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Principal Investigator: Jennifer Manuzak
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2024
Award: $621,740
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY/ABSTRACT
HIV remains one of the world’s most devastating diseases, with more than 38 million people living with HIV
(PLWH) and an additional 1.7 million new infections per year. Moreover, in 2019, infection with malaria was
reported to have reached 229 million cases worldwide and caused over 409,000 deaths. Although advances
have been made in reducing the incidence of both HIV and malaria, the risk of infection with either disease is
still great, especially in resource-limited countries. Importantly, the geographical overlap in endemic HIV and
malaria constitutes a high risk for co-infection, fueling transmission and pathogenesis of both diseases. The
burdens of HIV and malaria are particularly elevated in pregnant women, leading to increased risk of poor birth
outcomes and maternal and infant mortality. Notably, malaria in pregnancy (MIP) in women living with HIV (WLH)
results in even greater risk of adverse outcomes and the treatments currently available for MIP have only shown
limited success in WLH. Therefore, our long-term goal is to identify key factors in MIP immunopathogenesis to
aid in development of new therapeutics that can safely and effectively reduce maternal and fetal morbidity and
mortality in WLH. The overall objectives for this application are to (1) dissect the pathogenic outcomes of P.
fragile infection in SIV+ pregnant rhesus macaques (RMs) and (2) mechanistically elucidate the role of
neutrophils and innate lymphoid cells (ILCs) in decidual inflammation during SIV/P. fragile co-infection. Our
central hypothesis is that P. fragile and SIV co-infection of pregnant RMs will result in greater placental
parasitemia and dysfunction that associates with higher levels of decidual neutrophil accumulation and ILC
activation, as compared to mono-infected or healthy RMs. The rationale for the proposed research is that a better
understanding of the complex interplay of neutrophils and ILCs in placental dysfunction will promote subsequent,
targeted studies to leverage our findings to develop novel interventions to treat MIP in WLH. The central
hypothesis will be tested by pursuing three specific aims: 1) To identify key pathogenic consequences of P.
fragile infection and the impact of SIV co-infection during pregnancy; 2) To define the role of neutrophils in
peripheral and decidual inflammation during co-infection of pregnant RMs; and 3) To determine the role of ILCs
in regulating peripheral and decidual inflammation in co-infected pregnant RMs. The proposed research is
innovative because it focuses on using a highly translational animal model to open new scientific horizons on
key alterations in innate immune function that drive poor maternal and fetal outcomes in SIV and P. fragile co-
infection, which closely parallels the dynamics of HIV and P. falciparum infection. The proposed research is
significant because it is expected to provide a strong, evidence-based foundation for future pre-clinical studies
of the biological mechanisms of MIP in WLH. Ultimately, these studies will provide new opportunities to develop
therapies and prevention strategies to reduce morbidity and mortality due to malaria in highly vulnerable WLH.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adherence><African><Anemia><Animal Model><Animal Models and Related Studies><Assay><Bioassay><Biological><Biological Assay><Birth><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Cells Placenta-Tissue><Cessation of life><Chemotactic Cytokines><Clinical><Complex><Country><Death><Decidua><Decidua Basalis><Decidua Graviditas><Development><Disease><Disorder><Dysfunction><Endothelium><Fetal Growth><Foundations><Frequencies><Functional disorder><Future><Geography><Gestation><Goals><HIV><Health><Homologous Chemotactic Cytokines><Human><Human Immunodeficiency Viruses><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunologic Factors><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological Factors><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Immunology><In Vitro><Incidence><Infant Mortality><Infant Mortality Total><Infection><Inflammation><Inflammatory><Intercrines><Intervention><Intervention Strategies><Knowledge><LAV-HTLV-III><Low Birth Weight Infant><Lymphadenopathy-Associated Virus><Lymphoid Cell><M mulatta><M. mulatta><Macaca mulatta><Malaria><Marrow Neutrophil><Maternal Health><Maternal Mortality><Maternal placenta><Miscarriage><Mission><Modeling><Modern Man><Monitor><Morbidity><Morbidity - disease rate><NICHD><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Normal Placentoma><Outcome><P falciparum><P. falciparum><P.falciparum><Paludism><Parasitemia><Parasites><Parturition><Pathogenesis><Pathogenicity><Peripheral><Persons><Phenotype><Physiologic><Physiological><Physiopathology><Placenta><Placenta Embryonic Tissue><Placentome><Plasmodium><Plasmodium Infections><Plasmodium falciparum><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Preclinical Testing><Pregnancy><Pregnancy Outcome><Pregnant Women><Premature Birth><Prematurely delivering><Preterm Birth><Preventative strategy><Prevention strategy><Preventive strategy><Production><Public Health><Publishing><Reporting><Research><Research Resources><Resources><Rhesus Macaque><Rhesus Monkey><Risk><Role><SIS cytokines><SIV><Simian Immunodeficiency Viruses><Spontaneous abortion><Testing><Tissues><Transmission><Validation><Viremia><Virus-HIV><Vulnerable Populations><Woman><Women's mortality><Work><adverse consequence><adverse outcome><biologic><chemoattractant cytokine><chemokine><co-infection><coinfection><cytokine><death among females><death among infants><death among women><death in females><death in first year of life><death in infancy><death in infants><death in women><death rate among women><death rate in women><develop therapy><developmental><evidence base><expectant mother><expecting mother><female death><female mortality><fetal><fetal infection><gene signatures><genetic signature><high risk><host response><immune system response><immunologic substance><immunological substance><immunoresponse><infant death><infant demise><infantile death><infection risk><innate immune function><innate immune mechanisms><innovate><innovation><innovative><intervention design><intervention development><interventional strategy><intra-uterine growth><intrauterine growth><low birth weight><low birthweight><malaria infection><malaria-infected><malarial infection><maternal death><model of animal><mortality><mortality among females><mortality among women><mortality in females><mortality in infants><mortality in women><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><non-human primate><nonhuman primate><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><parasaetemia><pathophysiology><pre-clinical study><pre-clinical testing><preclinical study><pregnant><pregnant mothers><premature childbirth><premature delivery><preterm delivery><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stillbirth><stillborn><success><therapy design><therapy development><transmission process><treatment design><treatment development><validations><viraemia><viral sepsis><virusemia><vulnerable group><vulnerable individual><vulnerable people><women's death><women's death rate>