A5091537431- Bacterial Infections and Vaccines
- Complement system in diseases
- Reproductive tract infections research
- Pneumonia and Respiratory Infections
- Neonatal and Maternal Infections
- Transgenic Plants and Applications
- Monoclonal and Polyclonal Antibodies Research
- Streptococcal Infections and Treatments
- Blood groups and transfusion
- Escherichia coli research studies
- Trypanosoma species research and implications
- Influenza Virus Research Studies
- Glycosylation and Glycoproteins Research
- Research on Leishmaniasis Studies
- Neonatal Respiratory Health Research
- Syphilis Diagnosis and Treatment
- Retinal Diseases and Treatments
- Peptidase Inhibition and Analysis
- Neuroscience of respiration and sleep
- Galectins and Cancer Biology
- Plant Virus Research Studies
- Gene expression and cancer classification
- Antimicrobial Resistance in Staphylococcus
- Burkholderia infections and melioidosis
- Geochemistry and Elemental Analysis
University of Massachusetts Chan Medical School
2016-2025
University of Oxford
1977
Certain pathogens recruit host complement inhibitors such as factor H (fH) to evade the immune system. Microbial inhibitor-binding molecules can be promising vaccine targets by eliciting Abs that neutralize this microbial defense mechanism. One Ag, meningococcal H-binding protein (fHbp), was used in clinical trials before discovered bind fH. The potential effect of fH binding on immunogenicity had not been assessed experimental animals because fHbp binds human specifically. In study, we...
Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life a commercially competitive differentiator affecting dosing, frequency administration and thereby potentially patient compliance. Here, we report on Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances mucosal distribution, as well allows for needle-free delivery across...
Multidrug-resistant Neisseria gonorrhoeae is a global health problem. Monoclonal antibody (mAb) 2C7 recognizes gonococcal lipooligosaccharide epitope that expressed by >95% of clinical isolates and hastens vaginal clearance in mice. Chimeric mAb (human immunoglobulin G1 [IgG1]) with an E430G Fc modification enhances Fc:Fc interactions hexamerization following surface-target binding increases complement activation (HexaBody technology) showed significantly greater C1q engagement C4 C3...
ABSTRACT The identification of “factor H binding protein (fHbp)-null” invasive meningococcal isolates and the realization that widespread use fHbp-based vaccines could herald selection such strains prompted us to characterize novel mechanisms alternative pathway (AP) inhibition on meningococci. Of seven engineered lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, neisserial surface A (quadruple mutants), inhibited human AP-mediated C3...
The alternative pathway of the complement system is implicated in etiology age-related macular degeneration (AMD). Complement depletion with pegcetacoplan and avacincaptad pegol are FDA-approved treatments for geographic atrophy AMD that, while effective, have clinically observed risks choroidal neovascular (CNV) conversion, optic neuritis, retinal vasculitis, leaving room other equally efficacious but safer therapeutics, including Poly Sialic acid (PSA) nanoparticle (PolySia-NP)-actuated...
Little is known about sialic acids of the human retina, despite their integral role in self/non-self-discrimination by complement factor H (CFH), alternative pathway inhibitor. A custom sialoglycan microarray was used to characterize acid-binding specificity native CFH or recombinant molecules where IgG Fc fused domains 16-20 (contains a site), 6-7 glycosaminoglycan-binding site) CFH-related proteins (CFHRs) 1 and 3. We analyzed macular peripheral retinal tissue from post-mortem ocular...
Streptococcus pyogenes, also known as Group A (GAS), is an important human bacterial pathogen that can cause invasive infections. Once it colonizes its exclusively host, GAS needs to surmount numerous innate immune defense mechanisms, including opsonization by complement and consequent phagocytosis. Several strains of bind human-specific inhibitors, C4b-binding protein (C4BP) and/or Factor H (FH), curtail C3 (a critical opsonin) deposition. This results in diminished activation phagocytes...
Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine urgently needed. Lipooligosaccharide (LOS), the abundant outer membrane molecule, indispensable for gonococcal pathogenesis. glycan epitope on LOS that recognized by monoclonal antibody (MAb) 2C7 (called epitope) expressed almost universally gonococci in vivo . Previously, we identified a peptide mimic (mimitope) epitope, which...
The binding of human complement inhibitors to vaccine antigens in vivo could diminish their immunogenicity. A meningococcal ligand for the down-regulator, factor H (fH), is fH-binding protein (fHbp), which specific fH. Vaccines containing recombinant fHbp or native outer membrane vesicles (NOMV) from mutant strains with over-expressed are clinical development. In a previous study transgenic mice, presence fH impaired immunogenicity vaccine. present study, we prepared two NOMV vaccines group...
ABSTRACT Neisseria meningitidis binds the complement downregulating protein, factor H (fH), which enables organism to evade host defenses. Two fH ligands, fHbp and NspA, are known bind specifically human fH. We developed a transgenic infant rat model investigate effect of on meningococcal bacteremia. At 18 h after intraperitoneal challenge with 560 CFU group B strain H44/76, all 19 fH-positive rats had positive blood cultures compared 0 7 fH-negative control littermates ( P < 0.0001)....
Abstract Neisseria gonorrhoeae, the causative agent of sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need develop novel therapies against gonorrhea. Many pathogens, including N. bind complement inhibitor factor H (FH) evade complement-dependent killing. Sialylation gonococcal lipooligosaccharide, as occurs in vivo, augments binding human FH through its domains 18–20 (FH18–20). We explored use fusing FH18–20 with...
Gonorrhea has become resistant to most conventional antimicrobials used in clinical practice. The global spread of multidrug-resistant isolates Neisseria gonorrhoeae could lead an era untreatable gonorrhea. New therapeutic modalities with novel mechanisms action that do not lend themselves the development resistance are urgently needed. Gonococcal lipooligosaccharide (LOS) sialylation is critical for complement and establishing infection humans experimental mouse models. Here we describe two...
ABSTRACT The emergence of antimicrobial resistance among several medically important pathogens represents a serious threat to human health globally and necessitates the development novel therapeutics. Complement forms key arm innate immune defenses against invading pathogens. A mechanism complement evasion employed by many is binding inhibitors, including factor H (FH), downregulator alternative pathway. Most FH-binding bacteria engage FH through regions in spanned domains 6 7 and/or 18 20....
Complement is a tightly controlled arm of the innate immune system, facilitating phagocytosis and killing invading pathogens. Factor H (FH) main fluid-phase inhibitor alternative pathway. Many pathogens can hijack FH from host protect themselves complement-dependent killing. Candida albicans clinically important opportunistic yeast, expressing different binding molecules on its cell surface, which allow complement evasion. One such molecule transmembrane protein "High affinity glucose...
Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack binding of the inhibitor C4b-binding protein (C4BP). We screened 107 porin B1a (PorB1a) and 83 PorB1b clinical isolates randomly selected from Swedish strain collection over last 10 years noted 96/107 (89.7%) PorB1a 16/83 (19.3%) bound C4BP; C4BP substantially...
Both Neisseria meningitidis and gonorrhoeae recruit the alternative pathway complement inhibitory protein factor H (fH) to their surfaces evade complement-dependent killing. Meningococci bind fH via binding (fHbp), a surface-exposed lipoprotein that is subdivided into three variant families based on one classification scheme. Chimeric proteins comprise contiguous domains of fused murine Fc were used localize site for all fHbp variants short consensus repeat 6 (SCR 6). As expected, fH-like 1...
Nontypeable Haemophilus influenzae (NTHi) cause a range of illnesses including otitis media, sinusitis, and exacerbation chronic obstructive pulmonary disease, infections that contribute to the problem antibiotic resistance are themselves often intractable standard treatment regimens. We investigated strategy exploit binding complement inhibitor Factor H (FH) NTHi as functional target for an immunotherapeutic containing domain FH fused Fc IgG1. Chimeric proteins regions most FH-binding...
Abstract Streptococcus pyogenes is an exclusively human pathogen that can provoke mild skin and throat infections but also cause fatal septicemia. This gram-positive bacterium has developed several strategies to evade the immune system, enabling S. survive in host. These include recruiting plasma proteins, such as complement inhibitor, C4b-binding protein (C4BP), (hu)-IgG through its Fc region bacterial surface recognition. We identified a novel virulence mechanism whereby IgG-enhanced...
Vaccines to curb the global spread of multidrug-resistant gonorrhea are urgently needed. Here, 26 vaccine candidates identified by an artificial intelligence-driven platform (Efficacy Discriminative Educated Network[EDEN]) were screened for efficacy in mouse vaginal colonization model. Complement-dependent bactericidal activity antisera and EDEN protective scores both correlated positively with reduction overall bacterial burden. NGO1549 (FtsN) NGO0265, involved cell division, displayed best...
Abstract Bacteria can cause life-threatening infections, such as pneumonia, meningitis, or sepsis. Antibiotic therapy is a mainstay of treatment, although antimicrobial resistance has drastically increased over the years. Unfortunately, safe and effective vaccines against most pathogens have not yet been approved, thus developing alternative treatments important. We analyzed efficiency factor H (FH)6-7/Fc, novel antibacterial immunotherapeutic protein Gram-positive bacterium Streptococcus...
Meningococcal factor H-binding protein (fHbp) is a promising antigen that part of two vaccines in clinical development. The specifically binds human complement H (fH), which downregulates activation on the bacterial surface and enables organism to evade host defenses. In humans, vaccine forms complex with fH, may affect anti-fHbp antibody repertoire decrease serum bactericidal activity by covering important fHbp epitopes. recent study, residues contact fH were identified from crystal...