scholarly journals The OspE-Related Proteins Inhibit Complement Deposition and Enhance Serum Resistance ofBorrelia burgdorferi, the Lyme Disease Spirochete

2011 ◽  
Vol 79 (4) ◽  
pp. 1451-1457 ◽  
Author(s):  
Melisha R. Kenedy ◽  
Darrin R. Akins
Keyword(s):  
Lyme Disease ◽  
Mutant Strain ◽  
Membrane Attack Complex ◽  
Factor H ◽  
Serum Resistance ◽  
Complement Components ◽  
Complement Inhibitors ◽  
Related Proteins ◽  
Complement Deposition

ABSTRACTBorrelia burgdorferi, the Lyme disease spirochete, binds the host complement inhibitors factor H (FH) and FH-like protein 1 (FHL-1). Binding of FH/FHL-1 by theB. burgdorferiproteins CspA and the OspE-related proteins is thought to enhance resistance to serum-mediated killing. While previous reports have shown that CspA confers serum resistance inB. burgdorferi, it is unclear whether the OspE-related proteins are relevant inB. burgdorferiserum resistance when OspE is expressed on the borrelial surface. To assess the role of the OspE-related proteins, we overexpressed them in a serum-sensitive CspA mutant strain. OspE overexpression enhanced serum resistance of the CspA-deficient organisms. Furthermore, FH was more efficiently bound to theB. burgdorferisurface when OspE was overexpressed. Deposition of complement components C3 and C5b-9 (the membrane attack complex), however, was reduced on the surface of the OspE-overexpressing strain compared to that on the CspA mutant strain. These data demonstrate that OspE proteins expressed on the surface ofB. burgdorferibind FH and protect the organism from complement deposition and subsequent serum-mediated destruction.

scholarly journals CspA-Mediated Binding of Human Factor H Inhibits Complement Deposition and Confers Serum Resistance in Borrelia burgdorferi

2009 ◽  
Vol 77 (7) ◽  
pp. 2773-2782 ◽  
Author(s):  
Melisha R. Kenedy ◽  
Santosh R. Vuppala ◽  
Corinna Siegel ◽  
Peter Kraiczy ◽  
Darrin R. Akins
Keyword(s):  
Borrelia Burgdorferi ◽  
Human Serum ◽  
Virulent Strain ◽  
Factor H ◽  
Serum Resistance ◽  
Complement Components ◽  
Affinity Ligand ◽  
Complement Inhibitors ◽  
Mammalian Infection ◽  
Complement Deposition

ABSTRACT Borrelia burgdorferi has developed efficient mechanisms for evading the innate immune response during mammalian infection and has been shown to be resistant to the complement-mediated bactericidal activity of human serum. It is well recognized that B. burgdorferi expresses multiple lipoproteins on its surface that bind the human complement inhibitors factor H and factor H-like protein 1 (FH/FHL-1). The binding of FH/FHL-1 on the surface of B. burgdorferi is thought to enhance its ability to evade serum-mediated killing during the acute phase of infection. One of the key B. burgdorferi FH/FHL-1 binding proteins identified thus far was designated CspA. While it is known that CspA binds FH/FHL-1, it is unclear how the interaction between CspA and FH/FHL-1 specifically enhances serum resistance. To better understand how CspA mediates serum resistance in B. burgdorferi, we inactivated cspA in a virulent strain of B. burgdorferi. An affinity ligand blot immunoassay and indirect immunofluorescence revealed that the CspA mutant does not efficiently bind human FH to its surface. Consistent with the lack of FH binding, the CspA mutant was also highly sensitive to killing by human serum. Additionally, the deposition of complement components C3, C6, and C5b-9 was enhanced on the surface of the CspA mutant compared to that of the wild-type strain. The combined data lead us to conclude that the CspA-mediated binding of human FH confers serum resistance by directly inhibiting complement deposition on the surface of B. burgdorferi.

scholarly journals Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens

2021 ◽  
Vol 9 ◽  
Author(s):  
Nehemiah T. Zewde ◽  
Rohaine V. Hsu ◽  
Dimitrios Morikis ◽  
Giulia Palermo
Keyword(s):  
Complement System ◽  
Membrane Attack Complex ◽  
Factor H ◽  
Immunoglobulin M ◽  
The Body ◽  
Complement Components ◽  
Invasive Pathogens ◽  
Time Profiles ◽  
Related Proteins ◽  
The Complement System

The complement system is assembled from a network of proteins that function to bring about the first line of defense of the body against invading pathogens. However, complement deficiencies or invasive pathogens can hijack complement to subsequently increase susceptibility of the body to infections. Moreover, invasive pathogens are increasingly becoming resistant to the currently available therapies. Hence, it is important to gain insights into the highly dynamic interaction between complement and invading microbes in the frontlines of immunity. Here, we developed a mathematical model of the complement system composed of 670 ordinary differential equations with 328 kinetic parameters, which describes all three complement pathways (alternative, classical, and lectin) and includes description of mannose-binding lectin, collectins, ficolins, factor H-related proteins, immunoglobulin M, and pentraxins. Additionally, we incorporate two pathogens: (type 1) complement susceptible pathogen and (type 2) Neisseria meningitidis located in either nasopharynx or bloodstream. In both cases, we generate time profiles of the pathogen surface occupied by complement components and the membrane attack complex (MAC). Our model shows both pathogen types in bloodstream are saturated by complement proteins, whereas MACs occupy <<1.0% of the pathogen surface. Conversely, the MAC production in nasopharynx occupies about 1.5–10% of the total N. meningitidis surface, thus making nasal MAC levels at least about eight orders of magnitude higher. Altogether, we predict complement-imbalance, favoring overactivation, is associated with nasopharynx homeostasis. Conversely, orientating toward complement-balance may cause disruption to the nasopharynx homeostasis. Thus, for sporadic meningococcal disease, our model predicts rising nasal levels of complement regulators as early infection biomarkers.

scholarly journals ErpY-like lipoprotein of Leptospira outsmart host complement regulation by acquiring complement regulators, activating alternate pathway, and intervening membrane attack complex

2021 ◽  
Author(s):  
Saswat Hota ◽  
Md Saddam Hussain ◽  
Manish Kumar
Keyword(s):  
Serum Proteins ◽  
Membrane Attack Complex ◽  
Factor H ◽  
Classical Pathway ◽  
Complement Components ◽  
Pathogenic Leptospira ◽  
Bacterial Surface ◽  
Alternate Complement Pathway ◽  
Complement Regulators

The survival of pathogenic Leptospira in the host pivots on its proficiency to circumvent the immune response. These pathogens evade the complement system in serum by enticing and amassing the serum complement regulators onto their surface. ErpY-like lipoprotein, a surface-exposed protein of Leptospira spp., is conserved and exclusively present in the pathogenic spirochete. The recombinant form of this protein is comprehended to interact with multiple extracellular matrix (ECM) components and serum proteins like soluble complement regulators factor H (FH) and factor I (FI). Here, we document that the supplementation of recombinant ErpY-like protein (40 µg/mL) in the host (humans) serum augments the viability of E. coli and saprophytic L. biflexa by more than 2-fold. Pure complement regulators FH and FI, when bound to rErpY-like protein, preserve their respective cofactor and protease activity mandated to cleave the complement component C3b. The supplementation of rErpY-like protein (40 µg/mL) in serum ensued in ~90 % reduction of membrane attack complex (C5b-9/MAC) deposition through alternate complement pathway (AP) activation. However, rErpY-like protein could moderately reduce (~16%) MAC deposition in serum through the classical pathway (CP). In addition, the rErpY-like protein solely activated the AP, suggesting its role in the rapid consumption and depletion of the complement components. Blocking the pathogenic L. interrogans surface with anti-rErpY resulted in an increase in MAC formation on the bacterial surface, indicating a specific role of the ErpY-like lipoprotein in complement-mediated immune evasion. This study underscores the role of the ErpY-like lipoprotein of Leptospira in complement evasion.

scholarly journals Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex

1999 ◽  
Vol 277 (6) ◽  
pp. C1263-C1268 ◽  
Author(s):  
Constantinos Kyriakides ◽  
William Austen ◽  
Yong Wang ◽  
Joanne Favuzza ◽  
Lester Kobzik ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Reperfusion Injury ◽  
Membrane Attack Complex ◽  
Wild Type ◽  
Complement Components ◽  
Neutrophil Activity ◽  
Deficient Mice ◽  
Terminal Complement

The relative inflammatory roles of neutrophils, selectins, and terminal complement components are investigated in this study of skeletal muscle reperfusion injury. Mice underwent 2 h of hindlimb ischemia followed by 3 h of reperfusion. The role of neutrophils was defined by immunodepletion, which reduced injury by 38%, as did anti-selectin therapy with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin (Ig) fusion protein. Injury in C5-deficient and soluble complement receptor type 1-treated wild-type mice was 48% less than that of untreated wild-type animals. Injury was restored in C5-deficient mice reconstituted with wild-type serum, indicating the effector role of C5–9. Neutropenic C5-deficient animals showed additive reduction in injuries (71%), which was lower than C5-deficient neutrophil-replete mice, indicating neutrophil activity without C5a. Hindlimb histological injury was worse in ischemic wild-type and C5-deficient animals reconstituted with wild-type serum. In conclusion, the membrane attack complex and neutrophils act additively to mediate skeletal muscle reperfusion injury. Neutrophil activity is independent of C5a but is dependent on selectin-mediated adhesion.

scholarly journals Regulation of regulators: Role of the complement factor H-related proteins

2019 ◽  
Vol 45 ◽  
pp. 101341 ◽  
Author(s):  
Marcell Cserhalmi ◽  
Alexandra Papp ◽  
Bianca Brandus ◽  
Barbara Uzonyi ◽  
Mihály Józsi
Keyword(s):  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Related Proteins

scholarly journals Complement Proteins as Soluble Pattern Recognition Receptors for Pathogenic Viruses

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 824
Author(s):  
Valarmathy Murugaiah ◽  
Praveen M. Varghese ◽  
Nazar Beirag ◽  
Syreeta De Cordova ◽  
Robert B. Sim ◽  
...  
Keyword(s):  
Complement System ◽  
Membrane Attack Complex ◽  
Factor H ◽  
Complement Components ◽  
Diverse Range ◽  
Effector Functions ◽  
Pathogenic Viruses ◽  
Viral Survival ◽  
Chemotactic Factors ◽  
The Complement System

The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components (especially C1q, C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses and their consequences.

scholarly journals Killing of dsrA Mutants of Haemophilus ducreyi by Normal Human Serum Occurs via the Classical Complement Pathway and Is Initiated by Immunoglobulin M Binding

2005 ◽  
Vol 73 (6) ◽  
pp. 3431-3439 ◽  
Author(s):  
Malikah Abdullah ◽  
Igor Nepluev ◽  
Galyna Afonina ◽  
Sanjay Ram ◽  
Peter Rice ◽  
...  
Keyword(s):  
Parent Strain ◽  
Factor H ◽  
Immunoglobulin M ◽  
Haemophilus Ducreyi ◽  
Serum Resistance ◽  
Classical Pathway ◽  
Negative Regulators ◽  
Complement Components ◽  
Resistant Parent ◽  
Classical Complement

ABSTRACT Previously, we showed that serum resistance in Haemophilus ducreyi type strain 35000HP required expression of the outer membrane protein DsrA because the isogenic dsrA mutant FX517 is highly serum susceptible. In this study, we confirmed this finding by construction of additional serum-susceptible dsrA mutants in more recently isolated serum-resistant strains. We also demonstrated that killing of dsrA mutants required an intact classical complement cascade but not the alternative or mannan-binding lectin pathways. Between 5- and 10-fold more purified human immunoglobulin M (IgM) but not IgG was deposited onto dsrA mutant FX517 than onto parent strain 35000HP, consistent with IgM initiation of the classical cascade. Depletion of IgM, but not IgG, from complement-intact serum inhibited killing of FX517. As predicted from the amounts of IgM bound, more of the individual complement components were bound by FX517 than by parent strain 35000HP. Examination of the binding of negative regulators of complement as an explanation for serum resistance indicated that parent strain 35000HP bound more C4 binding protein and vitronectin than FX517 but not factor H. However, the degree and pattern of complement component binding observed suggested that IgM binding to the serum-susceptible mutant FX517 was responsible for the activation of the classical pathway and the observed killing of FX517 as opposed to binding of negative regulators of complement by the serum-resistant parent. We speculate that an undefined neo-epitope, possibly carbohydrate, is exposed in the dsrA mutant that is recognized by naturally occurring bactericidal IgM antibodies present in human sera.

scholarly journals Serum Resistance in an Invasive, NontypeableHaemophilus influenzae Strain

2001 ◽  
Vol 69 (2) ◽  
pp. 695-705 ◽  
Author(s):  
Bryan J. Williams ◽  
Gregory Morlin ◽  
Nathan Valentine ◽  
Arnold L. Smith
Keyword(s):  
Membrane Attack Complex ◽  
Laboratory Strain ◽  
Serum Resistance ◽  
Classical Pathway ◽  
Type B ◽  
Complement Components ◽  
Igg Binding ◽  
Virulent Type ◽  
Bactericidal Effects ◽  
Normal Human

ABSTRACT A common feature of many different organisms causing bacteremia is the ability to avoid the bactericidal effects of normal human serum. InHaemophilus influenzae encapsulated strains are particularly serum resistant; however, we found that a nonencapsulated strain (R2866) isolated from the blood of an immunocompetent child with meningitis who had been successfully immunized with H. influenzae type b conjugate vaccine was serum resistant. Since serum resistance usually involves circumventing the action of the complement system, we defined the deposition of various complement components on the surfaces of this H. influenzae strain (R2866), a nonencapsulated avirulent laboratory strain (Rd), and a virulent type b encapsulated strain (Eagan). Membrane attack complex (MAC) accumulation correlated with the loss of bacterial viability; correspondingly, the rates of MAC deposition on the serum-sensitive strain Rd and the serum-resistant strains differed. Analysis of cell-associated immunoglobulin G (IgG), C1q, C3b, and C5b indicated that serum-resistant H. influenzae prevents MAC accumulation by delaying the synthesis of C3b through the classical pathway. Among the initiators of the classical pathway, IgG deposition contributes most of the C3 convertase activity necessary to start the cascade ending with MAC deposition. Despite similar IgG binding, strain R2866 delays C3 convertase activity compared to strain Rd. We conclude that strain R2866 can persist in the bloodstream, in part by inhibiting or delaying C3 deposition on the cell surface, escaping complement mediated killing.

scholarly journals The possible role of factor H in complement activation-related pseudoallergy (CARPA): a failed attempt to correlate blood levels of FH with liposome-induced hypersensitivity reactions in patients with autoimmune disease

2015 ◽  
Vol 7 (1) ◽  
Author(s):  
Tamas Gyula Fülöp ◽  
Mihály Józsi ◽  
Josbert Metselaar ◽  
Gert Storm ◽  
Laszló Rosivall ◽  
...  
Keyword(s):  
Initial Data ◽  
Alternative Pathway ◽  
Technical Problem ◽  
Factor H ◽  
Blood Levels ◽  
Hypersensitivity Reactions ◽  
Short Consensus Repeats ◽  
Unexpected Outcome ◽  
Related Proteins

AbstractFactor H (FH) is a natural inhibitor of the alternative pathway (AP) of complement (C) activation, an abundant protein in blood whose reduced level has been associated with proneness for increased C activation. There are also 5 FH-related proteins (FHR), which have different impacts on C function. After brief outlines of the C system and its activation via the AP, this review focuses on FH and FHR, collecting data from the literature that suggest that reduced levels or function of FH is associated with C activation-related hypersensitivity reactions (HSRs), called C activation related pseudoallergy (CARPA). Based on such observations we initiated the measurement of FH in the blood of patients with inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), and examined the correlation between FH levels and HSRs following i.v. administration of PEGylated liposomal prednisolone phosphate (PLPP). ELISA assay of FH was conducted on plasma samples before treatment, immediately after treatment and at follow-up visits up to 7 weeks, and an attempt was made to correlate the FH levels obtained with the presence or absence of HSR that occurred in five of twenty patients. However, the initial data presented here on three reactive and three non-reactive patients showed FH levels >600 μg/mL, while the normal range of FH is 2–300 μg/mL. This unexpected outcome of the test led us to realize that the ELISA we used was based on antibodies raised against the short consensus repeats (SCR) in FH, which are also present in FHR. Thus the kit cannot distinguish these proteins and we most likely measured the combined levels of FH and FHR. These initial data highlighted an unforeseen technical problem in assessing FH function when using a FH ELISA that cross reacts with FHR, information that helps in further studies exploring the role of FH in CARPA.

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