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Viral and host factors in neuroinvasion of encephalitis alphaviruses

脑炎甲病毒神经侵袭的病毒和宿主因素

基本信息

批准号：
10389982
负责人：
WILLIAM B KLIMSTRA
金额：
$ 63.49万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10389982
关键词：
3&apos Untranslated Regions Alphavirus Alphavirus Infections Area Astrocytes Binding Binding Sites Biological Warfare Bioterrorism Blood - brain barrier anatomy Brain Brain imaging Category B pathogen Caveolins Cells Cessation of life Dendritic Cells Disease Disease Outbreaks Encephalitis Exhibits Future Hematogenous Hematopoietic Heparitin Sulfate Heterogeneity Human Human Activities IFNAR1 gene Imaging Techniques Immune Immunoelectron Microscopy In Vitro Incidence Infection Injury Innate Immune Response Integration Host Factors Interferon Type I Interferons Intranasal Administration Invaded Latin America Lymphoid Tissue Maps Mediating MicroRNAs Microglia Modeling Myeloid Cells Neuraxis Neurons New England Pericytes Peripheral Phenotype Publishing Registries Role Route Sentinel Serum Signal Transduction Site South America Testing Therapeutic Tropism United States United States National Institutes of Health Venezuelan Venezuelan Equine Encephalitis Virus Viral Viral Vector Virulence Virulence Factors Virus Virus Replication Western Equine Encephalitis Virus adaptive immune response blood-brain barrier disruption brain cell brain endothelial cell cell type climate change cytokine experimental study genomic locus gulf coast human model in vivo macrophage member mortality mouse model mutant nanoluciferase neurotropic virus neurovascular unit novel pathogen prevent receptor response subcutaneous trafficking transcytosis vector mosquito vector-borne

项目摘要

SUMMARY The long-term objective of this multi-PI project is to determine how host-pathogen interactions impact entry, infection, and spread of encephalitic alphaviruses in the central nervous system (CNS). The vector-borne neurotropic viruses, Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, WEEV), invade the CNS after subcutaneous inoculation and initial interaction with immune sentinel cells, such as macrophages and dendritic cells (DCs) (VEEV), or fibroblastic, osteoblastic and other cell types (EEEV, WEEV). Both EEEV and VEEV enter the brain via the hematogenous route but only VEEV is found in olfactory neurons. The CNS lacks intraparenchymal lymphoid tissues and cannot initiate adaptive immune responses; thus, it mainly relies on innate responses communicated through local and systemic cytokine secretion, which modulate the status of resident neural cells and limits viral neuroinvasion and the extent of infection. CNSresident cells may include multiple members of the neurovascular unit (NVU) such as brain microvascular endothelial cells (BMECs), pericytes, astrocytes, microglia and neurons themselves that may be infected directly or acted upon by regionally or systemically produced cytokines. VEEV is a highly lymphotropic virus eliciting robust serum cytokine responses after peripheral inoculation, while EEEV tropism in lymphoid tissues is highly restricted, and serum cytokine responses are much lower, and in the case of type I IFN, often undetectable. In published studies, two primary virulence factors for EEEV in human and murine models defined mechanisms that suppresses replication in immune sentinel myeloid cells and greatly limit innate immune (especially interferon) responses to EEEV infection in vitro and in vivo1. How these factors, which include the presence of binding sites for the hematopoietic cell-specific microRNA, mir142-3p, in the EEEV 3' untranslated region (UTR)1-3, and efficient binding of EEEV to heparan sulfate (HS) receptors on cells4,5, impact the differential neuroinvasion and CNS dissemination of EEEV versus VEEV is unknown. Supporting the idea that differences in EEEV versus VEEV cytokine induction may be critical to neuroinvasion, we found that type I IFN-dependent responses directly regulate transcytosis, preventing alphavirus entry across the BBB and modulating the level of infection and injury in cells of the NVU6. Thus, systemic and local cytokine responses during alphavirus infection induce BMECs and pericytes to regulate viral entry at the blood-brain barrier (BBB) and potentially other CNS sites. This is consistent with the relative extent of virus replication at terminal stages of disease as EEEV exhibits widespread infection of neurons throughout the CNS while VEEV replication is much more focal (unpublished). Using mutant VEEV and EEEV, novel viral vectors that express indicators of infection (e.g., eGFP, nanoLuciferase) in vivo, we have observed regional heterogeneity in dominant sites of entry between these alphaviruses. With regard to BBB entry, our studies also indicate that viral neuroinvasion precedes BBB disruption, utilizing caveolin-mediated transcytosis to cross the BBB. We hypothesize that type I interferon responses differentially impact the entry and infection of EEEV and VEEV at the NVU via virus-specific induction of replication-restricting innate immune responses. To test these hypotheses we will: Aim 1. Define alphavirus and host specific mechanism in vitro that regulate viral entry and infection at the NVU. Aim 2: Define the in vivo functional role of type I IFN in protection from alphavirus neuroinvasion at the NVU.

总结