Presentation Title

Evasion of Complement System Immune Response by Neisseria Meningitidis, through the Formation of the Factor H – Factor H Binding Protein Complex

Faculty Mentor

Dimitrios Morikis

Start Date

17-11-2018 8:30 AM

End Date

17-11-2018 10:30 AM

Location

HARBESON 19

Session

POSTER 1

Type of Presentation

Poster

Subject Area

engineering_computer_science

Abstract

Neisseria meningitidis, the leading cause of bacterial meningitis and septic shock, proliferates by disguising itself and manipulating the host’s immune system. The complement system, part of the innate immune system, comprises of a large number of plasma proteins that participate in cascades of biochemical reaction pathways leading to attack against foreign pathogens. The end-results of complement activation are inflammation, opsonophagocytosis, and bacterial cell lysis. Factor H (fH), a modular plasma regulator of the complement system, protects host tissues from complement attack by deactivating key complement proteins. Neisseria m. sequesters fH to its surface through a receptor called factor H binding protein (fHbp). This results to (i) evasion of complement-mediated attack because fH, typically acting on host surfaces, can regulate complement on bacterial surfaces as well, and (ii) decrease of circulating fH levels in the plasma, causing susceptibility of host cells to complement-mediated damage. Previous research has identified modules 6 and 7 of fH to be sites of high affinity interaction with fHbp. Given the high content of polar amino acids at the fH-fHbp interface, we hypothesized that electrostatic interactions are important in driving this protein-protein complex formation. To explore this hypothesis, we performed molecular modeling and Poisson-Boltzmann electrostatic calculations using two different strains of fHbp. We utilized biomolecular modeling software, Chimera, to visualize the crystallographic structures of the protein complexes and to identify polar/non-polar intermolecular pairwise amino acid interactions. We also utilized AESOP (Analysis of Electrostatic Structures Of Proteins), a computational python framework to evaluate contributions of each ionizable amino acid to binding through alanine scans and directed mutagenesis. Consistent with our hypothesis, the results indicate strong electrostatic contributions to formation of the binding interface, including the presence of an unusually large number of participating histidines. This study further suggests that fHbp may be a strong antigen for N. meningitidis.

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Nov 17th, 8:30 AM Nov 17th, 10:30 AM

Evasion of Complement System Immune Response by Neisseria Meningitidis, through the Formation of the Factor H – Factor H Binding Protein Complex

HARBESON 19

Neisseria meningitidis, the leading cause of bacterial meningitis and septic shock, proliferates by disguising itself and manipulating the host’s immune system. The complement system, part of the innate immune system, comprises of a large number of plasma proteins that participate in cascades of biochemical reaction pathways leading to attack against foreign pathogens. The end-results of complement activation are inflammation, opsonophagocytosis, and bacterial cell lysis. Factor H (fH), a modular plasma regulator of the complement system, protects host tissues from complement attack by deactivating key complement proteins. Neisseria m. sequesters fH to its surface through a receptor called factor H binding protein (fHbp). This results to (i) evasion of complement-mediated attack because fH, typically acting on host surfaces, can regulate complement on bacterial surfaces as well, and (ii) decrease of circulating fH levels in the plasma, causing susceptibility of host cells to complement-mediated damage. Previous research has identified modules 6 and 7 of fH to be sites of high affinity interaction with fHbp. Given the high content of polar amino acids at the fH-fHbp interface, we hypothesized that electrostatic interactions are important in driving this protein-protein complex formation. To explore this hypothesis, we performed molecular modeling and Poisson-Boltzmann electrostatic calculations using two different strains of fHbp. We utilized biomolecular modeling software, Chimera, to visualize the crystallographic structures of the protein complexes and to identify polar/non-polar intermolecular pairwise amino acid interactions. We also utilized AESOP (Analysis of Electrostatic Structures Of Proteins), a computational python framework to evaluate contributions of each ionizable amino acid to binding through alanine scans and directed mutagenesis. Consistent with our hypothesis, the results indicate strong electrostatic contributions to formation of the binding interface, including the presence of an unusually large number of participating histidines. This study further suggests that fHbp may be a strong antigen for N. meningitidis.