scholarly journals The Pneumococcal Surface Proteins PspA and PspC Sequester Host C4-Binding Protein To Inactivate Complement C4b on the Bacterial Surface

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Kashif S. Haleem ◽  
Youssif M. Ali ◽  
Hasan Yesilkaya ◽  
Thomas Kohler ◽  
Sven Hammerschmidt ◽  
...  
Keyword(s):  
Binding Protein ◽  
Surface Proteins ◽  
Host Cells ◽  
Regulatory Proteins ◽  
Content Type ◽  
Complement Regulatory Proteins ◽  
Bacterial Surface ◽  
Bacterial Pathogenicity ◽  
Activation Products ◽  
Antimicrobial Immunity

ABSTRACTComplement is a critical component of antimicrobial immunity. Various complement regulatory proteins prevent host cells from being attacked. Many pathogens have acquired the ability to sequester complement regulators from host plasma to evade complement attack. We describe here howStreptococcus pneumoniaeadopts a strategy to prevent the formation of the C3 convertase C4bC2a by the rapid conversion of surface bound C4b and iC4b into C4dg, which remains bound to the bacterial surface but no longer forms a convertase complex. Noncapsular virulence factors on the pneumococcus are thought to facilitate this process by sequestering C4b-binding protein (C4BP) from host plasma. WhenS. pneumoniaeD39 was opsonized with human serum, the larger C4 activation products C4b and iC4b were undetectable, but the bacteria were liberally decorated with C4dg and C4BP. With targeted deletions of either PspA or PspC, C4BP deposition was markedly reduced, and there was a corresponding reduction in C4dg and an increase in the deposition of C4b and iC4b. The effect was greatest when PspA and PspC were both knocked out. Infection experiments in mice indicated that the deletion of PspA and/or PspC resulted in the loss of bacterial pathogenicity. Recombinant PspA and PspC both bound serum C4BP, and both led to increased C4b and reduced C4dg deposition onS. pneumoniaeD39. We conclude that PspA and PspC help the pneumococcus to evade complement attack by binding C4BP and so inactivating C4b.

scholarly journals Cyclic Dimeric GMP Signaling Regulates Intracellular Aggregation, Sessility, and Growth of Ehrlichia chaffeensis

2011 ◽  
Vol 79 (10) ◽  
pp. 3905-3912 ◽  
Author(s):  
Yumi Kumagai ◽  
Junji Matsuo ◽  
Zhihui Cheng ◽  
Yoshihiro Hayakawa ◽  
Yasuko Rikihisa
Keyword(s):  
Serine Protease ◽  
Serine Proteases ◽  
Matrix Protein ◽  
Response Regulator ◽  
Bacterial Biofilm ◽  
Surface Proteins ◽  
Host Cells ◽  
Ehrlichia Chaffeensis ◽  
Content Type ◽  
Bacterial Surface

ABSTRACTCyclic dimeric GMP (c-di-GMP), a bacterial second messenger, is known to regulate bacterial biofilm and sessility. Replication of an obligatory intracellular pathogen,Ehrlichia chaffeensis, is characterized by formation of bacterial aggregates called morulae inside membrane-bound inclusions. WhenE. chaffeensismatures into an infectious form, morulae become loose to allow bacteria to exit from host cells to infect adjacent cells.E. chaffeensisexpresses a sensor kinase, PleC, and a cognate response regulator, PleD, which can produce c-di-GMP. A hydrophobic c-di-GMP antagonist, 2′-O-di(tert-butyldimethysilyl)-c-di-GMP (CDGA) inhibitsE. chaffeensisinternalization into host cells by facilitating degradation of some bacterial surface proteins via endogenous serine proteases. In the present study, we found that PleC and PleD were upregulated synchronously during exponential growth of bacteria, concomitant with increased morula size. While CDGA did not affect host cells, when infected cells were treated with CDGA, bacterial proliferation was inhibited, morulae became less compact, and the intracellular movement of bacteria was enhanced. Concurrently, CDGA treatment facilitated the extracellular release of bacteria with lower infectivity than those spontaneously released from sham-treated cells. Addition of CDGA to isolated inclusions induced dispersion of the morulae, degradation of an inclusion matrix protein TRP120, and bacterial intrainclusion movement, all of which were blocked by a serine protease inhibitor. These results suggest that c-di-GMP signaling regulates aggregation and sessility ofE. chaffeensiswithin the inclusion through stabilization of matrix proteins by preventing the serine protease activity, which is associated with bacterial intracellular proliferation and maturation.

scholarly journals Invasion mechanisms of Gram-positive pathogenic cocci

2007 ◽  
Vol 98 (09) ◽  
pp. 488-496 ◽  
Author(s):  
Patric Nitsche-Schmitz ◽  
Manfred Rohde ◽  
Gursharan Chhatwal
Keyword(s):  
Surface Proteins ◽  
Host Cells ◽  
Human Pathogens ◽  
Gram Positive ◽  
Bacterial Surface ◽  
Surface Receptors ◽  
Major Threat ◽  
Invasion Mechanisms ◽  
Invasive Infections ◽  
Gram Positive Cocci

SummaryGram-positive cocci are important human pathogens. Streptococci and staphylococci in particular are a major threat to human health,since they cause a variety of serious invasive infections. Their invasion into normally sterile sites of the host depends on elaborated bacterial mechanisms that involve adhesion to the host tissue, its degradation, internalisation by host cells, and passage through epithelia and endothelia. Interactions of bacterial surface proteins with proteins of the host’s extracellular matrix as well as with cell surface receptors are crucial factors in these processes, and some of the key mechanisms are similar in many pathogenic Gram-positive cocci.Therapies that interfere with these mechanisms may become efficient alternatives to today’s antibiotic treatments.

scholarly journals Release of C8 binding protein (C8bp) from the cell membrane by phosphatidylinositol-specific phospholipase C

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 1089-1092
Author(s):  
GM Hansch ◽  
PF Weller ◽  
A Nicholson-Weller
Keyword(s):  
Plasma Membrane ◽  
Cell Membrane ◽  
Phospholipase C ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Binding Protein ◽  
Regulatory Proteins ◽  
Membrane Expression ◽  
Normal Cells ◽  
Complement Regulatory Proteins ◽  
Common Defect

Abstract Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) are abnormally sensitive to complement. Two membrane proteins, the C8 binding protein (C8bp) and the decay accelerating factor (DAF), which are expressed on normal cells, function to restrict lysis by homologous complement, and both of these proteins are absent from PNH erythrocytes. DAF is anchored to the plasma membrane on normal cells by a phosphatidylinositol linkage. The investigators found that a purified phosphatidylinositol-specific phospholipase C cleaved C8bp from the surface of normal lymphocytes and monocytes. This finding indicates that the abnormal complement sensitivity of PNH erythrocytes arises from a common defect, the inability to attach the phosphatidylinositol- containing anchor that is necessary for the membrane expression of both membrane complement regulatory proteins, the C8bp, and DAF.

scholarly journals Biotinylated Surfome Profiling Identifies Potential Biomarkers for Diagnosis and Therapy of Aspergillus fumigatus Infection

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Lei-Jie Jia ◽  
Thomas Krüger ◽  
Matthew G. Blango ◽  
Ferdinand von Eggeling ◽  
Olaf Kniemeyer ◽  
...  
Keyword(s):  
Immune Responses ◽  
Aspergillus Fumigatus ◽  
Dynamic Change ◽  
Invasive Pulmonary Aspergillosis ◽  
Direct Interaction ◽  
Surface Proteins ◽  
Host Cells ◽  
Human Immune System ◽  
Data Set ◽  
Content Type

ABSTRACT Aspergillus fumigatus is one of the most common airborne molds capable of causing mycoses and allergies in humans. During infection, fungal surface proteins mediate the first contact with the human immune system to evade immune responses or to induce hypersensitivity. Several methods have been established for surface proteomics (surfomics). Biotinylation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of peptides is a particularly efficient method to identify the surface-exposed regions of proteins that potentially mediate interaction with the host. After biotinylation of surface proteins during spore germination, we detected 231 different biotinylated surface proteins (including several well-known proteins such as RodA, CcpA, and DppV; allergens; and heat shock proteins [HSPs]), as well as some previously undescribed surface proteins. The dynamic change of the surface proteome was illustrated by detection of a relatively high number of proteins exclusively at one developmental stage. Using immunofluorescence microscopy, we confirmed the surface localization of several HSPs of the HSP70 family, which may have moonlighting functions. Collectively, by comparing our data with data representative of previously published A. fumigatus surface proteomes, our study generated a comprehensive data set corresponding to the A. fumigatus surfome and uncovered the surface-exposed regions of many proteins on the surface of conidia or hyphae. These surface-exposed regions are candidates for direct interaction with host cells and may represent antigenic epitopes that either induce protective immune responses or mediate immune evasion. Thus, our data sets provided and compiled here represent reasonable immunotherapy and diagnostic targets for future investigations. IMPORTANCE Aspergillus fumigatus is the most important airborne human-pathogenic mold, capable of causing both life-threatening invasive pulmonary aspergillosis in immunocompromised patients and allergy-inducing infections in individuals with atopic allergy. Despite its obvious medical relevance, timely diagnosis and efficient antifungal treatment of A. fumigatus infection remain major challenges. Proteins on the surface of conidia (asexually produced spores) and mycelium directly mediate host-pathogen interaction and also may serve as targets for diagnosis and immunotherapy. However, the similarity of protein sequences between A. fumigatus and other organisms, sometimes even including the human host, makes selection of targets for immunological-based studies difficult. Here, using surface protein biotinylation coupled with LC-MS/MS analysis, we identified hundreds of A. fumigatus surface proteins with exposed regions, further defining putative targets for possible diagnostic and immunotherapeutic design.

scholarly journals Release of C8 binding protein (C8bp) from the cell membrane by phosphatidylinositol-specific phospholipase C

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 1089-1092 ◽  
Author(s):  
GM Hansch ◽  
PF Weller ◽  
A Nicholson-Weller
Keyword(s):  
Plasma Membrane ◽  
Cell Membrane ◽  
Phospholipase C ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Binding Protein ◽  
Regulatory Proteins ◽  
Membrane Expression ◽  
Normal Cells ◽  
Complement Regulatory Proteins ◽  
Common Defect

Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) are abnormally sensitive to complement. Two membrane proteins, the C8 binding protein (C8bp) and the decay accelerating factor (DAF), which are expressed on normal cells, function to restrict lysis by homologous complement, and both of these proteins are absent from PNH erythrocytes. DAF is anchored to the plasma membrane on normal cells by a phosphatidylinositol linkage. The investigators found that a purified phosphatidylinositol-specific phospholipase C cleaved C8bp from the surface of normal lymphocytes and monocytes. This finding indicates that the abnormal complement sensitivity of PNH erythrocytes arises from a common defect, the inability to attach the phosphatidylinositol- containing anchor that is necessary for the membrane expression of both membrane complement regulatory proteins, the C8bp, and DAF.

scholarly journals Entamoeba histolytica Cell Surface Calreticulin Binds Human C1q and Functions in Amebic Phagocytosis of Host Cells

2012 ◽  
Vol 80 (6) ◽  
pp. 2008-2018 ◽  
Author(s):  
Archana Vaithilingam ◽  
Jose E. Teixeira ◽  
Peter J. Miller ◽  
Bradley T. Heron ◽  
Christopher D. Huston
Keyword(s):  
Cell Surface ◽  
Entamoeba Histolytica ◽  
Calcium Ionophore ◽  
Surface Expression ◽  
Surface Proteins ◽  
Host Cells ◽  
Content Type ◽  
Amebic Dysentery ◽  
Host Cell Apoptosis ◽  
Phagocytic Cups

ABSTRACTPhagocytosis of host cells is characteristic of tissue invasion by the intestinal amebaEntamoeba histolytica, which causes amebic dysentery and liver abscesses.Entamoeba histolyticainduces host cell apoptosis and uses ligands, including C1q, on apoptotic cells to engulf them. Two mass spectrometry analyses identified calreticulin in amebic phagosome preparations, and, in addition to its function as an endoplasmic reticulum chaperone, calreticulin is believed to be the macrophage receptor for C1q. The purpose of this study was to determine if calreticulin functions as anE. histolyticaC1q receptor during phagocytosis of host cells. Calreticulin was localized to the surface ofE. histolyticaduring interaction with both Jurkat lymphocytes and erythrocytes and was present in over 75% of phagocytic cups during amebic erythrophagocytosis. Presence of calreticulin on the cell surface was further demonstrated using a method that selectively biotinylated cell surface proteins and by flow cytometry using trophozoites overexpressing epitope-tagged calreticulin. Regulated overexpression of calreticulin increasedE. histolytica's ability to phagocytose apoptotic lymphocytes and calcium ionophore-treated erythrocytes but had no effect on amebic adherence to or destruction of cell monolayers or surface expression of the GalNAc lectin and serine-richE. histolyticaprotein (SREHP) receptors. Finally,E. histolyticacalreticulin bound specifically to apoptotic lymphocytes and to human C1q. Collectively, these data implicate cell surface calreticulin as a receptor for C1q duringE. histolyticaphagocytosis of host cells.

Interplay of host–pathogen microvesicles and their role in infectious disease

2013 ◽  
Vol 41 (1) ◽  
pp. 258-262 ◽  
Author(s):  
Jameel M. Inal ◽  
Ephraim A. Ansa-Addo ◽  
Sigrun Lange
Keyword(s):  
Immune Evasion ◽  
Drug Efficacy ◽  
Infection Process ◽  
Host Cells ◽  
Regulatory Proteins ◽  
Future Research ◽  
Target Cells ◽  
Complement Regulatory Proteins ◽  
Vaccination Strategies ◽  
Immune Attack

The release of extracellular vesicles, whether MVs (microvesicles) or exosomes, from host cells or intracellular pathogens is likely to play a significant role in the infection process. Host MVs may fuse with pathogen surfaces to deliver host complement regulatory proteins. They may also deliver cytokines that enhance invasion. Decoy functions are also possible. Whereas host MVs may direct pathogens away from their target cells, pathogen MVs may in turn redirect complement membrane-attack complexes away from their target pathogen. An understanding of the mechanisms of this interplay, bringing about both immune evasion and enhanced invasion, will help to direct future research with a view to rendering pathogens more susceptible to immune attack or in improving drug efficacy. It should also be possible to use MVs or exosomes isolated directly from the pathogens, or from the cells infected with pathogens, to provide alternative vaccination strategies.

Common themes in microbial pathogenicity revisited

1997 ◽  
Vol 61 (2) ◽  
pp. 136-169
Author(s):  
B B Finlay ◽  
S Falkow
Keyword(s):  
Virulence Factors ◽  
Antigenic Variation ◽  
Regulatory Elements ◽  
Bacterial Virulence ◽  
Host Cells ◽  
Secretion Systems ◽  
Bacterial Surface ◽  
Bacterial Pathogenicity ◽  
Regulatory Circuits ◽  
Functional Factors

Bacterial pathogens employ a number of genetic strategies to cause infection and, occasionally, disease in their hosts. Many of these virulence factors and their regulatory elements can be divided into a smaller number of groups based on the conservation of similar mechanisms. These common themes are found throughout bacterial virulence factors. For example, there are only a few general types of toxins, despite a large number of host targets. Similarly, there are only a few conserved ways to build the bacterial pilus and nonpilus adhesins used by pathogens to adhere to host substrates. Bacterial entry into host cells (invasion) is a complex mechanism. However, several common invasion themes exist in diverse microorganisms. Similarly, once inside a host cell, pathogens have a limited number of ways to ensure their survival, whether remaining within a host vacuole or by escaping into the cytoplasm. Avoidance of the host immune defenses is key to the success of a pathogen. Several common themes again are employed, including antigenic variation, camouflage by binding host molecules, and enzymatic degradation of host immune components. Most virulence factors are found on the bacterial surface or secreted into their immediate environment, yet virulence factors operate through a relatively small number of microbial secretion systems. The expression of bacterial pathogenicity is dependent upon complex regulatory circuits. However, pathogens use only a small number of biochemical families to express distinct functional factors at the appropriate time that causes infection. Finally, virulence factors maintained on mobile genetic elements and pathogenicity islands ensure that new strains of pathogens evolve constantly. Comprehension of these common themes in microbial pathogenicity is critical to the understanding and study of bacterial virulence mechanisms and to the development of new "anti-virulence" agents, which are so desperately needed to replace antibiotics.

scholarly journals Peptide-Based Inhibitors of Fimbrial Biogenesis inPorphyromonas gingivalis

2019 ◽  
Vol 87 (3) ◽  
Author(s):  
Sarah R. Alaei ◽  
Jin Ho Park ◽  
Stephen G. Walker ◽  
David G. Thanassi
Keyword(s):  
Periodontal Disease ◽  
Bacterial Pathogen ◽  
Proteolytic Processing ◽  
Host Cells ◽  
Content Type ◽  
Bacterial Surface ◽  
Fimbrial Subunit ◽  
Biofilm Model ◽  
Assembly Mechanism ◽  
And Function

ABSTRACTPeriodontitis is a progressive inflammatory disease that affects roughly half of American adults. Colonization of the oral cavity by the Gram-negative bacterial pathogenPorphyromonas gingivalisis a key event in the initiation and development of periodontal disease. Adhesive surface structures termed fimbriae (pili) mediate interactions ofP. gingivaliswith other bacteria and with host cells throughout the course of disease. TheP. gingivalisfimbriae are assembled via a novel mechanism that involves proteolytic processing of lipidated precursor subunits and their subsequent polymerization on the bacterial surface. Given their extracellular assembly mechanism and central roles in pathogenesis, theP. gingivalisfimbriae are attractive targets for anti-infective therapeutics to prevent or treat periodontal disease. Here we confirm that conserved sequences in the N and C termini of the Mfa1 fimbrial subunit protein perform critical roles in subunit polymerization. We show that treatment ofP. gingivaliswith peptides corresponding to the conserved C-terminal region inhibits the extracellular assembly of Mfa fimbriae on the bacterial surface. We also show that peptide treatment interferes with the function of Mfa fimbriae by reducingP. gingivalisadhesion toStreptococcus gordoniiin a dual-species biofilm model. Finally, we show that treatment of bacteria with similar peptides inhibits extracellular polymerization of the Fim fimbriae, which are also expressed byP. gingivalis. These results support a donor strand-based assembly mechanism for theP. gingivalisfimbriae and demonstrate the feasibility of using extracellular peptides to disrupt the biogenesis and function of these critical periodontal disease virulence factors.

scholarly journals Anaplasma phagocytophilum Asp14 Is an Invasin That Interacts with Mammalian Host Cells via Its C Terminus To Facilitate Infection

2012 ◽  
Vol 81 (1) ◽  
pp. 65-79 ◽  
Author(s):  
Amandeep Kahlon ◽  
Nore Ojogun ◽  
Stephanie A. Ragland ◽  
David Seidman ◽  
Matthew J. Troese ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Anaplasma Phagocytophilum ◽  
Affinity Purification ◽  
Surface Protein ◽  
Surface Proteins ◽  
Host Cells ◽  
Mammalian Host ◽  
Content Type

Anaplasma phagocytophilum, a member of the familyAnaplasmataceae, is the tick-transmitted obligate intracellular bacterium that causes human granulocytic anaplasmosis. The life cycle ofA. phagocytophilumis biphasic, transitioning between the noninfectious reticulate cell (RC) and infectious dense-cored (DC) forms. We analyzed the bacterium's DC surface proteome by selective biotinylation of surface proteins, NeutrAvidin affinity purification, and mass spectrometry. Transcriptional profiling of selected outer membrane protein candidates over the course of infection revealed thataph_0248(designatedasp14[14-kDaA. phagocytophilumsurface protein]) expression was upregulated the most duringA. phagocytophilumcellular invasion.asp14transcription was induced during transmission feeding ofA. phagocytophilum-infected ticks on mice and was upregulated when the bacterium engaged its receptor, P-selectin glycoprotein ligand 1. Asp14 localized to theA. phagocytophilumsurface and was expressed duringin vivoinfection. Treating DC organisms with Asp14 antiserum or preincubating mammalian host cells with glutathioneS-transferase (GST)–Asp14 significantly inhibited infection of host cells. Moreover, preincubating host cells with GST-tagged forms of both Asp14 and outer membrane protein A, anotherA. phagocytophiluminvasin, pronouncedly reduced infection relative to treatment with either protein alone. The Asp14 domain that is sufficient for cellular adherence and invasion lies within the C-terminal 12 to 24 amino acids and is conserved among otherAnaplasmaandEhrlichiaspecies. These results identify Asp14 as anA. phagocytophilumsurface protein that is critical for infection, delineate its invasion domain, and demonstrate the potential of targeting Asp14 in concert with OmpA for protecting against infection byA. phagocytophilumand otherAnaplasmataceaepathogens.

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