGN preparation was free of TLR2 and TLR4 agonists [ 37 ], and promoted proinflammatory and procoagulant responses in primary human monocytes [ 35 , 39 ].…”

Section: Methodsmentioning

confidence: 99%

C3 Opsonization of Anthrax Bacterium and Peptidoglycan Supports Recognition and Activation of Neutrophils

et al. 2020

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Neutrophils are the most abundant innate cell population and a key immune player against invading pathogens. Neutrophils can kill both bacterium and spores of Bacillus anthracis, the causative anthrax pathogen. Unlike interactions with professional phagocytes, the molecular recognition of anthrax by neutrophils is largely unknown. In this study, we investigated the role of complement C3 deposition on anthrax particles for neutrophil recognition of bacterium and/or its cell wall peptidoglycan, an abundant pathogen-associated molecular pattern that supports anthrax sepsis. C3 opsonization and recognition by complement receptors accounted for 70–80% of the affinity interactions between neutrophils and anthrax particles at subphysiologic temperatures. In contrast, C3 supported up to 50% of the anthrax particle ingestion under thermophysiologic conditions. Opsonin-dependent low affinity interactions and, to a lower extent, opsonin-independent mechanisms, provide alternative entry routes. Similarly, C3 supported 58% of peptidoglycan-induced degranulation and, to a lower extent, 23% of bacterium-induced degranulation. Interestingly, an opsonin independent mechanism mediated by complement C5, likely through C5a anaphylatoxin, primes azurophilic granules in response to anthrax particles. Overall, we show that C3 deposition supports anthrax recognition by neutrophils but is dispensable for pathogen ingestion and neutrophil degranulation, highlighting immune recognition redundancies that minimize the risk of pathogen evasion.

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“…Thus, the capsule of B. anthracis active bacteria inhibits the binding of IgG, CRP, and SAP, which is associated with reduced C3b/iC3b deposition on the bacterial surface. The observation of naïve human serum, exhibiting a higher binding affinity of IgG and other soluble PRMs such as SAP with the non-encapsulated Sterne strain than the encapsulated strain, suggests that a significant fraction of naturally acquired PRMs recognize sub-capsular antigens such as cell wall peptidoglycan or cell surface protein antigens (53). It appears that the capsule masks the sub-capsular antigens from human serum IgG and complement proteins, which has been consistently observed in our complement-dependent and complement-independent phagocytosis experiments.…”

Section: Discussionmentioning

confidence: 99%

Bacillus anthracis Poly-γ-D-Glutamate Capsule Inhibits Opsonic Phagocytosis by Impeding Complement Activation

2020

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Bacillus anthracis poly-γ-D-glutamic acid (PGA) capsule is an essential virulent factor that helps the bacterial pathogen to escape host immunity. Like other encapsulated bacterial species, the B. anthracis capsule may also inhibit complement-mediated clearance and ensure bacterial survival in the host. Previous reports suggest that B. anthracis spore proteins inhibit complement activation. However, the mechanism through which the B. anthracis capsule imparts a survival advantage to the active bacteria has not been demonstrated till date. Thus, to evaluate the role of the PGA capsule in evading host immunity, we have undertaken the present head-to-head comparative study of the phagocytosis and complement activation of non-encapsulated and encapsulated B. anthracis strains. The encapsulated virulent strain exhibited resistance toward complement-dependent and complement-independent bacterial phagocytosis by human macrophages. The non-encapsulated Sterne strain was highly susceptible to phagocytosis by THP-1 macrophages, after incubation with normal human serum (NHS), heat-inactivated serum, and serum-free media, thus indicating that the capsule inhibited both complement-dependent and complement-independent opsonic phagocytosis. An increased binding of C3b and its subsequent activation to C3c and C3dg, which functionally act as potent opsonins, were observed with the non-encapsulated Sterne strain compared with the encapsulated strain. Other known mediators of complement fixation, IgG, C-reactive protein (CRP), and serum amyloid P component (SAP), also bound more prominently with the non-encapsulated Sterne strain. Studies with complement pathway-specific, component-deficient serum demonstrated that the classical pathway was primarily involved in mediating C3b binding on the non-encapsulated bacteria. Both strains equally bound the complement regulatory proteins C4BP and factor H. Importantly, we demonstrated that the negative charge of the PGA capsule was responsible for the differential binding of the complement proteins between the non-encapsulated and encapsulated strains. At lower pH closer to the isoelectric point of PGA, the neutralization of the negative charge was associated with Sharma et al. Bacillus anthracis Poly-γ-D-Glutamate Capsule an increased binding of C3b and IgG with the encapsulated B. anthracis strain. Overall, our data have demonstrated that the B. anthracis capsule inhibits complement fixation and opsonization resulting in reduced phagocytosis by macrophages, thus allowing the bacterial pathogen to evade host immunity.

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Serum Amyloid P and IgG Exhibit Differential Capabilities in the Activation of the Innate Immune System in Response to Bacillus anthracis Peptidoglycan

Cited by 10 publications

References 29 publications

Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways

Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways

C3 Opsonization of Anthrax Bacterium and Peptidoglycan Supports Recognition and Activation of Neutrophils

Bacillus anthracis Poly-γ-D-Glutamate Capsule Inhibits Opsonic Phagocytosis by Impeding Complement Activation

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