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Principal Investigator: Edward M. Schwarz
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2022
Award: $274,504
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Abstract
Osteomyelitis is the bane of orthopaedic surgery, of which the majority is caused by Staphylococcus aureus.
Prior to this P50 Center of Research Translation on the Osteoimmunology of Bone Infection
(CoRTOBI), it was known that these rare infections following elective surgery (~1%), and our inability to control
them (~40% reinfection rate), are due to specific host-pathogen interactions. While co-morbidities associated
with infection were also known, the roles of adaptive immunity and S. aureus strain on clinical outcome had yet
to be studied. Thus, Project 2 of CoRTOBI tested this using custom multiplex immunoassays, whole genome
sequencing (WGS), animal models, and the AO-CPP Bone Infection Registry of 297 patients with confirmed S.
aureus infection. The results formally established anti-Gmd antibodies as protective and anti-IsdB antibodies
as susceptible determinants of the immune proteome, and that virtually all people have a susceptible immune
proteome. Thus, we now hypothesize that: 1) there is a defect in anti-Gmd vs. anti-IsdB antibody secreting B
cells, plasmablasts and/or long-lived plasma cells (LLPCs) that is responsible for the native susceptible
immune proteome. 2) S. aureus strain specific factors contribute to susceptible immune proteome genesis.
And, 3) multivalent nanoparticle mRNA vaccines can reverse the susceptible immune proteome. Three
Specific Aims are proposed for Project 2 in this CoRTOBI renewal. In Aim 1 we will elucidate the mechanism
of susceptible anti-S. aureus immune proteome genesis by quantifying anti-Gmd vs. anti-IsdB specific B cells
and plasmablasts in blood, and LLPCs in bone marrow, in experimental mice and patients with S. aureus bone
infections versus uninfected healthy controls. In Aim 2 we will complete WGS of the 297 S. aureus strains in
the AO-CPP registry, and identify unique genes in the strains associated with the worst clinical outcomes. And
in Aim 3 we will demonstrate the efficacy of multivalent mRNA nanoparticle vaccines to overcome the
susceptible immune proteome against S. aureus, and protect mice from implant-associated osteomyelitis. In
addition to Gmd, we have also demonstrated that anti-Amd, Hla, CHIPS & SCIN antibodies are significantly
associated with infection control in osteomyelitis patients. Given the historic success of mRNA nanoparticle
vaccines during the COVID-19 pandemic, we will use this technology to develop candidate vaccines for the five
antigens. Dose response studies will be performed for monovalent vaccines to determine the minimal mRNA
concentration that can induce antibodies >10ng/ml in sera. Then the efficacy of the mono and multivalent
vaccines will be tested against the most virulent S. aureus strains in the AO-CPP registry using our
prophylactic and therapeutic murine models of implant-associate osteomyelitis. Overall Impact: We will
identify the mechanism responsible for the susceptible immune proteome, establish candidate mRNA vaccines
with potential to overcome it, and add S. aureus strain variables into our multiparametric nomogram for pre-op
treatment response prediction, which could be used for personalized prophylaxis and treatments.
Terms: <Animal Model><Animal Models and Related Studies><Antibodies><Antibody-Secreting Cells><Antigens><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biologic Assays><Biological Assay><Biological Markers><Blood><Blood Plasma Cell><Blood Reticuloendothelial System><Bone Infection><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><Clinical><Clinical Treatment Moab><Cross-Product Ratio><Custom><DNA seq><DNA sequencing><DNAseq><Defect><Dose><ED patient><ER patient><Emergency Department patient><Emergency Room patient><Fe element><Funding><Genes><Glucosaminidase><Goals><Host Factor><Host Factor Protein><Immune><Immunes><Immunoassay><Immunochemical Immunologic><Immunoglobulin-Secreting Cells><Immunologic><Immunologic Tests><Immunological><Immunological Tests><Immunologically><Immunologics><Implant><Infection><Infection Control><Integration Host Factors><Iron><MRSA><Messenger RNA><Methicillin Resistant S Aureus><Methicillin Resistant S. Aureus><Methods><Mice><Mice Mammals><Modeling><Monoclonal Antibodies><Murine><Mus><Nomograms><Odds Ratio><Operative Procedures><Operative Surgical Procedures><Orthopedic Surgery><Osteomyelitis><Outcome><Paper><Pathogenicity Factors><Patients><Persons><Plasma Cells><Plasmablast><Plasmacytes><Population><Prediction of Response to Therapy><Predisposition><Prophylactic treatment><Prophylaxis><Proteome><RNA vaccine><RNA-based vaccine><Registries><Relative Odds><Research><Risk Factors><Risk Ratio><Role><S aureus><S. aureus><S. aureus infection><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Staph aureus><Staph aureus infection><Staphylococcus aureus><Staphylococcus aureus infection><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><Technology><Testing><Therapeutic><Time><Translational Research><Translational Science><Trauma><Vaccines><Virulence Factors><Virulent><Work><adaptive immunity><adverse consequence><adverse outcome><bio-markers><biologic marker><biomarker><co-morbid><co-morbidity><comorbidity><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><entire genome><experience><full genome><genome sequencing><immunogen><infected with S. aureus><infected with Staph aureus><infected with Staphylococcus aureus><infection rate><mAbs><mRNA><mRNA vaccine><mRNA-based vaccine><methicillin resistant Staphylococcus aureus><methicillin-resistant S. aureus><model of animal><model organism><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><osteoimmunology><pathogen><plasmocyte><predict therapeutic response><predict therapy response><predict treatment response><prognostic><prophylactic><rate of infection><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><success><surgery><therapy prediction><translation research><treatment prediction><treatment response prediction><vaccine candidate><virtual><whole genome>