2007 — 2009 |
Khader, Shabaana A. |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Novel Il-17 Producing Memory Cells Are Key to Vaccine-Based Immunity in the Lung @ Children's Hosp Pittsburgh/Upmc Hlth Sys
Project summary: Tuberculosis (TB) kills more than 2 million people every year worldwide. The only TB vaccine available, Bacille Calmette Guerin (BCG) has variable efficacy and this has prompted the search for more effective vaccines. Although significant progress has been made in identification of Mycobacterium tuberculosis (Mtb) antigen candidates, a significant hurdle to successful vaccine design remains our poor understanding of how the memory response mediates protection in the lung. The long-term goal of this proposal is to define the basic requirements for induction of protective memory immunity in the lung against pulmonary pathogens such as Mtb. The protective recall response to TB is associated with the appearance of CD4+ T cells that produce interferon (IFN)-y and many studies have focused on inducing these cells in the hope of improving vaccination. Unfortunately improvement over that mediated by BCG has not occurred. It is possible therefore that other factors play a role in protective memory and that determining what these factors are and how they can be modulated will lead to substantial improvement in vaccine efficacy. In this regard we have recently found that interleukin (IU-17-producina memory cells precede the IFN-Y memory cell response in the lung, and that in the absence of these cells the IFN-v memory response does not occur. Based on preliminary data we propose a three-phase model of vaccine-induced protection in TB. Firstly vaccination induces both IFN-y and IL-17-producing cells but only IL-17-producing cells populate the noninflamed lung. Upon challenge with Mtb, the lung resident memory cells produce IL-17 and trigger local expression of chemokines (phase 1). The chemokine gradient attracts IFN-y memory cells from the lymphoid pool (phase 2). In turn, these IFN-y cells activate myeloid cells in the lung to halt Mtb growth (phase 3). The absence of an effective IL-17 response (phase 1) ablates the ability of vaccinated mice to generate a protective recall immune response to Mtb challenge (phases 2 and 3). The finding that a lung-resident IL-17- producing population of CD4+ memory cells is generated by vaccination and that these cells are a critical component of vaccine-induced protection against TB is entirely novel. Determining the specific factors that are required for the persistence and survival of these cells in the lung following vaccination is crucial. We propose two aims. In Aim One the factors required for the survival and maintenance of IL-17-producing memory cells in the lung will be investigated. In Aim two, the location of the cells and the factors that impact the establishment of this population in the lung will be determined. The relevance of this work to public health is that it will promote rational development of vaccine strategies and will therefore have the potential to reduce the incidence of TB.
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1 |
2009 — 2010 |
Khader, Shabaana A. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Impact of Mucosal Immunization On Generation of Protective Lung-Resident Il-17 Pr @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year. Our limited understanding of how vaccine responses mediates protection in the lung remains a major hurdle to successful vaccine design against TB. The protective immune response to TB has conventionally been associated with the appearance of CD4+ T helper cells that produce the cytokine interferon gamma (IFN-?), and activates macrophages to control Mtb. We have recently identified that in addition to the IFN-? producing population, a second population of vaccine-induced CD4+ T helper cells that - produce the cytokine interleukin (IL)-17, is key for protection against TB. Subcutaneous immunization of mice with a defined immunodominant IAb-restricted peptide from the Mtb 6kDa Early Secretory Antigenic Protein (ESAT-61-20) in an adjuvant induces both antigen-specific IFN-?-producing and IL-17-producing memory cell populations. However, only the IL-17-producing cells populate the lung while the IFN-?-producing cells are found in the secondary lymphoid organs. The lung-resident memory cells upon exposure to Mtb, produce IL-17 and trigger local expression of chemokines in the lung. This chemokine gradient then attracts protective IFN-?- producing memory cells from the circulation. The arrival of the IFN-?-producing memory cells in the lung and production of IFN? then activates macrophages to halt Mtb growth. Importantly, in the absence of the IL-17 recall response, the accelerated IFN-? memory response does not occur and protection is lost. A majority of approaches to the development of new TB vaccines have focused on subcutaneous route of antigen delivery. However more recently, mucosal immunization has been shown to be more protective upon challenge with virulent Mtb than other routes of immunization. This is consistent with the hypothesis that immunization at the mucosal sites generates superior protection against mucosal infectious diseases. However, the immune mechanisms underlying enhanced protection by respiratory mucosal immunization against TB remains unexplored. Most studies that have used mucosal immunization against Mtb have studied the generation of IFN? responses as a readout of immune activation. However, our recent discovery that IL-17-producing memory cells generated by subcutaneous immunization are a critical component of vaccine-induced protection against TB leads us to raise several basic questions about the induction of IL-17 responses by mucosal immunizations. In Aim One, we will determine whether mucosal immunization generates protective lung- resident IL-17-producing memory cells and whether altering the adjuvant and including mucosal coadjuvants will generate more effective IL-17 memory responses. In Aim Two, we will characterize the antigen presenting cells that prime T cell populations and we will define the inductive sites of T cell priming following mucosal immunization. The aims of the current proposal will promote rational development of mucosal vaccine strategies with the long term goal of improving immunization strategies against Mtb. Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year, the major hurdle to successful vaccine design against TB is our poor understanding of the requirements for early memory responses to TB in the lung. The need to improve immunization strategies against TB makes it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will promote rational development of mucosal vaccine strategies and will therefore have the potential to reduce the incidence of TB.
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1 |
2011 — 2019 |
Khader, Shabaana A. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Il-17 in Protective Vaccine-Induced Immune Responses Against Tuberculosis
? DESCRIPTION (provided by applicant): Approximately one-third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb) with a 10% risk of developing pulmonary tuberculosis (TB) over their lifetime. Global efforts to combat TB are hampered by the emergence of drug-resistant strains of Mtb and variable efficacy of the currently available vaccine, M. bovis BCG (BCG). Thus, the development of an effective vaccine is critical for the elimination of TB as a public health problem. Studies in the past decade have mainly utilized induction of T helper 1 (Th1) responses and production of interferon gamma (IFN?) as readouts for vaccine efficacy against TB. However, despite inducing high levels of IFN-?, MVA85A, the first recombinant TB vaccine tested in human clinical trials, failed to protect against TB disease. These data highlight the importance of exploring new approaches to improve vaccine-induced immunity against TB. During the prior funding period, we demonstrated that T helper type 17 (Th17) cells, which produce the cytokine interleukin-17 (IL-17), are the primary effector cell mediating vaccine-induced protection against Mtb. Although IFN? is dispensable for vaccine-induced immunity against TB, IL-17 production by vaccine-induced Th17 cells is absolutely necessary to confer vaccine-induced protection against TB. Importantly, mucosal vaccination with the Mtb antigen in adjuvant induced potent lung-resident Th17 cells and improved BCG vaccine-induced protection following Mtb challenge. Our mechanistic studies showed that IL-17 induced chemokines, including CXCL-13, to localize CXCR5-expressing T cells near Mtb-infected macrophages, resulting in the formation of lymphoid follicles and activating macrophages to mediate Mtb control. Despite these major advances in understanding the role of Th17 vaccine-induced cells in TB, the accumulation of vaccine-induced Th17 recall responses in the lung is not accelerated enough to provide sterilizing immunity to Mtb infection. However, we show that vaccine-induced Th17 immunity can be harnessed using DC therapy to achieve near sterilizing immunity against Mtb challenge. Thus, in this renewal, in Aim 1, we will first determine if accelerating Th17 cell accumulation by modulating antigen-presenting cell (APC) function will improve Mtb control. In Aim 2, we will address the functional role of IL-17 in DC therapy in vaccinated mice, and the relationship between a Single Nucleotide Polymorphism (SNP) in the IL-17 promoter and vaccine-induced responses in humans. Finally, in Aim 3, we will identify and incorporate potent Th17- inducing adjuvants into protective mucosal TB vaccines to translate for future use in humans. These objectives will be addressed using novel Mtb T-cell receptor (TCR) transgenic (Tg) mouse models in combination with gene-deficient mice, mouse models of Mtb infection, novel adjuvants and vaccination strategies, and hypothesis testing in humans. The work proposed in this grant will allow us to promote Th17 responses to generate long-lasting vaccine-induced immunity against TB.
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1 |
2015 — 2021 |
Kaushal, Deepak (co-PI) [⬀] Khader, Shabaana A. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Inducible Bronchus Associated Lymphoid Tissue in Latent Tuberculosis
? DESCRIPTION (provided by applicant): The global syndemic interaction between the acquired immunodeficiency syndrome (AIDS) and tuberculosis (TB) epidemics has deadly consequences. One third of the 38.6 million people infected with HIV are co-infected with Mycobacterium tuberculosis (Mtb), resulting in TB being the largest single cause of death in AIDS patients. However, the mechanism(s) that mediates loss of Mtb control in TB/HIV co- infected hosts are not known. HIV-induced decline in CD4+ T cells correlates with increased susceptibility to TB. In addition, HIV-induced CD4+ T cell depletion may also occur within the lung granuloma, impairing Mtb control, and facilitating progression from latent TB (LTBI) to Pulmonary TB (PTB). Thus, although the granuloma is considered important for Mtb control, the immunological differences between a protective granuloma seen during LTBI, and a non-protective granuloma seen during PTB have not been described until recently. Our recent work in human, Nonhuman primate (NHP) and mouse models of TB, has demonstrated a role for inducible Bronchus Associated Lymphoid tissue (iBALT) in TB. iBALT contains spatially organized T cells, B cells and macrophages and its presence is associated with better protective outcomes during TB. In addition, our new published data show that in PTB, a dominant feature of the granulomatous inflammation is the accumulation of neutrophils that produce inflammatory molecules such as S100A8/A9 proteins. Incidentally, increased neutrophil accumulation has also been recently associated with increased Mtb and viral burden in TB/HIV co-infected patients. Based on these new data, we propose the paradigm-shifting hypothesis that a protective TB granuloma is one that contains iBALT and contributes to Mtb containment during LTBI. In contrast, progression to a more neutrophilic, inflammatory granuloma causes TB reactivation, loss of Mtb control and progression to PTB. In this proposal, we will test this overall hypothesis through three specific Aims. In Aim 1, using mouse and NHP models of TB, we will mechanistically identify Mtb genes and pathways that modulate iBALT formation, providing crucial new information about the mechanism(s) employed by Mtb in interfering with the formation of protective iBALTs. In Aim 2, we will address the functional role of persistent iBALT in limiting reactivation and dissemination in latently infected mice. In addition, we will also address the relevance of CD4+ T cells in iBALT function using the NHP model of TB/SIV co-infection. In Aim 3, we will determine whether iBALT structures can be enhanced, or neutrophilic granulomas reversed, to decrease TB reactivation and disease severity during latency and SIV co-infection. Together, these aims will provide new information on the clinical relevance of iBALT in latency, reactivation of TB, and identify novel HDTs to decrease TB reactivation rates, particularly in a setting of HIV co-infection. Without doubt, any decrease in global TB burdens will also significantly decrease the deadly consequences of the HIV-TB syndemic.
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0.948 |
2016 — 2019 |
Kaushal, Deepak (co-PI) [⬀] Khader, Shabaana A. Scriba, Thomas Jens |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Common Immune Correlates of Risk of Tb Disease in Animal Models and Humans
? DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) infects about one third of the world's population, killing ~1.3 million individuals worldwide every year. Although, te majority of infected persons are asymptomatically infected, latent tuberculosis (LTBI) can reactivate into pulmonary tuberculosis (PTB). A clear understanding of immune correlates associated with risk of disease progression and inflammation during TB is necessary for design of new immunotherapies and treatments to promote control of Mtb. Animal models such as the inbred mouse model of TB are commonly used to study mechanisms of immunity or inflammation in TB. However, disease outcomes seen in inbred mouse models do not reflect the heterogeneity seen in human TB. Thus, we established a mouse model of TB in diversity outbred (DO) mice that demonstrate considerable heterogeneity in disease severity following Mtb infection. In addition, non-human primate (NHP) animal model of TB is a pre-clinical model for studying TB disease progression, where granulomas mirror the morphology and physiology observed in human TB. Thus, using the DO Mtb mouse model, NHP model of TB and human clinical samples, we recently implicated neutrophils and S100A8/A9 proteins in mediating inflammation and disease severity in TB. However, the pace of such translational discoveries will be much more robust and rapid if we have a more comprehensive understanding of common immune correlates of protection and inflammation across relevant animal models and the spectrum of TB in humans. To overcome this bottleneck, we propose the following Aims. In Aim 1, we will identify common gene expression signatures from peripheral blood and lung samples from DO Mtb-infected mice, NHPs with PTB and LTBI, and compare them to existing whole blood transcriptional profiles from a well characterized longitudinal study of SA adolescents. In addition, we will validate the expression of genes identified from the inter-species gene expression analysis by measuring protein levels in our human adolescent progressor cohort. In Aim 2, using animal models of Mtb infection, we will mechanistically address the functional role of specific genes identified as correlates of risk of TB in human progressors, specifically focusing on the Type I Interferon pathway. Together, these aims will provide novel information on common immune protective and inflammatory pathways that exist between relevant animal models and human TB. Identifying such common correlates will allow us to more effectively use animal models to screen for new vaccines and therapies that have a better likelihood of translating to improved efficacy in human TB.
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0.948 |
2016 — 2017 |
Khader, Shabaana A. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Modifying the Lung to Induce Sterile Vaccine-Induced Protection Against Mtb Infection
PROJECT ABSTRACT Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) together represent the world's biggest killers. There are an estimated nine million new cases of tuberculosis (TB) diagnosed each year, resulting in 1.4 million deaths annually. It is therefore of paramount importance that we develop novel strategies for controlling Mtb infection. The only currently-licensed vaccine for TB, M.bovis Bacille Calmette Guerin (BCG), is effective against childhood forms of TB, but has limited efficacy against pulmonary TB after adolescence. Thus, development of novel vaccines and therapeutics for TB that will provide improved protection upon Mtb exposure are urgently required. Modern candidate TB vaccines under development have focussed on induction of strong T cell responses, primarily CD4+ T cells producing the cytokine interferon gamma (IFN-?, Th1 cells). More recently, a key role for mucosal interleukin 17A (IL-17) in vaccine-induced protection against TB disease has also been shown. Thus, induction of lung-resident IL- 17-producing CD4+ T cell populations (Th17 cells) by mucosal TB vaccines is also being explored. However, most TB vaccines do not confer sterilizing immunity, instead, inducing a reduction of only ~0.5 to 1.5 logs in lung Mtb burden in animal challenge models. Our new data presented here, show that the lack of sterilizing vaccine-induced immunity to TB vaccines is not due to poor function of vaccine-induced CD4+ T cells, but due to delayed activation and accumulation of recall CD4+ T cell responses in the lung following Mtb infection. Using novel strategies, we show that this bottleneck can be overcome by delivery of activated Mtb antigen (Ag)-pulsed dendritic cells (DCs) into the lungs of vaccinated Mtb-infected mice. DC transfer substantially accelerates the timing of CD4+ T cell accumulation in the lungs, and leads to superior vaccine- induced immunity in Mtb-infected vaccinated mice. Using RNASeq analysis, we have further generated a gene signature in vaccinated mice receiving DC transfer, that is associated with the superior vaccine immunity induced upon Mtb infection. This gene signature reflects upregulation of pathways associated with rapid and effective activation of lung DCs and T cell pathways. Specifically, we found genes associated with activation of CD103+ DC and CD40 pathways upregulated in DC transfer-recipient vaccinated Mtb-infected mice, exhibiting superior Mtb control. In this exploratory proposal, using mouse models of vaccination and Mtb infection, we will investigate whether targeting host lung CD103+ DCs and the CD40 pathway with novel host-directed therapeutics (HDTs) can induce sterilizing vaccine- induced immunity following Mtb infection. These studies will functionally determine the mechanisms that mediate rapid activation of vaccine-induced T cell recall responses to TB. Importantly, these studies will also provide novel HDTs to enhance vaccine responses to either control Mtb burden in infected hosts, or delay TB reactivation in latently-infected individuals.
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0.948 |
2017 — 2021 |
Colonna, Marco (co-PI) [⬀] Khader, Shabaana A. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Group 3 Innate Lymphoid Cells (Ilc3) in Tuberculosis
PROJECT SUMMARY/ABSTRACT Approximately one-third of the world's population is latently infected with TB (LTBI) and have a 10% lifetime risk of developing clinical pulmonary TB (PTB). Global efforts to combat TB are hampered by the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), and variable efficacy of the currently licensed vaccine, M.bovis BCG (BCG). After pulmonary infection with Mtb, aerosolized bacteria are inhaled and interact with the host, resulting in the recruitment of immune cells to the lung to form the tubercle granuloma. Although the presence of granuloma has long been considered a hallmark of TB, the immunological differences between a protective granuloma and a non-protective granuloma has been elusive. Our recent published data, suggest that the presence of inducible Bronchus Associated Lymphoid Tissue (iBALT) within granulomas is indicative of protective granulomas that mediate Mtb control. In contrast, infiltrating neutrophils are characteristic of granulomatous inflammation in PTB patients. These new findings significantly change the overall consensus that TB granulomas in general are protective, but instead put forth the new paradigm that during TB, protective granulomas contain iBALT, while non-protective granulomas are neutrophilic. Our new preliminary data demonstrate that Group 3 Innate Lymphoid cells (ILC3) are among the first innate cells to rapidly accumulate in the lungs upon Mtb infection, and localize within B cell follicles in iBALT-containing granulomas. ILC3 deficiency in mice also results in increased early Mtb susceptibility, and coincides with reduced macrophage accumulation and poorly formed iBALT structures. Thus, the work proposed in this grant will mechanistically address a functional innate role for ILC3 in Mtb infection. In Specific Aim 1 we will define the host factors that mediate early lung ILC3 accumulation following Mtb infection. In Specific Aim 2, we will determine the mechanism(s) via which ILC3 mediate formation of iBALT-containing granulomas and facilitate Mtb control. In Specific Aim 3, we will determine a role for ILC3 in vaccine-induced immunity against TB, and identify new ways to target ILC3 to improve immunity against Mtb infection. Together these aims will provide novel evidence for a critical role for ILC3 in mediating iBALT formation and inducing protective host immunity to TB. Identifying new ways to target ILC3 cells to improve vaccine-immunity as proposed here, will open up novel avenues that can be harnessed for TB vaccine design.
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0.948 |
2020 — 2021 |
Khader, Shabaana A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Novel Th17-Inducing Mucosal Vaccine For Tuberculosis
PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (Mtb) latently infects one-fourth of the world's population, causing pulmonary tuberculosis (TB) in ~10 million people and resulting in ~1.6 million deaths each year. The currently available TB vaccine, Mycobacterium bovis BCG (BCG), shows variable efficacy. In addition, multi-drug resistant (MDR) Mtb strains have recently emerged. Thus, there is a great need for new TB vaccines. Our recent work has demonstrated that T helper type 17 (Th17) cells which produce the cytokine interleukin-17 (IL-17), are a primary effector cell mediating vaccine-induced protection against Mtb. Additionally, mucosal vaccines induce better mucosal immunity and confer superior protection against TB, when compared to systemic routes of immunization. Despite the ability of experimental mucosal adjuvants to induce protective Th17 responses and confer vaccine-induced protection, development of Th17-inducing mucosal TB vaccines for human use is slow. Therefore, there is an urgent need to identify safe and effective mucosal TB vaccines that can induce lung mucosal Th17 responses and understand their mechanism(s) of action. Nanoemulsions (NE) are oil-in-water emulsions formulated with antigen. NE adjuvant was safe and well-tolerated in human volunteers when used as a flu vaccine, and elicited both systemic and mucosal immunity following a single mucosal vaccination. In new published data, we show that mucosal delivery of NE along with Mtb antigens (NE-TB vaccine) can confer Mtb control, and is associated with decreased TB disease in mice. The overall goal of this proposal is to characterize and optimize the protective immune responses induced by NE-TB vaccine thus enabling development of a novel, safe, effective, first-of-kind Th17-inducing TB mucosal vaccine. Thus, we propose the following Specific Aims. In Specific Aim 1, using mouse model of TB, we will identify the prime-boost strategy and the antigen combination that enhances immunogenicity, and improves vaccine-induced protection of NE-TB vaccines, to exceed protection afforded by BCG vaccination. In Specific Aim 2, using the mouse model of TB, we will evaluate the efficacy of the best performing prime-boost NE-TB vaccine strategy against different Mtb strains, in genetically diverse hosts and upon pre-exposure to environmental mycobacteria. In Specific Aim 3, we will carry out preclinical development and proof-of-concept testing of NE-TB vaccines in non-human primates (NHP) infected with Mtb and identify correlates of protection. The work proposed in this grant will determine the mechanism(s) of action, and validate a novel first-of- kind Th17-inducing mucosal NE-TB lead candidate vaccine for use in humans in the near future.
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0.948 |
2020 — 2021 |
Kaushal, Deepak (co-PI) [⬀] Khader, Shabaana A. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Understanding the Functional Role of Myeloid Derived Suppressor Cells in Tuberculosis
PROJECT SUMMARY. Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), is estimated to infect one-fourth of the world's population, resulting in approximately 1.6 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb infection. The tubercle granuloma is long been considered a hallmark of TB. Our published data suggest that the presence of inducible bronchus-associated lymphoid tissue (iBALT)-containing granulomas is indicative of protective granulomas that mediate Mtb control during TB latency. In contrast, infiltrating myeloid derived suppressor cells (MDSCs) as well as neutrophils producing proinflammatory molecules are characteristic of non-protective granulomas during pulmonary TB. MDSCs are induced during pulmonary TB in humans, nonhuman primates (NHPs) and mice and suppress protective T cell responses. Our new data show a protective role for the proinflammatory cytokine, Interleukin (IL)-17 in dampening lung MDSC accumulation and limiting T cell suppression in the lung during TB. Additionally, we show that the MDSC-derived proinflammatory proteins, S100A8/A9 heterodimers are induced upon Mtb infection in humans, NHPs and mice. Furthermore, S100A8/A9-expressing myeloid cells accumulate within the tubercle granuloma and amplify lung MDSC accumulation to mediate Mtb susceptibility. In the current proposal, using mouse and NHP models of TB, we will elucidate the mechanism(s) which regulate and promote MDSC accumulation during TB, and characterize whether MDSCs and their pathways can be targeted as host-directed therapeutics (HDTs) for TB. In Specific Aim 1, using gene deficient and conditional gene deficient mouse models we will determine the IL-17-dependent pathways that limit MDSC accumulation during TB. In Specific Aim 2, we will evaluate the role of S100A8/A9 proteins in driving MDSC accumulation and susceptibility to TB, and also determine whether blocking S100A8/A9 signaling will limit TB relapse. Finally, in Specific Aim 3 we will evaluate if MDSC depletion can prevent TB progression in nonhuman primates (NHPs). At the completion of the aims proposed here, we will have considerably expanded our understanding of the Mtb-specific signaling pathways and factors that positively (S100A8/A9 pathways) and negatively (IL-17 dependent pathways) regulate MDSC accumulation during TB. Additionally, our translational studies in NHPs will enable the use of HDTs to limit MDSCs during TB.
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0.948 |
2021 |
Divangahi, Maziar Kaushal, Deepak (co-PI) [⬀] Khader, Shabaana A |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting Trained Immunity and Th1/Th17 Axis With Combination Adjuvants
PROJECT SUMMARY/ABSTRACT The lack of effective vaccines against most infectious diseases is largely a result of our fundamental lack of understanding of mechanisms involved in protective immunity. Adjuvants incorporated into vaccine formulations have a major impact on vaccine efficacy via modulating and prolonging host immune responses; however, our understanding of their underlying mechanism(s) of action in driving specific immune parameters is incomplete. While vaccines are the most effective way to prevent and control infectious diseases, many pathogens that significantly impact human health remain without an effective vaccine. For example, one-fourth of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB)1, the leading infectious disease killer in the world. It is likely that for TB, and other major infectious diseases (e.g. AIDS and malaria), new adjuvants or adjuvant combinations will be essential for instructing a protective immune response. We and others have shown that targeting both the type 1 T helper (Th1) cells and type 17 T helper (Th17) cells enhance vaccine-induced immunity for TB5-8. Additionally, we have recently demonstrated that live vaccines (e.g. BCG) and adjuvants (e.g. ?-glucan) generate innate memory response, termed trained immunity, via epigenetic reprogramming of monocytes/macrophages, thereby conferring protection against Mtb infection9,10. These data together suggest that combination adjuvants targeting both innate trained immunity and adaptive Th1/Th17 cellular responses can enhance protective immunity against pathogens. Thus, defining the mechanisms of action of combination adjuvants that generate potent trained immunity and protective Th1/Th17 axis, are the overall goals of this proposal. In the current proposal, we hypothesize that combinations of adjuvants that drive Th1 responses (AS01 or UM-1007, a novel TLR7/8 agonist) and Th17 responses (?- glucan, nanoemulsion, or UM-1098, a novel Mincle agonist) will result in Th1/Th17 adaptive responses and/or enhance trained immunity. We will achieve these overall goals through the following four Specific Aims. Specific Aim 1: To determine the mechanisms by which combination adjuvants elicit Th1/Th17 immune responses. Specific Aim 2. To determine the impact of combination adjuvants on hematopoietic stem cells and trained immunity. Specific Aim 3. To determine whether use of combination adjuvants improves recall Th1/Th17 responses and trained immunity upon challenge. Specific Aim 4. Determine the mechanism of action of combination adjuvants in a pre-clinical human-like rhesus macaque model. Together, the aims of this study will map out the pathways induced by combination of adjuvants that effectively drive Th1/Th17 responses and trained immunity. Through Mtb challenge studies, we will demonstrate whether the mechanisms by which Th1/Th17 and trained immunity are elicited are involved in protection against pathogen challenge. While we will use TB as a model system, we envision that dissecting the mechanism of adjuvants-mediated immunity has broader impact on many other infectious diseases.
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0.948 |