Angela Haczku - Academia.edu (original) (raw)

Papers by Angela Haczku

Research paper thumbnail of Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial

Research paper thumbnail of Wildfire Smoke Exposure Increases Circulating Group 2 Innate Lymphoid Cell (ILC2) Number and Serum Eotaxin 2 (CCL24), D-Dimer and Surfactant Protein D (SP-D)

D16. WILDFIRES AND WOODSMOKE, May 1, 2022

Research paper thumbnail of SP-A binding to the SARS-CoV-2 spike protein using hybrid quantum and classical in silico modeling and molecular pruning by Quantum Approximate Optimization Algorithm (QAOA) Based MaxCut with ZDOCK

Frontiers in Immunology

The pulmonary surfactant protein A (SP-A) is a constitutively expressed immune-protective collage... more The pulmonary surfactant protein A (SP-A) is a constitutively expressed immune-protective collagenous lectin (collectin) in the lung. It binds to the cell membrane of immune cells and opsonizes infectious agents such as bacteria, fungi, and viruses through glycoprotein binding. SARS-CoV-2 enters airway epithelial cells by ligating the Angiotensin Converting Enzyme 2 (ACE2) receptor on the cell surface using its Spike glycoprotein (S protein). We hypothesized that SP-A binds to the SARS-CoV-2 S protein and this binding interferes with ACE2 ligation. To study this hypothesis, we used a hybrid quantum and classical in silico modeling technique that utilized protein graph pruning. This graph pruning technique determines the best binding sites between amino acid chains by utilizing the Quantum Approximate Optimization Algorithm (QAOA)-based MaxCut (QAOA-MaxCut) program on a Near Intermediate Scale Quantum (NISQ) device. In this, the angles between every neighboring three atoms were Fouri...

Research paper thumbnail of Dynamics of Temporal Immune Responses in Nonhuman Primates and Humans Immunized with COVID-19 Vaccines

We assessed the humoral immune responses to a COVID-19 vaccine in a well-controlled rhesus macaqu... more We assessed the humoral immune responses to a COVID-19 vaccine in a well-controlled rhesus macaque model in comparison to humans immunized with two mRNA vaccines over several months post-second dose. The plasma IgG levels against seven coronaviruses (including SARS-CoV-2) and antibody subtypes (IgG1-4 and IgM) against SARS-CoV-2 were evaluated using multiplex assays. The neutralization capacity of plasma antibodies against original SAR-CoV-2 isolate and nine variants was evaluated in vaccinated humans and non-human primates. Immunization of macaques and humans with SARS-CoV-2 vaccines induced a robust neutralizing antibody response. In non-SIV infected adult macaques immunized with an adenoviral vector expressing S-RBD (n = 7) or N protein (n = 3), elevated levels of IgG and neutralizing antibodies were detected 2 weeks post-second dose. Immune responses to the S-RBD vaccine in SIV-infected adult macaques (n = 2) were similar to the non-SIV-infected animals. Adult humans immunized w...

Research paper thumbnail of Phenotypic Evaluation of Natural Killer (NK) Cells in Response to BNT162b2 mRNA Covid-19 Vaccine During Wildfire Smoke Exposure

D16. WILDFIRES AND WOODSMOKE, May 1, 2022

Research paper thumbnail of Wildfire Smoke Exposure Activates Circulating Innate Immune Cells

Journal of Allergy and Clinical Immunology, 2021

Research paper thumbnail of Allergic Asthma and its Treatments

Journal of Allergy and Therapy, 2021

Research paper thumbnail of Clinical trial design during and beyond the pandemic: the I-SPY COVID trial

Nature Medicine, 2022

Fig. 1 | Timeline of major funded epidemiological studies on long COViD in the uK. *PHOSP-COVID h... more Fig. 1 | Timeline of major funded epidemiological studies on long COViD in the uK. *PHOSP-COVID has ethical approval for 25-year follow-up and rEACT-LC for 20-year follow-up, with plans highlighting how each study will evolve, ask new questions and seek further resources. # rEACT-LC is funded from February 2021 but the timeline of the project starts in May 2020 with the use of the first baseline data from rEACT participants, which form the sampling for follow-up.

Research paper thumbnail of SARS-CoV-2 detection and genomic sequencing from hospital surface samples collected at UC Davis

RationaleThere is little doubt that aerosols play a major role in the transmission of SARS-CoV-2.... more RationaleThere is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear.ObjectivesWe aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis.MethodsSamples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing.Measurements and Main ResultsImproved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, non...

Research paper thumbnail of Role of Surfactant Protein D (SP-D) in COVID-19

TP91. TP091 EPIDEMIOLOGY AND TRANSLATIONAL ADVANCES IN SARS-COV-2, 2021

Rationale: Surfactant protein D (SP-D) is a major immune protective molecule produced in the resp... more Rationale: Surfactant protein D (SP-D) is a major immune protective molecule produced in the respiratory epithelium. SP-D binds to specific pathogen surfaces through its carbohydrate recognition (lectin) domain, that helps in their neutralization and clearance by phagocytes. SP-D also acts as an anti-inflammatory molecule. We hypothesized that SP-D plays a protective role in COVID-19. Methods: Polar+, a novel quantum computing algorithm for molecular pruning, and classical in silico modeling were used to investigate potential binding sites between SP-D and SARS CoV2. Electronegativity and topologically oriented molecular pruning, calculation of electronic force-fields and electrostatic binding combined with protein-protein docking, geometric fitting and assessment of protein glycosylation sites were employed. SP-D-/- mouse lung was used to study expression of the SARS-CoV-2 viral entry molecules TMPRSS2 and ACE2. Plasma from COVID-19 patients was studied for SP-D leakage, cytokine levels and lipid mediators. Results: We found that SP-D potentially binds to the same SARS CoV-2 glycoprotein (S protein) that it utilizes to bind the cellular receptor, ACE2, with high affinity. However, SP-D binds to subunit 2, instead of subunit 1 (that ACE2 utilizes). Additional studies will need to determine if SP-D binding affects S protein and ACE2 interactions. We also found that SP-D-/- mice had increased expression of the TMRSS2 gene in the lung and that both TMPRSS2 and ACE2 mRNA levels were increased during lung injury, amplified by the lack of SP-D. SP-D leakage from the lung to the circulation was significantly increased in COVID- 19 patients and correlated with expression of pro-neutrophilic inflammatory markers. Conclusions: We speculate that SP-D aids in the protection from SARS CoV2 infection by both acting as a potential natural decoy to prevent coronavirus entry into airway epithelial cells and by attenuating the expression of the viral entry receptor TMPRSS2. Oxidative lung injury results in SP-D leak into the circulation denoting disease severity in COVID-19 patients. (AH) .

Research paper thumbnail of A Community-transmitted Case of Severe Acute Respiratory Distress Syndrome (SARS) Due to SARS-CoV-2 in the United States

Clinical Infectious Diseases, 2020

This is the first known community transmission case of the novel coronavirus disease (COVID-19) i... more This is the first known community transmission case of the novel coronavirus disease (COVID-19) in the United States, with significant public health implications. Diagnosis of COVID-19 is currently confirmed with PCR based testing of appropriate respiratory samples. Given the absence of travel or known exposure history, this patient did not meet the criteria for testing according to CDC guidelines at the time of her presentation. Since this case, any patient with severe disease (eg, ARDS or pneumonia) requiring hospitalization without an explanatory diagnosis can be tested even if no clear source of exposure is identified. While influencing national health policies for revising screening criteria, this case also highlighted significant knowledge gaps in diagnosis and treatment and a desperate need for early, widespread, fast and cheap testing for COVID-19.

Research paper thumbnail of The Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020

International Archives of Allergy and Immunology, 2019

Eosinophils and their secretory mediators play an important role in the pathogenesis of infectiou... more Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also refl...

Research paper thumbnail of Group 2 innate lymphoid cells display ILC3-like functional plasticity in asthmatics and non-human primates

Journal of Allergy and Clinical Immunology, 2018

Research paper thumbnail of Allergic Airway Inflammation and Airway Hyperresponsiveness Are Independently Controlled by Diacylglycerol Kinase

B29. MECHANISMS FOR AIRWAY HYPERRESPONSIVENESS: FROM CELL TO ORGANISM, 2019

Research paper thumbnail of A burning need to redefine airways disease: Biomass smoke exposure identified as a unique risk factor for asthma–chronic obstructive pulmonary disease overlap in low- and middle-income countries

Journal of Allergy and Clinical Immunology, 2018

Research paper thumbnail of Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma

Pharmacology & Therapeutics, 2017

Research paper thumbnail of Obesity-related, metabolic asthma: a new role for glucagon-like peptide 1 agonists

The Lancet Respiratory Medicine, 2017

during the writing of this Comment. D-VN reports personal fees from Veterans Aff airs Northern Ca... more during the writing of this Comment. D-VN reports personal fees from Veterans Aff airs Northern California Healthcare System. AH declares no competing interests.

Research paper thumbnail of Paradigms in chronic obstructive pulmonary disease: phenotypes, immunobiology, and therapy with a focus on vascular disease

Journal of investigative medicine : the official publication of the American Federation for Clinical Research, Aug 3, 2017

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome that represe... more Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome that represents a major global health burden. COPD phenotypes have recently emerged based on large cohort studies addressing the need to better characterize the syndrome. Though comprehensive phenotyping is still at an early stage, factors such as ethnicity and radiographic, serum, and exhaled breath biomarkers have shown promise. COPD is also an immunological disease where innate and adaptive immune responses to the environment and tobacco smoke are altered. The frequent overlap between COPD and other systemic diseases, such as cardiovascular disease, has influenced COPD therapy, and treatments for both conditions may lead to improved patient outcomes. Here, we discuss current paradigms that center on improving the definition of COPD, understanding the immunological overlap between COPD and vascular inflammation, and the treatment of COPD-with a focus on comorbid cardiovascular disease.

Research paper thumbnail of mTORC2 regulates multiple aspects of NKT-cell development and function

European journal of immunology, Mar 1, 2017

Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and... more Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictor(fl/fl) CD4cre(+) mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of develop...

Research paper thumbnail of Inhalational exposure to statins and drug vehicle induces transient immunological changes in both the airways and peripheral blood of non-human primates

Journal of Allergy and Clinical Immunology, 2017

RATIONALE: Farm exposure is protective against asthma and our preliminary findings suggest viral ... more RATIONALE: Farm exposure is protective against asthma and our preliminary findings suggest viral respiratory illnesses (VRIs). Type I interferon responses are immature in neonates, however the relationship between varied immune maturation markers has not been studied. Proteomic and flow cytometry assays were used to characterize neonatal immune responses to rhinovirus (HRV-A16) and viral-associated TLRs, and the results of these two assays were compared. METHODS: In a prospective birth cohort study, cord blood was collected from farm and non-farm neonates. 19 study subjects (10 farm and 9 nonfarm) were analyzed. Blood mononuclear cells were isolated and stimulated with HRV-A16 and viral-associated TLR agonists (R848 & CpGA). Multi-parameter flow cytometry and multiplex, bead-based assays were used to determine innate and adaptive immune responses. Spearman's rank coefficient was calculated to determine correlation between assays. RESULTS: For HRV and R848 agonists, IFNa2 supernatant levels were positively correlated with plasmacytoid dendritic cell (pDC) IFN integrated mean fluorescence intensity (iMFI, r s 50.560, p50.013 and r s 50.512, p50.025, respectively) and were not correlated with pDC maturation (CD40+CD86+). IP-10, important in effector T cell recruitment, was secreted by stimulated cord blood cells with the highest levels detected with HRV stimulation (p<0.0001). HRV stimulation demonstrated IP-10 correlation with B cells and conventional dendritic cells maturation (% CD40+CD86+, r s 50.595, p50.009 and r s 50.562, p50.015, respectively). CONCLUSIONS: Proteomic and flow cytometry assays provide a complementary, detailed characterization of neonatal anti-viral responses and will be used to identify correlates of immune protection against VRIs. These studies will determine the impact of farming exposure on anti-viral responses and clinical correlates.

Research paper thumbnail of Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial

Research paper thumbnail of Wildfire Smoke Exposure Increases Circulating Group 2 Innate Lymphoid Cell (ILC2) Number and Serum Eotaxin 2 (CCL24), D-Dimer and Surfactant Protein D (SP-D)

D16. WILDFIRES AND WOODSMOKE, May 1, 2022

Research paper thumbnail of SP-A binding to the SARS-CoV-2 spike protein using hybrid quantum and classical in silico modeling and molecular pruning by Quantum Approximate Optimization Algorithm (QAOA) Based MaxCut with ZDOCK

Frontiers in Immunology

The pulmonary surfactant protein A (SP-A) is a constitutively expressed immune-protective collage... more The pulmonary surfactant protein A (SP-A) is a constitutively expressed immune-protective collagenous lectin (collectin) in the lung. It binds to the cell membrane of immune cells and opsonizes infectious agents such as bacteria, fungi, and viruses through glycoprotein binding. SARS-CoV-2 enters airway epithelial cells by ligating the Angiotensin Converting Enzyme 2 (ACE2) receptor on the cell surface using its Spike glycoprotein (S protein). We hypothesized that SP-A binds to the SARS-CoV-2 S protein and this binding interferes with ACE2 ligation. To study this hypothesis, we used a hybrid quantum and classical in silico modeling technique that utilized protein graph pruning. This graph pruning technique determines the best binding sites between amino acid chains by utilizing the Quantum Approximate Optimization Algorithm (QAOA)-based MaxCut (QAOA-MaxCut) program on a Near Intermediate Scale Quantum (NISQ) device. In this, the angles between every neighboring three atoms were Fouri...

Research paper thumbnail of Dynamics of Temporal Immune Responses in Nonhuman Primates and Humans Immunized with COVID-19 Vaccines

We assessed the humoral immune responses to a COVID-19 vaccine in a well-controlled rhesus macaqu... more We assessed the humoral immune responses to a COVID-19 vaccine in a well-controlled rhesus macaque model in comparison to humans immunized with two mRNA vaccines over several months post-second dose. The plasma IgG levels against seven coronaviruses (including SARS-CoV-2) and antibody subtypes (IgG1-4 and IgM) against SARS-CoV-2 were evaluated using multiplex assays. The neutralization capacity of plasma antibodies against original SAR-CoV-2 isolate and nine variants was evaluated in vaccinated humans and non-human primates. Immunization of macaques and humans with SARS-CoV-2 vaccines induced a robust neutralizing antibody response. In non-SIV infected adult macaques immunized with an adenoviral vector expressing S-RBD (n = 7) or N protein (n = 3), elevated levels of IgG and neutralizing antibodies were detected 2 weeks post-second dose. Immune responses to the S-RBD vaccine in SIV-infected adult macaques (n = 2) were similar to the non-SIV-infected animals. Adult humans immunized w...

Research paper thumbnail of Phenotypic Evaluation of Natural Killer (NK) Cells in Response to BNT162b2 mRNA Covid-19 Vaccine During Wildfire Smoke Exposure

D16. WILDFIRES AND WOODSMOKE, May 1, 2022

Research paper thumbnail of Wildfire Smoke Exposure Activates Circulating Innate Immune Cells

Journal of Allergy and Clinical Immunology, 2021

Research paper thumbnail of Allergic Asthma and its Treatments

Journal of Allergy and Therapy, 2021

Research paper thumbnail of Clinical trial design during and beyond the pandemic: the I-SPY COVID trial

Nature Medicine, 2022

Fig. 1 | Timeline of major funded epidemiological studies on long COViD in the uK. *PHOSP-COVID h... more Fig. 1 | Timeline of major funded epidemiological studies on long COViD in the uK. *PHOSP-COVID has ethical approval for 25-year follow-up and rEACT-LC for 20-year follow-up, with plans highlighting how each study will evolve, ask new questions and seek further resources. # rEACT-LC is funded from February 2021 but the timeline of the project starts in May 2020 with the use of the first baseline data from rEACT participants, which form the sampling for follow-up.

Research paper thumbnail of SARS-CoV-2 detection and genomic sequencing from hospital surface samples collected at UC Davis

RationaleThere is little doubt that aerosols play a major role in the transmission of SARS-CoV-2.... more RationaleThere is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear.ObjectivesWe aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis.MethodsSamples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing.Measurements and Main ResultsImproved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, non...

Research paper thumbnail of Role of Surfactant Protein D (SP-D) in COVID-19

TP91. TP091 EPIDEMIOLOGY AND TRANSLATIONAL ADVANCES IN SARS-COV-2, 2021

Rationale: Surfactant protein D (SP-D) is a major immune protective molecule produced in the resp... more Rationale: Surfactant protein D (SP-D) is a major immune protective molecule produced in the respiratory epithelium. SP-D binds to specific pathogen surfaces through its carbohydrate recognition (lectin) domain, that helps in their neutralization and clearance by phagocytes. SP-D also acts as an anti-inflammatory molecule. We hypothesized that SP-D plays a protective role in COVID-19. Methods: Polar+, a novel quantum computing algorithm for molecular pruning, and classical in silico modeling were used to investigate potential binding sites between SP-D and SARS CoV2. Electronegativity and topologically oriented molecular pruning, calculation of electronic force-fields and electrostatic binding combined with protein-protein docking, geometric fitting and assessment of protein glycosylation sites were employed. SP-D-/- mouse lung was used to study expression of the SARS-CoV-2 viral entry molecules TMPRSS2 and ACE2. Plasma from COVID-19 patients was studied for SP-D leakage, cytokine levels and lipid mediators. Results: We found that SP-D potentially binds to the same SARS CoV-2 glycoprotein (S protein) that it utilizes to bind the cellular receptor, ACE2, with high affinity. However, SP-D binds to subunit 2, instead of subunit 1 (that ACE2 utilizes). Additional studies will need to determine if SP-D binding affects S protein and ACE2 interactions. We also found that SP-D-/- mice had increased expression of the TMRSS2 gene in the lung and that both TMPRSS2 and ACE2 mRNA levels were increased during lung injury, amplified by the lack of SP-D. SP-D leakage from the lung to the circulation was significantly increased in COVID- 19 patients and correlated with expression of pro-neutrophilic inflammatory markers. Conclusions: We speculate that SP-D aids in the protection from SARS CoV2 infection by both acting as a potential natural decoy to prevent coronavirus entry into airway epithelial cells and by attenuating the expression of the viral entry receptor TMPRSS2. Oxidative lung injury results in SP-D leak into the circulation denoting disease severity in COVID-19 patients. (AH) .

Research paper thumbnail of A Community-transmitted Case of Severe Acute Respiratory Distress Syndrome (SARS) Due to SARS-CoV-2 in the United States

Clinical Infectious Diseases, 2020

This is the first known community transmission case of the novel coronavirus disease (COVID-19) i... more This is the first known community transmission case of the novel coronavirus disease (COVID-19) in the United States, with significant public health implications. Diagnosis of COVID-19 is currently confirmed with PCR based testing of appropriate respiratory samples. Given the absence of travel or known exposure history, this patient did not meet the criteria for testing according to CDC guidelines at the time of her presentation. Since this case, any patient with severe disease (eg, ARDS or pneumonia) requiring hospitalization without an explanatory diagnosis can be tested even if no clear source of exposure is identified. While influencing national health policies for revising screening criteria, this case also highlighted significant knowledge gaps in diagnosis and treatment and a desperate need for early, widespread, fast and cheap testing for COVID-19.

Research paper thumbnail of The Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020

International Archives of Allergy and Immunology, 2019

Eosinophils and their secretory mediators play an important role in the pathogenesis of infectiou... more Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also refl...

Research paper thumbnail of Group 2 innate lymphoid cells display ILC3-like functional plasticity in asthmatics and non-human primates

Journal of Allergy and Clinical Immunology, 2018

Research paper thumbnail of Allergic Airway Inflammation and Airway Hyperresponsiveness Are Independently Controlled by Diacylglycerol Kinase

B29. MECHANISMS FOR AIRWAY HYPERRESPONSIVENESS: FROM CELL TO ORGANISM, 2019

Research paper thumbnail of A burning need to redefine airways disease: Biomass smoke exposure identified as a unique risk factor for asthma–chronic obstructive pulmonary disease overlap in low- and middle-income countries

Journal of Allergy and Clinical Immunology, 2018

Research paper thumbnail of Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma

Pharmacology & Therapeutics, 2017

Research paper thumbnail of Obesity-related, metabolic asthma: a new role for glucagon-like peptide 1 agonists

The Lancet Respiratory Medicine, 2017

during the writing of this Comment. D-VN reports personal fees from Veterans Aff airs Northern Ca... more during the writing of this Comment. D-VN reports personal fees from Veterans Aff airs Northern California Healthcare System. AH declares no competing interests.

Research paper thumbnail of Paradigms in chronic obstructive pulmonary disease: phenotypes, immunobiology, and therapy with a focus on vascular disease

Journal of investigative medicine : the official publication of the American Federation for Clinical Research, Aug 3, 2017

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome that represe... more Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome that represents a major global health burden. COPD phenotypes have recently emerged based on large cohort studies addressing the need to better characterize the syndrome. Though comprehensive phenotyping is still at an early stage, factors such as ethnicity and radiographic, serum, and exhaled breath biomarkers have shown promise. COPD is also an immunological disease where innate and adaptive immune responses to the environment and tobacco smoke are altered. The frequent overlap between COPD and other systemic diseases, such as cardiovascular disease, has influenced COPD therapy, and treatments for both conditions may lead to improved patient outcomes. Here, we discuss current paradigms that center on improving the definition of COPD, understanding the immunological overlap between COPD and vascular inflammation, and the treatment of COPD-with a focus on comorbid cardiovascular disease.

Research paper thumbnail of mTORC2 regulates multiple aspects of NKT-cell development and function

European journal of immunology, Mar 1, 2017

Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and... more Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictor(fl/fl) CD4cre(+) mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of develop...

Research paper thumbnail of Inhalational exposure to statins and drug vehicle induces transient immunological changes in both the airways and peripheral blood of non-human primates

Journal of Allergy and Clinical Immunology, 2017

RATIONALE: Farm exposure is protective against asthma and our preliminary findings suggest viral ... more RATIONALE: Farm exposure is protective against asthma and our preliminary findings suggest viral respiratory illnesses (VRIs). Type I interferon responses are immature in neonates, however the relationship between varied immune maturation markers has not been studied. Proteomic and flow cytometry assays were used to characterize neonatal immune responses to rhinovirus (HRV-A16) and viral-associated TLRs, and the results of these two assays were compared. METHODS: In a prospective birth cohort study, cord blood was collected from farm and non-farm neonates. 19 study subjects (10 farm and 9 nonfarm) were analyzed. Blood mononuclear cells were isolated and stimulated with HRV-A16 and viral-associated TLR agonists (R848 & CpGA). Multi-parameter flow cytometry and multiplex, bead-based assays were used to determine innate and adaptive immune responses. Spearman's rank coefficient was calculated to determine correlation between assays. RESULTS: For HRV and R848 agonists, IFNa2 supernatant levels were positively correlated with plasmacytoid dendritic cell (pDC) IFN integrated mean fluorescence intensity (iMFI, r s 50.560, p50.013 and r s 50.512, p50.025, respectively) and were not correlated with pDC maturation (CD40+CD86+). IP-10, important in effector T cell recruitment, was secreted by stimulated cord blood cells with the highest levels detected with HRV stimulation (p<0.0001). HRV stimulation demonstrated IP-10 correlation with B cells and conventional dendritic cells maturation (% CD40+CD86+, r s 50.595, p50.009 and r s 50.562, p50.015, respectively). CONCLUSIONS: Proteomic and flow cytometry assays provide a complementary, detailed characterization of neonatal anti-viral responses and will be used to identify correlates of immune protection against VRIs. These studies will determine the impact of farming exposure on anti-viral responses and clinical correlates.