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Neutrophil-driven mucosal dysfunction in SIV/malaria co-infection

SIV/疟疾混合感染中中性粒细胞驱动的粘膜功能障碍

基本信息

批准号：
10254609
负责人：
Jennifer Manuzak
金额：
$ 34万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254609
关键词：
Affect Area Biological Blood Circulation Blood Flow Cytometry Cessation of life Characteristics Clinical Research Coculture Techniques Communicable Diseases Country Data Development Disease Economic Burden Endemic Diseases Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Exposure to Flow Cytometry Frequencies Functional disorder Future Gastrointestinal tract structure Geographic Locations Geography Goals HIV HIV Infections Histology Homeostasis Human Hyperactivity Immune Immune System Diseases Immune response Immunophenotyping In Vitro Incidence Individual Infection Inflammation Inflammatory Inflammatory Response Intestinal Mucosa Intestinal parasite Kinetics Knowledge Link Macaca Macaca mulatta Malabsorption Syndromes Malaria Modeling Morbidity - disease rate Morphology Mucosal Immunity Mucous Membrane Neutrophil Infiltration Pathogenesis Pathology Permeability Phagocytes Plasmodium Population Property Public Health Rectum Reporting Research Resources Risk Role SIV Severity of illness Sum System Tissues Work co-infection effective therapy experience experimental study extracellular gastrointestinal gastrointestinal epithelium immune activation immune function infection risk inflammatory disease of the intestine innovation insight intestinal homeostasis malaria infection microbial mortality neutrophil nonhuman primate novel strategies novel therapeutic intervention pathogen preclinical study response therapeutic target transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT With more than 37 million people living with HIV (PLWH) and an additional 1.7 million new infections per year, HIV remains one of the world’s most devastating diseases. Moreover, in 2018, infection with malaria was reported to have reached 228 million cases worldwide and to have caused over 405,000 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, as HIV and malaria are endemic to similar areas, the geographical overlap constitutes a great risk for co-infection, fueling the transmission and pathogenesis of both diseases. HIV and malaria have each been shown to cause gastrointestinal (GI) pathologies, including disruption of the epithelial barrier and elevated microbial translocation. These disease characteristics are highly associated with risk of morbidity and mortality; however, the underlying biological mechanisms by which they occur remain unclear. Previous work suggested that inflammatory neutrophils accumulate, are hyperactivated, and have prolonged survival capabilities in the GI tract during SIV/HIV infection. Additionally, prior studies demonstrated that alterations in neutrophil function associates with malaria pathogenesis. However, the role of neutrophils in mucosal dysfunction and risk for morbidity and mortality in the context of HIV/malaria co-infection has not been established. Our global hypothesis is that malaria co-infection of SIV-infected rhesus macaques will result in increased neutrophil accumulation and hyperactivity in the GI tract, which will lead to elevated immune activation, epithelial barrier dysfunction and microbial translocation. In the proposed project, we aim to longitudinally assess neutrophil kinetics and function throughout malaria infection of SIV-infected rhesus macaques. Additionally, we will characterize the role of neutrophils in exacerbated mucosal immune activation, barrier integrity, and microbial translocation in SIV/malaria co-infected macaques. Finally, we will utilize in vitro co-culture systems to investigate the use of neutrophil targeting strategies to limit inflammatory responses and restore barrier integrity. In sum, these studies will generate critical knowledge of the impact of malaria co-infection on SIV-associated immune dysfunction. Moreover, these experiments will lay the groundwork for future pre-clinical and clinical studies targeting neutrophils to reduce intestinal inflammation and restore mucosal homeostasis. Ultimately, the successful completion of this project will propel the development of more effective therapies for use in resource-limited settings, where the burden of HIV and malaria are greatest.

项目总结/文摘