Ofer Levy | Harvard Medical School (original) (raw)

Papers by Ofer Levy

Research paper thumbnail of Proteomics on longitudinal serum samples differentiates localized and disseminated Lyme disease

Lyme disease (LD) is the most prevalent vector-borne disease in North America, with ~300,000 new ... more Lyme disease (LD) is the most prevalent vector-borne disease in North America, with ~300,000 new cases annually in the USA alone. LD is most often recognized by the appearance of the skin lesion erythema migrans (EM) at the tick bite site but also can present with signs of disseminated infection manifesting as multiple EM lesions and/or involvement of the heart, nervous system or joints. In this study, we examined the serum proteome of study participants presenting with either a single EM (localized LD) or early disseminated infection (disseminated LD). Samples collected at the time of diagnosis and at convalescent time points were assessed using our in-house developed MStern blotting-based serum proteomics platform. After technical validation of our platform, the temporal analysis from diagnosis to clinical resolution of the infection demonstrates LD stage-associated pathways activation such as a temporary upregulation of acute phase response specific to the participants with disseminated LD. In addition, we identified the members of the serum amyloid A protein family as potentially promising candidate biomarkers to identify those with disseminated LD. The results of this pilot study demonstrate the feasibility of using our timeand cost-effective sample sparing MStern blotting-based serum proteomics platform to efficiently interrogate proteome changes over time in those suffering infections such as LD. These observations establish a new approach to human serum proteomics, provide fresh insight into the host immune responses associated with disease severity (localized versus disseminated infection) and suggest novel biomarker candidate panels for LD stages. Importance We investigated the proteome changes of Borrelia burgdorferi-infected participants with either a single erythema migrans or early disseminated Lyme disease infection. Using our in-house time

Research paper thumbnail of Genetic Screening for Susceptibility to Infection in the NICU Setting: Commentary on the article by Ahrens et al. on page 652

Pediatric Research, Apr 1, 2004

Research paper thumbnail of Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines

Pediatric Research, Nov 6, 2013

nature publishing group Unique features of immunity early in life include a distinct immune syste... more nature publishing group Unique features of immunity early in life include a distinct immune system particularly reliant on innate immunity, with weak T helper (Th)1-polarizing immune responses, and impaired responses to certain vaccines leading to a heightened susceptibility to infection. To these important aspects, we now add an increasingly appreciated concept that the innate immune system displays epigenetic memory of an earlier infection or vaccination, a phenomenon that has been named "trained immunity. " Exposure of neonatal leukocytes in vitro or neonatal animals or humans in vivo to specific innate immune stimuli results in an altered innate immune set point. Given the particular importance of innate immunity early in life, trained immunity to early life infection and/or immunization may play an important role in modulating both acute and chronic diseases.

Research paper thumbnail of A Neutrophil-Derived Anti-Infective Molecule: Bactericidal/Permeability-Increasing Protein

Antimicrobial Agents and Chemotherapy, Nov 1, 2000

Research paper thumbnail of Reduced Steroid Metabolites Identify Infection-Prone Children in Two Independent Pre-Birth Cohorts

Metabolites, Nov 13, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Elevated third trimester corticosteroid levels are associated with fewer offspring infections

Scientific Reports, Jun 28, 2023

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurren... more Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquidchromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10-7 to 0.002) and improved lung function metrics (P = 0.020-0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life. Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226. Abbreviations BMI Body mass index COPSAC Copenhagen prospective studies on asthma in childhood EDTA Ethylenediaminetetraacetic acid FDR False discovery rate

Research paper thumbnail of SARS-CoV-2 mRNA Vaccine Attitudes as Expressed in U.S. FDA Public Commentary: Need for a Public-Private Partnership in a Learning Immunization System

Frontiers in Public Health, Jul 16, 2021

As part of the U.S. Food and Drug Administration COVID-19 vaccine review process, public commenta... more As part of the U.S. Food and Drug Administration COVID-19 vaccine review process, public commentary was solicited offering an opportunity to reflect on vaccine attitudes that may impact the uptake of coronavirus vaccines. We identified themes in the commentary that highlighted the safety, efficacy, ethics, and trustworthiness and transparency regarding the novel mRNA COVID-19 vaccines. A "Learning Immunization System" model is proposed to optimize public, private, and academic partnerships relating to vaccine development and implementation.

Research paper thumbnail of Longitudinal serum proteomics analyses identify unique and overlapping host response pathways in Lyme disease and West Nile virus infection

Frontiers in Immunology

Advancement in proteomics methods for interrogating biological samples has helped identify diseas... more Advancement in proteomics methods for interrogating biological samples has helped identify disease biomarkers for early diagnostics and unravel underlying molecular mechanisms of disease. Herein, we examined the serum proteomes of 23 study participants presenting with one of two common arthropod-borne infections: Lyme disease (LD), an extracellular bacterial infection or West Nile virus infection (WNV), an intracellular viral infection. The LC/MS based serum proteomes of samples collected at the time of diagnosis and during convalescence were assessed using a depletion-based high-throughput shotgun proteomics (dHSP) pipeline as well as a non-depleting blotting-based low-throughput platform (MStern). The LC/MS integrated analyses identified host proteome responses in the acute and recovery phases shared by LD and WNV infections, as well as differentially abundant proteins that were unique to each infection. Notably, we also detected proteins that distinguished localized from dissemin...

Research paper thumbnail of The Immune Signatures Data Resource: A compendium of systems vaccinology datasets

Vaccines are among the most cost-effective public health interventions for preventing infection-i... more Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern ‘omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository1,2. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effe...

Research paper thumbnail of Ensuring vaccine safety

Science, 2020

Comprehensive safety testing is based on experience with prior vaccines

Research paper thumbnail of Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for Candida albicans Cell Wall Maintenance

mBio, 2020

Candida species cause hundreds of thousands of invasive infections with high mortality each year.... more Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans . Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.

Research paper thumbnail of A Prime Time for Trained Immunity: Innate Immune Memory in Newborns and Infants

Neonatology, Dec 18, 2013

'nonspecific' response to foreign antigens. The concept whereby a prior exposure to an immune sti... more 'nonspecific' response to foreign antigens. The concept whereby a prior exposure to an immune stimulus might result in augmentation of innate immune function upon subsequent exposure to the same or a different stimulus was described in humans nearly 50 years ago [1]. Netea et al. [2] recently coined the term 'trained immunity' to specifically describe enhancement of innate immune function with reinfection; the development of innate immune memory. A trained innate immune response to a subsequent challenge has likely existed for millions of years in plants and invertebrates, both of which lack a classic adaptive immune system [3, 4]. In plants, the process by which protection against reinfection is mediated is termed systemic acquired resistance. Epigenetic reprogramming through specific histone acetylation (H3K9) is vital for this effect [5]. Because adaptive immunity is largely restricted to vertebrates, invertebrates represent excellent sources to look for the presence or absence of trained immunity [6]. Midgut barrier disruption by Plasmodium in Anopheles gambiae resulted in differentiation of hemocytes to an abundance of granulocytes associated with enhanced bacterial immunity that resulted in protection against reinfection with Plasmodium [3]. The mealworm beetle exhibited enhanced protection against antigenically unrelated secondary infection following lipopolysaccharide or bacterial priming [7]. These are but a few examples of many

Research paper thumbnail of Isolation of two isoforms of a novel 15-kDa protein from rabbit polymorphonuclear leukocytes that modulate the antibacterial actions of other leukocyte proteins

Journal of Biological Chemistry, Sep 1, 1990

Research paper thumbnail of Correction: Human alkaline phosphatase dephosphorylates microbial products and is elevated in preterm neonates with a history of late-onset sepsis

PLOS ONE, May 10, 2018

There is an error in the XML that is causing the seventh author's name, Jose Luis Millan, to be i... more There is an error in the XML that is causing the seventh author's name, Jose Luis Millan, to be indexed incorrectly. The name should be indexed as Millan, Jose Luis.

Research paper thumbnail of Human Blood Plasma Shapes Distinct Neonatal TLR-Mediated Dendritic Cell Activation via Expression of the MicroRNA Let-7g

ImmunoHorizons, Apr 1, 2021

Research paper thumbnail of Shaping neonatal immunization by tuning delivery of synergistic adjuvants via nanocarriers

bioRxiv (Cold Spring Harbor Laboratory), Jun 5, 2022

Research paper thumbnail of Precision Vaccines: Lessons Learned From the Coronavirus Pandemic

Clinical Infectious Diseases, Apr 19, 2022

Research paper thumbnail of Potential Therapeutic Intervention Suggested by Profound Deficiency of Neutrophil-Derived Bactericidal/Permeability-Increasing Protein (BPI) and Other Alterations in LPS-Directed Innate Immunity after Myeloablative Hematopoietic Stem Cell Transplantation (HSCT)

Blood, Nov 16, 2006

Myeloablative conditioning used for allogeneic HSCT damages the gut resulting in leakage of lipop... more Myeloablative conditioning used for allogeneic HSCT damages the gut resulting in leakage of lipopolysaccharide (LPS, or endotoxin) into the circulation. LPS activates antigen-presenting cells to secrete inflammatory cytokines, including TNF, that enhance donor T cell responses to alloantigens. The relationship of TNF production and responsiveness to aGVHD and HSCT mortality has been demonstrated in animal models and with human correlative data. Use of either TNF or LPS antagonists in animal models or mice deficient in TNF or LPS responsiveness has led to profound amelioration of aGVHD. To determine whether LPS antagonists might have a therapeutic role in allogeneic HSCT, we measured plasma levels of 3 soluble LPS-modulating proteins in 30 sibling donor:recipient pairs undergoing myeloablative HSCT. Measurements included: 1) BPI, a constituent of neutrophil primary (azurophilic) granules with potent LPS-neutralizing activity at nanomolar concentrations in all body fluids, 2) LPS-binding protein (LBP) and 3) soluble CD14 (sCD14), which are both acute phase reactants that at basal levels enhance LPS activity by delivering LPS to its cell surface receptor but that at high levels detoxify LPS by delivering it to plasma lipoproteins. Spontaneous TNF production by whole blood and monocyte surface expression of TLR4, a key component of the LPS receptor, were also measured. Peripheral blood was obtained from donors (single time point) and patients pre-HSCT (baseline), Days 0, 7, 14, 21, 28 and on day of aGVHD. Plasma BPI levels fall dramatically from baseline, concurrent with severe neutropenia, while LBP (D7) and then sCD14 (D21–28) rise. Monocyte TLR4 expression was elevated at D7 and at onset of aGVHD. Patients with high spontaneous TNF production were at higher risk of aGVHD (p

Research paper thumbnail of Myeloablative Hematopoietic Stem Cell Transplantation (HSCT) Is Accompanied by Endotoxemia, Activation of Endotoxin-Directed Innate Immunity, and Deficiency of Endogenous Proteins That Limit Endotoxin- Induced TNF Production

Blood, Nov 16, 2008

Background: HSCT is an important treatment modality complicated by a number of immune-mediated to... more Background: HSCT is an important treatment modality complicated by a number of immune-mediated toxicities, including acute graft vs host disease (aGVHD). In animal HSCT models, endotoxemia-induced production of TNF contributes to development of inflammatory regimen related toxicity and aGVHD. We tested the hypothesis that in human HSCT, myeloablative chemoradiotherapy regimens contribute to the early development of both endotoxemia and profound deficiency in host defense molecules that normally serve to inhibit endotoxin signaling, effects that may activate endotoxin–directed innate immunity and contribute to development of toxicities including aGVHD. Methods: Peripheral blood was obtained prospectively from HSCT recipients (N =35) at Baseline (B) prior to the start of conditioning, Days 0 (Day of HSCT), 7, 14, 21, and 28 and from their HSCT donors. Results on soluble biomarkers were also validated with frozen plasma samples from a retrospective HSCT cohort (N=21). Plasma was analyzed for endotoxin (Limulus amobocyte lysate and endotoxin activity assays), endotoxin-interactive proteins: bactericidal/permeability-increasing protein (BPI), LPS-binding protein (LBP), soluble CD14 (sCD14) and soluble MD-2 (sMD-2), as well as chemokine ligand 5 (CCL5)/Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), chemokines that inhibit Toll-like receptor-4 (TLR4)-mediated TNF and IL-6 production. Monocyte expression of LPS-receptor components mCD14 and TLR4 was measured by flow cytometry. Whole blood RNA was isolated for analysis of TLR transcriptome activation using quantitative real-time PCR. Findings: During myeloablative HSCT, endotoxemia was detectable by two independent methods (LAL and EAA) and was accompanied by a profound deficiency in plasma concentrations of BPI and RANTES that fell &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10-fold from baseline (B) to D7 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). At Day 0, monocyte surface expression of mCD14 fell and TLR4 increased (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and selective activation of a TLR pathway transcriptional response was detected in whole blood, suggesting early exposure to bioactive endotoxin. Febrile neutropenia was accompanied by a 10-fold decline by D7 in plasma concentrations of BPI and CCL5/RANTES and increased IL-6, consistent with an acute phase response. Subsequently, levels of endotoxin-modulating proteins LBP (D7–14) and sCD14 (D7, 21, and 28) increased (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Spontaneous TNF production was inversely correlated with plasma CCL2/MCP- 1, a chemokine known to inhibit TLR4-mediated TNF. Low plasma concentrations of RANTES/CCL5 (D0 and D7) significantly correlated with subsequent risk of aGVHD (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Interpretation: During myeloablative HSCT, endotoxemia occurs in the context of deficient BPI and RANTES, potentially contributing to TLR4-mediated production of TNF and consequent inflammatory sequelae, including aGVHD. Therefore, therapies aimed at enhancing endotoxin-neutralization, such as replenishment of deficient endotoxin antagonists, may be effective approaches to reduce toxicities associated with myeloablative HSCT. We are investigating this hypothesis in an ongoing phase I/II clinical trial of intravenous administration of the endotoxin-neutralizing anti-infective protein rBPI21 (Opebecan; XOMA (US) LLC) to reduce inflammatory, regimen-related toxicity in patients undergoing myeloablative HSCT.

Research paper thumbnail of Precision Vaccine Adjuvants for Older Adults: A Scoping Review

Clinical Infectious Diseases, Apr 19, 2022

Research paper thumbnail of Proteomics on longitudinal serum samples differentiates localized and disseminated Lyme disease

Lyme disease (LD) is the most prevalent vector-borne disease in North America, with ~300,000 new ... more Lyme disease (LD) is the most prevalent vector-borne disease in North America, with ~300,000 new cases annually in the USA alone. LD is most often recognized by the appearance of the skin lesion erythema migrans (EM) at the tick bite site but also can present with signs of disseminated infection manifesting as multiple EM lesions and/or involvement of the heart, nervous system or joints. In this study, we examined the serum proteome of study participants presenting with either a single EM (localized LD) or early disseminated infection (disseminated LD). Samples collected at the time of diagnosis and at convalescent time points were assessed using our in-house developed MStern blotting-based serum proteomics platform. After technical validation of our platform, the temporal analysis from diagnosis to clinical resolution of the infection demonstrates LD stage-associated pathways activation such as a temporary upregulation of acute phase response specific to the participants with disseminated LD. In addition, we identified the members of the serum amyloid A protein family as potentially promising candidate biomarkers to identify those with disseminated LD. The results of this pilot study demonstrate the feasibility of using our timeand cost-effective sample sparing MStern blotting-based serum proteomics platform to efficiently interrogate proteome changes over time in those suffering infections such as LD. These observations establish a new approach to human serum proteomics, provide fresh insight into the host immune responses associated with disease severity (localized versus disseminated infection) and suggest novel biomarker candidate panels for LD stages. Importance We investigated the proteome changes of Borrelia burgdorferi-infected participants with either a single erythema migrans or early disseminated Lyme disease infection. Using our in-house time

Research paper thumbnail of Genetic Screening for Susceptibility to Infection in the NICU Setting: Commentary on the article by Ahrens et al. on page 652

Pediatric Research, Apr 1, 2004

Research paper thumbnail of Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines

Pediatric Research, Nov 6, 2013

nature publishing group Unique features of immunity early in life include a distinct immune syste... more nature publishing group Unique features of immunity early in life include a distinct immune system particularly reliant on innate immunity, with weak T helper (Th)1-polarizing immune responses, and impaired responses to certain vaccines leading to a heightened susceptibility to infection. To these important aspects, we now add an increasingly appreciated concept that the innate immune system displays epigenetic memory of an earlier infection or vaccination, a phenomenon that has been named "trained immunity. " Exposure of neonatal leukocytes in vitro or neonatal animals or humans in vivo to specific innate immune stimuli results in an altered innate immune set point. Given the particular importance of innate immunity early in life, trained immunity to early life infection and/or immunization may play an important role in modulating both acute and chronic diseases.

Research paper thumbnail of A Neutrophil-Derived Anti-Infective Molecule: Bactericidal/Permeability-Increasing Protein

Antimicrobial Agents and Chemotherapy, Nov 1, 2000

Research paper thumbnail of Reduced Steroid Metabolites Identify Infection-Prone Children in Two Independent Pre-Birth Cohorts

Metabolites, Nov 13, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Elevated third trimester corticosteroid levels are associated with fewer offspring infections

Scientific Reports, Jun 28, 2023

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurren... more Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquidchromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10-7 to 0.002) and improved lung function metrics (P = 0.020-0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life. Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226. Abbreviations BMI Body mass index COPSAC Copenhagen prospective studies on asthma in childhood EDTA Ethylenediaminetetraacetic acid FDR False discovery rate

Research paper thumbnail of SARS-CoV-2 mRNA Vaccine Attitudes as Expressed in U.S. FDA Public Commentary: Need for a Public-Private Partnership in a Learning Immunization System

Frontiers in Public Health, Jul 16, 2021

As part of the U.S. Food and Drug Administration COVID-19 vaccine review process, public commenta... more As part of the U.S. Food and Drug Administration COVID-19 vaccine review process, public commentary was solicited offering an opportunity to reflect on vaccine attitudes that may impact the uptake of coronavirus vaccines. We identified themes in the commentary that highlighted the safety, efficacy, ethics, and trustworthiness and transparency regarding the novel mRNA COVID-19 vaccines. A "Learning Immunization System" model is proposed to optimize public, private, and academic partnerships relating to vaccine development and implementation.

Research paper thumbnail of Longitudinal serum proteomics analyses identify unique and overlapping host response pathways in Lyme disease and West Nile virus infection

Frontiers in Immunology

Advancement in proteomics methods for interrogating biological samples has helped identify diseas... more Advancement in proteomics methods for interrogating biological samples has helped identify disease biomarkers for early diagnostics and unravel underlying molecular mechanisms of disease. Herein, we examined the serum proteomes of 23 study participants presenting with one of two common arthropod-borne infections: Lyme disease (LD), an extracellular bacterial infection or West Nile virus infection (WNV), an intracellular viral infection. The LC/MS based serum proteomes of samples collected at the time of diagnosis and during convalescence were assessed using a depletion-based high-throughput shotgun proteomics (dHSP) pipeline as well as a non-depleting blotting-based low-throughput platform (MStern). The LC/MS integrated analyses identified host proteome responses in the acute and recovery phases shared by LD and WNV infections, as well as differentially abundant proteins that were unique to each infection. Notably, we also detected proteins that distinguished localized from dissemin...

Research paper thumbnail of The Immune Signatures Data Resource: A compendium of systems vaccinology datasets

Vaccines are among the most cost-effective public health interventions for preventing infection-i... more Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern ‘omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines, including those targeting seasonal influenza, yellow fever, and hepatitis B. These data are made available to the broader scientific community through the ImmuneSpace data portal and analysis engine leveraging the NIH/NIAID ImmPort repository1,2. However, a barrier to progress in this area is that comparative analyses have been limited by the distributed nature of some data, potential batch effe...

Research paper thumbnail of Ensuring vaccine safety

Science, 2020

Comprehensive safety testing is based on experience with prior vaccines

Research paper thumbnail of Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for Candida albicans Cell Wall Maintenance

mBio, 2020

Candida species cause hundreds of thousands of invasive infections with high mortality each year.... more Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans . Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.

Research paper thumbnail of A Prime Time for Trained Immunity: Innate Immune Memory in Newborns and Infants

Neonatology, Dec 18, 2013

'nonspecific' response to foreign antigens. The concept whereby a prior exposure to an immune sti... more 'nonspecific' response to foreign antigens. The concept whereby a prior exposure to an immune stimulus might result in augmentation of innate immune function upon subsequent exposure to the same or a different stimulus was described in humans nearly 50 years ago [1]. Netea et al. [2] recently coined the term 'trained immunity' to specifically describe enhancement of innate immune function with reinfection; the development of innate immune memory. A trained innate immune response to a subsequent challenge has likely existed for millions of years in plants and invertebrates, both of which lack a classic adaptive immune system [3, 4]. In plants, the process by which protection against reinfection is mediated is termed systemic acquired resistance. Epigenetic reprogramming through specific histone acetylation (H3K9) is vital for this effect [5]. Because adaptive immunity is largely restricted to vertebrates, invertebrates represent excellent sources to look for the presence or absence of trained immunity [6]. Midgut barrier disruption by Plasmodium in Anopheles gambiae resulted in differentiation of hemocytes to an abundance of granulocytes associated with enhanced bacterial immunity that resulted in protection against reinfection with Plasmodium [3]. The mealworm beetle exhibited enhanced protection against antigenically unrelated secondary infection following lipopolysaccharide or bacterial priming [7]. These are but a few examples of many

Research paper thumbnail of Isolation of two isoforms of a novel 15-kDa protein from rabbit polymorphonuclear leukocytes that modulate the antibacterial actions of other leukocyte proteins

Journal of Biological Chemistry, Sep 1, 1990

Research paper thumbnail of Correction: Human alkaline phosphatase dephosphorylates microbial products and is elevated in preterm neonates with a history of late-onset sepsis

PLOS ONE, May 10, 2018

There is an error in the XML that is causing the seventh author's name, Jose Luis Millan, to be i... more There is an error in the XML that is causing the seventh author's name, Jose Luis Millan, to be indexed incorrectly. The name should be indexed as Millan, Jose Luis.

Research paper thumbnail of Human Blood Plasma Shapes Distinct Neonatal TLR-Mediated Dendritic Cell Activation via Expression of the MicroRNA Let-7g

ImmunoHorizons, Apr 1, 2021

Research paper thumbnail of Shaping neonatal immunization by tuning delivery of synergistic adjuvants via nanocarriers

bioRxiv (Cold Spring Harbor Laboratory), Jun 5, 2022

Research paper thumbnail of Precision Vaccines: Lessons Learned From the Coronavirus Pandemic

Clinical Infectious Diseases, Apr 19, 2022

Research paper thumbnail of Potential Therapeutic Intervention Suggested by Profound Deficiency of Neutrophil-Derived Bactericidal/Permeability-Increasing Protein (BPI) and Other Alterations in LPS-Directed Innate Immunity after Myeloablative Hematopoietic Stem Cell Transplantation (HSCT)

Blood, Nov 16, 2006

Myeloablative conditioning used for allogeneic HSCT damages the gut resulting in leakage of lipop... more Myeloablative conditioning used for allogeneic HSCT damages the gut resulting in leakage of lipopolysaccharide (LPS, or endotoxin) into the circulation. LPS activates antigen-presenting cells to secrete inflammatory cytokines, including TNF, that enhance donor T cell responses to alloantigens. The relationship of TNF production and responsiveness to aGVHD and HSCT mortality has been demonstrated in animal models and with human correlative data. Use of either TNF or LPS antagonists in animal models or mice deficient in TNF or LPS responsiveness has led to profound amelioration of aGVHD. To determine whether LPS antagonists might have a therapeutic role in allogeneic HSCT, we measured plasma levels of 3 soluble LPS-modulating proteins in 30 sibling donor:recipient pairs undergoing myeloablative HSCT. Measurements included: 1) BPI, a constituent of neutrophil primary (azurophilic) granules with potent LPS-neutralizing activity at nanomolar concentrations in all body fluids, 2) LPS-binding protein (LBP) and 3) soluble CD14 (sCD14), which are both acute phase reactants that at basal levels enhance LPS activity by delivering LPS to its cell surface receptor but that at high levels detoxify LPS by delivering it to plasma lipoproteins. Spontaneous TNF production by whole blood and monocyte surface expression of TLR4, a key component of the LPS receptor, were also measured. Peripheral blood was obtained from donors (single time point) and patients pre-HSCT (baseline), Days 0, 7, 14, 21, 28 and on day of aGVHD. Plasma BPI levels fall dramatically from baseline, concurrent with severe neutropenia, while LBP (D7) and then sCD14 (D21–28) rise. Monocyte TLR4 expression was elevated at D7 and at onset of aGVHD. Patients with high spontaneous TNF production were at higher risk of aGVHD (p

Research paper thumbnail of Myeloablative Hematopoietic Stem Cell Transplantation (HSCT) Is Accompanied by Endotoxemia, Activation of Endotoxin-Directed Innate Immunity, and Deficiency of Endogenous Proteins That Limit Endotoxin- Induced TNF Production

Blood, Nov 16, 2008

Background: HSCT is an important treatment modality complicated by a number of immune-mediated to... more Background: HSCT is an important treatment modality complicated by a number of immune-mediated toxicities, including acute graft vs host disease (aGVHD). In animal HSCT models, endotoxemia-induced production of TNF contributes to development of inflammatory regimen related toxicity and aGVHD. We tested the hypothesis that in human HSCT, myeloablative chemoradiotherapy regimens contribute to the early development of both endotoxemia and profound deficiency in host defense molecules that normally serve to inhibit endotoxin signaling, effects that may activate endotoxin–directed innate immunity and contribute to development of toxicities including aGVHD. Methods: Peripheral blood was obtained prospectively from HSCT recipients (N =35) at Baseline (B) prior to the start of conditioning, Days 0 (Day of HSCT), 7, 14, 21, and 28 and from their HSCT donors. Results on soluble biomarkers were also validated with frozen plasma samples from a retrospective HSCT cohort (N=21). Plasma was analyzed for endotoxin (Limulus amobocyte lysate and endotoxin activity assays), endotoxin-interactive proteins: bactericidal/permeability-increasing protein (BPI), LPS-binding protein (LBP), soluble CD14 (sCD14) and soluble MD-2 (sMD-2), as well as chemokine ligand 5 (CCL5)/Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), chemokines that inhibit Toll-like receptor-4 (TLR4)-mediated TNF and IL-6 production. Monocyte expression of LPS-receptor components mCD14 and TLR4 was measured by flow cytometry. Whole blood RNA was isolated for analysis of TLR transcriptome activation using quantitative real-time PCR. Findings: During myeloablative HSCT, endotoxemia was detectable by two independent methods (LAL and EAA) and was accompanied by a profound deficiency in plasma concentrations of BPI and RANTES that fell &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10-fold from baseline (B) to D7 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). At Day 0, monocyte surface expression of mCD14 fell and TLR4 increased (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and selective activation of a TLR pathway transcriptional response was detected in whole blood, suggesting early exposure to bioactive endotoxin. Febrile neutropenia was accompanied by a 10-fold decline by D7 in plasma concentrations of BPI and CCL5/RANTES and increased IL-6, consistent with an acute phase response. Subsequently, levels of endotoxin-modulating proteins LBP (D7–14) and sCD14 (D7, 21, and 28) increased (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Spontaneous TNF production was inversely correlated with plasma CCL2/MCP- 1, a chemokine known to inhibit TLR4-mediated TNF. Low plasma concentrations of RANTES/CCL5 (D0 and D7) significantly correlated with subsequent risk of aGVHD (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Interpretation: During myeloablative HSCT, endotoxemia occurs in the context of deficient BPI and RANTES, potentially contributing to TLR4-mediated production of TNF and consequent inflammatory sequelae, including aGVHD. Therefore, therapies aimed at enhancing endotoxin-neutralization, such as replenishment of deficient endotoxin antagonists, may be effective approaches to reduce toxicities associated with myeloablative HSCT. We are investigating this hypothesis in an ongoing phase I/II clinical trial of intravenous administration of the endotoxin-neutralizing anti-infective protein rBPI21 (Opebecan; XOMA (US) LLC) to reduce inflammatory, regimen-related toxicity in patients undergoing myeloablative HSCT.

Research paper thumbnail of Precision Vaccine Adjuvants for Older Adults: A Scoping Review

Clinical Infectious Diseases, Apr 19, 2022