Structure of a Complex of Human Lactoferrin N-lobe with Pneumococcal Surface Protein A Provides Insight into Microbial Defense Mechanism

Senkovich, Olga; Cook, William J.; Mirza, Shaper; Hollingshead, Susan K.; Protasevich, I.I.; Briles, David E.; Chattopadhyay, Debasish

doi:10.1016/j.jmb.2007.04.075

Cited by 70 publications

(61 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the mice immunized with PspAN-terminal-repeat were not protected against a lethal intranasal challenge with ATCC 6303 (PspA clade 5). Since the N-terminal portion of PspA forms an antiparallel coiled-coil structure (49), this initial N-terminal region may be largely unexposed or camouflaged by the thick polysaccharide capsule present in the serotype 3 strains used in the flow cytometry and in the challenge experiments. Nevertheless, the experiments with a strain with a thinner serotype 14 capsule and with a nonencapsulated strain showing no binding of antibodies against PspAN-terminal-repeat ruled out this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC

Vadesilho

Ferreira

Gordon

et al. 2014

Clin. Vaccine Immunol.

Self Cite

View full text Add to dashboard Cite

cPneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC) are important candidates for an alternative vaccine against pneumococcal infections. Since these antigens show variability, the use of variants that do not afford broad protection may lead to the selection of vaccine escape bacteria. Epitopes capable of inducing antibodies with broad cross-reactivities should thus be the preferred antigens. In this work, experiments using peptide arrays show that most linear epitopes recognized by antibodies induced in mice against different PspAs were located at the initial 44 amino acids of the mature protein and that antibodies against these linear epitopes did not confer protection against a lethal challenge. Conversely, linear epitopes recognized by antibodies to PspC included the consensus sequences involved in the interaction with human factor H and secretory immunoglobulin A (sIgA). Since linear epitopes of PspA were not protective, larger overlapping fragments containing 100 amino acids of PspA of strain Rx1 were constructed (fragments 1 to 7, numbered from the N terminus) to permit the mapping of antibodies with conformational epitopes not represented in the peptide arrays. Antibodies from mice immunized with fragments 1, 2, 4, and 5 were capable of binding onto the surface of pneumococci and mediating protection against a lethal challenge. The fact that immunization of mice with 100-amino-acid fragments located at the more conserved N-terminal region of PspA (fragments 1 and 2) induced protection against a pneumococcal challenge indicates that the induction of antibodies against conformational epitopes present at this region may be important in strategies for inducing broad protection against pneumococci.

show abstract

Section: Discussionmentioning

confidence: 99%

Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC

Vadesilho

Ferreira

Gordon

et al. 2014

Clin. Vaccine Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…To determine if lactoferrin, a molecule known to be bactericidal for S. pneumoniae (39,58), is responsible for the bactericidal activity we observed with S. pneumoniae, we first determined if the strain we were working with was susceptible to lactoferrin-mediated bactericidal activity. Specifically, 1 ϫ 10 6 organisms were resuspended and incubated in Hanks balanced salt solution (HBSS; Gibco) containing 2% FBS, alone or with 10 g/ml polyclonal rabbit anti-PspA antibody for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Mucosal Immunization with an Unadjuvanted Vaccine That Targets Streptococcus pneumoniae PspA to Human Fcγ Receptor Type I Protects against Pneumococcal Infection through Complement- and Lactoferrin-Mediated Bactericidal Activity

Bitsaktsis

Iglesias

et al. 2012

Infect Immun

Self Cite

View full text Add to dashboard Cite

Targeting an antigen to Fc receptors (FcR) can enhance the immune response to the antigen in the absence of adjuvant. Furthermore, we recently demonstrated that intranasal immunization with an Fc␥R-targeted antigen enhances protection against a category A intracellular mucosal pathogen, Francisella tularensis. To determine if a similar strategy could be applied to the important pathogen Streptococcus pneumoniae, we used an improved mucosal FcR-targeting strategy that specifically targets human Fc␥R type I (hFc␥RI). A humanized single-chain antibody component in which the variable domain binds to hFc␥RI [antihFc␥RI (H22)] was linked in a fusion protein with the pneumococcal surface protein A (PspA). PspA is known to elicit protection against pneumococcal sepsis, carriage, and pneumonia in mouse models when administered with adjuvants. Anti-hFc␥RI-PspA or recombinant PspA (rPspA) alone was used to intranasally immunize wild-type (WT) and hFc␥RI transgenic (Tg) mice in the absence of adjuvant. The hFc␥RI Tg mice receiving anti-hFc␥RI-PspA exhibited elevated S. pneumoniae-specific IgA, IgG2c, and IgG1 antibodies in serum and bronchoalveolar lavage fluid. Neither immunogen was effective in protecting WT mice in the absence of adjuvant, but when PspA was targeted to hFc␥RI as the anti-hFc␥RI-PspA fusion, enhanced protection against lethal S. pneumoniae challenge was observed in the hFc␥RI Tg mice compared to mice given nontargeted rPspA alone. Immune sera from the anti-hFc␥RI-PspA-immunized Tg mice showed enhanced complement C3 deposition on bacterial surfaces, and protection was dependent upon an active complement system. Immune serum also showed an enhanced bactericidal activity directed against S. pneumoniae that appears to be lactoferrin mediated.

show abstract

“…Unbound lactoferrin (apolactoferrin) also has direct bactericidal properties, independent of iron scavenging, toward various pathogens, including S. pneumoniae (20,21,447). The mechanism by which apolactoferrin destroys bacteria is not completely clear, but it appears to disrupt the bacterial cell, leading to cell lysis (446). Lactoferrin is also present in neutrophils and may enhance bacterial phagocytosis and killing (140).…”

Section: Host Mucosal Immune Systemmentioning

confidence: 99%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

View full text Add to dashboard Cite

SUMMARY Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae , which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

show abstract

Structure of a Complex of Human Lactoferrin N-lobe with Pneumococcal Surface Protein A Provides Insight into Microbial Defense Mechanism

Cited by 70 publications

References 61 publications

Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC

Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC

Mucosal Immunization with an Unadjuvanted Vaccine That Targets Streptococcus pneumoniae PspA to Human Fcγ Receptor Type I Protects against Pneumococcal Infection through Complement- and Lactoferrin-Mediated Bactericidal Activity

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Contact Info

Product

Resources

About