Functional domains, structural variations and pathogen interactions of MCP, DAF and CR1

Hourcade, Dennis E.; Liszewski, M. Kathryn; Krych-Goldberg, Malgorzata; Atkinson, John P.

doi:10.1016/s0162-3109(00)80296-9

Cited by 73 publications

(78 citation statements)

References 120 publications

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“…CD46 is a member of a family of glycoproteins called regulators of complement activation (RCA); these proteins serve to protect autologous host cells from complement-mediated lysis (reviewed in 7,8). The human genome encodes at least 6 RCA glycoproteins, some membrane-associated and others fluidphase.…”

Section: Human Herpesvirus 6 (Hhv-6)mentioning

confidence: 99%

“…For each pathogen whose CD46-interacting regions have been defined, the determinants are distinct from (although overlapping with) those involved in normal ligand binding and cofactor function, i.e. CD46 SCRs 2-4 are involved in binding of both C3b and C4b; SCR1 also influences C4b binding (7,8,15,35,43).…”

Section: Cd46 Domains Required For Hhv-6 Receptor Functionmentioning

confidence: 99%

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Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function

Greenstone

Santoro²,

Lusso³

et al. 2002

Journal of Biological Chemistry

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We employed a quantitative cell fusion assay to identify structural domains of CD46 required for its function as a receptor for human herpesvirus 6 (HHV-6). We examined the activities of recombinant variants of CD46, including different isoforms as well as engineered truncations and molecular chimeras with decay-accelerating factor, a related protein in the family of regulators of complement activation (RCA). We observed strong receptor activity for all four CD46 isoforms, which differ in the membrane-proximal extracellular and cytoplasmic domains, indicating that the critical determinants for HHV-6 receptor activity reside outside the C-terminal portion of CD46. Analysis of the short consensus repeat (SCR) regions that comprise most of the extracellular portion of CD46 indicated a strong dependence on SCRs 2 and 3 and no requirement for SCRs 1 or 4. Fusion-inhibition studies with SCR-specific monoclonal antibodies supported the essential role of SCRs 2 and 3 in HHV-6 receptor activity. These findings contrast markedly with fusion mediated by measles virus glycoproteins for which we observed a strict dependence on SCRs 1 and 2, consistent with previous reports. These results expand the emerging notion that CD46 and other members of the RCA family are co-opted in distinct manners by different infectious pathogens.

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Section: Human Herpesvirus 6 (Hhv-6)mentioning

confidence: 99%

Section: Cd46 Domains Required For Hhv-6 Receptor Functionmentioning

confidence: 99%

Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function

Greenstone

Santoro²,

Lusso³

et al. 2002

Journal of Biological Chemistry

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“…Because CR1 has cofactor activity, it also participates directly in complement activation by facilitating the factor I-mediated conversion of C3b to iC3b. This action of CR1 can down-regulate further complement activation (17). A closely related, but nonphagocytic, receptor, CR2 (CD21), binds C3dg/C3d and thereby influences B cell activation and development (16,18).…”

mentioning

confidence: 99%

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

Ren¹,

McCrory

Pass

et al. 2004

The Journal of Immunology

106

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Complement is important for elimination of invasive microbes from the host, an action achieved largely through interaction of complement-decorated pathogens with various complement receptors (CR) on phagocytes. Pneumococcal surface protein A (PspA) has been shown to interfere with complement deposition onto pneumococci, but to date the impact of PspA on CR-mediated host defense is unknown. To gauge the contribution of CRs to host defense against pneumococci and to decipher the impact of PspA on CR-dependent host defense, wild-type C57BL/6J mice and mutant mice lacking CR types 1 and 2 (CR1/2−/−), CR3 (CR3−/−), or CR4 (CR4−/−) were challenged with WU2, a PspA+ capsular serotype 3 pneumococcus, and its PspA− mutant JY1119. Pneumococci also were used to challenge factor D-deficient (FD−/−), LFA-1-deficient (LFA-1−/−), and CD18-deficient (CD18−/−) mice. We found that FD−/−, CR3−/−, and CR4−/− mice had significantly decreased longevity and survival rate upon infection with WU2. In comparison, PspA− pneumococci were virulent only in FD−/− and CR1/2−/− mice. Normal mouse serum supported more C3 deposition on pneumococci than FD−/− serum, and more iC3b was deposited onto the PspA− than the PspA+ strain. The combined results confirm earlier conclusions that the alternative pathway of complement activation is indispensable for innate immunity against pneumococcal infection and that PspA interferes with the protective role of the alternative pathway. Our new results suggest that complement receptors CR1/2, CR3, and CR4 all play important roles in host defense against pneumococcal infection.

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“…Therefore, we propose that NO generated in endometrial epithelial cells down-regulates DAF and thus reduces invasion of these cells, thereby playing a role in epithelial resistance to an invasive pathogen. DAF (CD55) is a complement-regulatory protein that protects cells from autologous complement-mediated damage (15). DAF is widely expressed on blood cells, epithelial cells, endometrial cells, uterus, and kidney (15), and its levels of expression may play a role in modulating the pathophysiology of many disease processes.…”

Section: Discussionmentioning

confidence: 99%

“…DAF (CD55) is a complement-regulatory protein that protects cells from autologous complement-mediated damage (15). DAF is widely expressed on blood cells, epithelial cells, endometrial cells, uterus, and kidney (15), and its levels of expression may play a role in modulating the pathophysiology of many disease processes. Low levels of DAF have been implicated in the destruction of red cells in patients with paroxysmal nocturnal hemoglobinuria and in luteal phase defect of the endometrium associated with infertility or pregnancy loss (37).…”

Section: Discussionmentioning

confidence: 99%

Epithelial Invasion by Escherichia coli Bearing Dr Fimbriae Is Controlled by Nitric Oxide-Regulated Expression of CD55

Li¹,

Nowicki

Urvil³

et al. 2004

Infect Immun

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We previously reported that inhibition of nitric oxide (NO) increases the rate of bacteremia and maternal mortality in pregnant rats with uterine infection by Escherichia coli expressing the Dr fimbria (Dr ؉ ). Epithelial binding and invasion by Dr ؉ E. coli has also been shown to be dependent upon the expression level of the cellular receptor decay-accelerating factor (DAF; CD55). Here, we hypothesize that NO-related severity of infection could be mediated by changes in DAF expression and in the rate of epithelial invasion. The cellular basis of NO effects on epithelial invasion with Dr ؉ E. coli was studied using Ishikawa endometrial carcinoma cells as an in vitro model of the human endometrial epithelium. Initially, we show that Ishikawa cells produce NO and express both NO synthase enzymes, NOS II and NOS III, and DAF protein. We next tested the abilities of both Dr ؉ E. coli and a Dr ؊ E. coli mutant to invade Ishikawa cells, and invasion was seen only with Dr ؉ E. coli. Invasion by Dr ؉ E. coli was decreased by elevated NO production and increased by NO inhibition. Elevated NO production significantly decreased DAF protein and mRNA expression in Ishikawa cells in a time-and dose-dependent manner. Here, we propose that in vitro invasion of an epithelial cell line is directly related to NO-regulated expression of DAF. The significance of NO-regulated receptor-ligand invasion is that it may represent a novel unrecognized phenomenon of epithelial defense against infection.Although urogenital microbial infection in pregnancy is an important cause of maternal and neonatal morbidity and mortality, the mechanisms of defense against gestational intrauterine infection are poorly understood (8,14,23). Evidence obtained in studies of both humans and rats suggests that the bacteriostatic actions of nitric oxide (NO) are an important component of defense against urogenital infection (16,30,33). Nitric oxide is synthesized in situ from an L-arginine substrate by one or more of three NO synthase isoforms (NOS I, NOS II, and NOS III), each of which has been identified in the mouse, rat, and human (1,27,40,41).Several lines of evidence have demonstrated the involvement of intracellular NO in the host defense mechanisms against bacterial infections (5, 27). Recently, NO production and three NOS isoforms were reported to be present in rat uterine tissues, and elevated NOS II expression was demonstrated to contribute to the increased NO production in the rat uterus and consequent uterine quiescence during gestation (3, 4, 40). However, the role of the NO system in uterine defense mechanisms is not well understood.Three separate lines of evidence from our laboratories have suggested that increased NO production by the urogenital tract in pregnancy protects against Escherichia coli infection. First, inhibition of NO synthesis in pregnant rats with an intrauterine infection increases maternal death (30). Second, the sensitivity of the female rat or mouse urinary tract to E. coli infection was increased with inhibition of NO (30,3...

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Functional domains, structural variations and pathogen interactions of MCP, DAF and CR1

Cited by 73 publications

References 120 publications

Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function

Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

Epithelial Invasion by Escherichia coli Bearing Dr Fimbriae Is Controlled by Nitric Oxide-Regulated Expression of CD55

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