Biology subjects

Harty, J. T.

Publications and source records attributed to Harty, J. T..

6 recordsLinked to original sources

bioRxiv2025

mRNA vaccination overcomes hemozoin-mediated impairment of whole parasite vaccine efficacy for malaria

Malaria is a persistent global public health threat. Immunization with Radiation Attenuated Sporozoites (RAS) drives efficient CD8+ T cell dependent sterilizing immunity to malaria in humans. However, this protection is compromised in individuals living in malaria endemic regions and the mechanism(s) of the vaccine failure remain incompletely understood. In this study, we develop a murine model of Plasmodium infection where prior blood-stage exposure compromises RAS-induced CD8+ T cell responses and subsequent protection. We further identify the persisting malarial pigment hemozoin as a mediator of impaired CD8+ T cell responses. Mechanistically, we link this defect to impaired antigen uptake by dendritic cells, leading to reduced T cell activation. Importantly, we designed a lipid nanoparticle-encapsulated mRNA vaccine that encodes a string of Plasmodium CD8+ T cell epitopes and found that this vaccine overcomes the T cell defect and restores protection in Plasmodium exposed mice. Moreover, a combined RAS+mRNA vaccine regimen enhances liver resident memory T cells and protection even in malaria experienced hosts. These findings support the identification of hemozoin as a long-lived obstacle to vaccine efficacy in malaria endemic areas and provide a rational framework for designing malaria vaccines that are effective in endemic settings.

microbiology↗

bioRxiv2024

Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria

Plasmodium parasites undergo development and replication within the hepatocytes before infecting the erythrocytes and initiating clinical malaria. Although type-I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1 disruption of the PV activates caspase-1 inflammasome, inducing pyroptosis to remove the infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium; their pharmacologic or genetic inhibition led to profound malarial susceptibility, and are essential in vivo. In addition to identifying the IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, this study extends our understanding of how non-immune cells are integral to protective immunity against malaria.

immunology↗

bioRxiv2023

Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury

Accumulating evidence suggests that type I interferon (IFN-I) signaling is a key contributor to immune cell-mediated neuropathology in neurodegenerative diseases. Recently, we demonstrated a robust upregulation of type I interferon-stimulated genes in microglia and astrocytes following experimental traumatic brain injury (TBI). The specific molecular and cellular mechanisms by which IFN-I signaling impacts the neuroimmune response and neuropathology following TBI remains unknown. Using the lateral fluid percussion injury model (FPI) in adult male mice, we demonstrated that IFN /{beta} receptor (IFNAR) deficiency resulted in selective and sustained blockade of type I interferon-stimulated genes following TBI as well as decreased microgliosis and monocyte infiltration. Phenotypic alteration of reactive microglia also occurred with diminished expression of molecules needed for MHC class I antigen processing and presentation following TBI. This was associated with decreased accumulation of cytotoxic T cells in the brain. The IFNAR-dependent modulation of the neuroimmune response was accompanied by protection from secondary neuronal death, white matter disruption, and neurobehavioral dysfunction. These data support further efforts to leverage the IFN-I pathway for novel, targeted therapy of TBI.

neuroscience↗

bioRxiv2022

ISG15-modification of the Arp2/3 complex restricts pathogen spread

The ubiquitin-like protein, ISG15, can act as a cytokine or can covalently modify host and pathogen-derived proteins. The consequences of ISG15 modification on substrate fate remain unknown. Here we reveal that ISGylation of the Arp2/3 complex slows actin filament formation and stabilizes Arp2/3 dependent structures including cortical actin and lamella. When properly controlled, this serves as an antibacterial and antiviral host defense strategy to directly restrict actin-mediated pathogen spread. However, Listeria monocytogenes takes advantage in models of dysregulated ISGylation, leading to increased mortality due to augmented spread. The underlying molecular mechanism responsible for the ISG15-dependent impact on actin-based motility is due to failed bacterial separation after division. This promotes spread by enabling the formation of multi-headed bacterial "bazookas" with stabilized comet tails that can disseminate deeper into tissues. A bacterial mutant that cannot recruit Arp2/3 or a non-ISGylatable mutant of Arp3 is sufficient to rescue slowed comet tail speed and restrict spread. Importantly, ISG15-deficient neonatal mice have aberrant epidermal epithelia characterized by keratinocytes with diffuse cortical actin, which could underlie observed defects in wound healing in human patients who lack ISG15. Ultimately, our discovery links host innate immune responses to cytoskeletal dynamics with therapeutic implications for viral infection and metastasis.

cell biology↗

bioRxiv2022

Antigen presentation by discrete class I molecules on brain endothelium dynamically regulates T-cell mediated neuropathology in experimental cerebral malaria

CD8 T cell engagement of brain vasculature is a putative mechanism of neuropathology in human cerebral malaria. To define contributions of brain endothelial cell MHC class I antigen-presentation to CD8 T cells in establishing this pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules on brain endothelium. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observe that H-2Kb and H-2Db regulate distinct patterns of disease onset, CD8 T cell infiltration, targeted cell death, and regional blood-brain barrier (BBB) disruption. Strikingly, ablation of H-2Kb or H-2Db from brain endothelial cells resulted in reduced CD8 T cell activation, attenuated T cell interaction with brain vasculature, lessened targeted cell death, preserved BBB integrity, and prevented ECM and the death of the animal. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

neuroscience↗

bioRxiv2021

Altered cleavage of Caspase-1 in hepatocytes limits control of malaria in the liver

Malaria, caused by Plasmodium parasites, is a devastating disease that kills over half a million people each year1. Plasmodium sporozoites inoculated by mosquitoes into mammalian hosts undergo a clinically silent phase of obligatory development and replication in hepatocytes before initiating the life-threatening blood-stage of malaria2. Thus, understanding the immune responses elicited by Plasmodium infection in the liver is key to controlling clinical malaria and transmission3,4. Here, we show that Plasmodium DNA can be detected by AIM2 (absent in melanoma 2) sensors in the infected hepatocytes, resulting in Caspase-1 activation and pyroptotic cell-death. However, Caspase-1 was observed to undergo only partial cleavage in hepatocytes, limiting pyroptosis, and the maturation of pro-inflammatory cytokines classically associated with Caspase-1 activation. We discovered that the extent of Caspase-1 cleavage in cells is determined by the expression of ASC (apoptosis-associated speck-like protein containing a CARD). ASC expression is inherently low in hepatocytes, and transgenically enhancing it in the hepatocytes induced complete processing of Caspase-1, efficient secretion of pro-inflammatory cytokines, enhanced pyroptotic cell-death, and markedly improved control of malaria infection in the liver. In addition to describing a novel pathway of natural immunity to malaria, our findings uncover a key aspect of liver biology that may have been exploited during evolution by successful hepatotropic pathogens.

immunology↗