Olfactory Plays a Key Role in Spatiotemporal Pathogenesis of Cerebral Malaria

Zhao, Hong; Aoshi, Taiki; Kawai, Shinya; Mori, Yutaka; Konishi, Aki; Özkan, Mustafa; Fujita, Yukiko; Haseda, Yasunari; Shimizu, Mikiko; Kohyama, Masanori; Kobiyama, Kouji; Eto, Kojiro; Nabekura, Junichi; Horii, Toshihiro; Ishino, Tomoko; Yuda, Masao; Hemmi, Hiroaki; Kaisho, Tsuneyasu; Akira, Shizuo; Kinoshita, Manabu; Tohyama, Koujiro; Yoshioka, Yoshichika; Ishii, Ken J.; Coban, Cevayir

doi:10.1016/j.chom.2014.04.008

Cited by 54 publications

(64 citation statements)

References 55 publications

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“…Our results on CD8 + T cell activation confirm previous ex vivo data showing a superior efficiency of CD8 + DC at priming OT-I cells after exposure to transgenic PbA parasites expressing SIINFEKL (9). They are also consistent with in vivo studies showing a reduced number of activated endogenous CD8 + T cells after PbA infection of mice deficient in CD8 + DC (37,38,69). As CD8 + DC possess specialized machinery for cross-presentation (34), this likely underlies their unique capacity to prime CD8 + T cells during infection by Plasmodium species.…”

Section: Discussionsupporting

confidence: 81%

“…Batf3-deficient mice contain all DC subsets except CD8 + DC and their migratory equivalents, the CD103 + DC, and have been shown to sustain low CD8 + T cell proliferation after PbA infection (69). However, on a B6 background, some CD8 + DC can be found in the LN of Batf3-deficient mice (70) and precursors capable of MHC II-restricted presentation but not cross-presentation are found in the spleen (71).…”

Section: Cd8 + DC Are the Main Apc For Pbt-ii Cellsmentioning

confidence: 97%

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Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Fernandez‐Ruiz

Lau

Ghazanfari

et al. 2017

The Journal of Immunology

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We describe an MHC class II (I-Ab)–restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.

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Section: Discussionsupporting

confidence: 81%

Section: Cd8 + DC Are the Main Apc For Pbt-ii Cellsmentioning

confidence: 97%

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Fernandez‐Ruiz

Lau

Ghazanfari

et al. 2017

The Journal of Immunology

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“…This region is populated with an intricate network of microvessels. Recently, Zhao et al showed that microhemorrhages occur early during ECM in this region (47). Our data corroborate this finding and also show that functionally, these hemorrhages are associated with a leaky BBB.…”

Section: Discussionsupporting

confidence: 81%

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

et al. 2017

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Human cerebral malaria (HCM) is a serious complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology. Approximately 70% of fatal malaria cases occur in children less than 5 years old (1). While uncomplicated Plasmodium falciparum infection is highly treatable, the most severe complication, cerebral malaria, presents a significant problem for patients. Human cerebral malaria (HCM) is characterized by disruption of the blood-brain barrier (BBB), coma, seizures, and death (2, 3). Patients that survive HCM are prone to persisting cognitive and neurological deficits after they have recovered from the infection (4, 5). While antimalarial drugs have shown efficacy in killing parasites, treatments to improve the outcome of HCM are lacking (6). Furthermore, the cellular mechanisms regulating

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“…Neither capillaries nor arterioles in the cortical microvasculature of mice with ECM nor PCV, arterioles, or capillaries of mice with hyperparasitemia were affected (Nacer et al, in press), thus emphasizing the central role of the postcapillary venule BBB in the ECM-associated vasculopathy (Nacer et al, 2012). Similarly, CD8+ T cells were observed to actively crawl along the wall of larger vessels of the olfactory bulb of PbA-infected mice (Zhao et al, 2014). Because leukocyte adhesion occurred in PCV and larger venules, the center of these vessels remained perfused and complete vascular occlusion was not observed.…”

Section: Lessons From the Murine Modelmentioning

confidence: 93%

Fatal cerebral malaria: a venous efflux problem

Frevert

Nacer

2014

Front. Cell. Infect. Microbiol.

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Most Plasmodium falciparum-infected children with cerebral malaria (CM) die from respiratory arrest, but the underlying pathology is unclear. Here we present a model in which the ultimate cause of death from CM is severe intracranial hypertension. Dynamic imaging of mice infected with P. berghei ANKA, an accepted model for experimental CM, revealed that leukocyte adhesion impairs the venous blood flow by reducing the functional lumen of postcapillary venules (PCV). The resulting increase in intracranial pressure (ICP) exacerbates cerebral edema formation, a hallmark of both murine and pediatric CM. We propose that two entirely different pathogenetic mechanisms—cytoadherence of P. falciparum-infected erythrocytes in pediatric CM and leukocyte arrest in murine CM—result in the same pathological outcome: a severe increase in ICP leading to brainstem herniation and death from respiratory arrest. The intracranial hypertension (IH) model unifies previous hypotheses, applies to human and experimental CM alike, eliminates the need to explain any selective recognition mechanism Plasmodium might use to target multiple sensitive sites in the brain, and explains how an intravascular parasite can cause so much neuronal dysfunction.

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Olfactory Plays a Key Role in Spatiotemporal Pathogenesis of Cerebral Malaria

Cited by 54 publications

References 55 publications

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

Fatal cerebral malaria: a venous efflux problem

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