2014 Fiscal Year Annual Research Report
マラリア感染における脳内免疫反応の4次元イメージング
| Project/Area Number |
25293100
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| Research Institution | Osaka University |
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Principal Investigator |
COBAN Cevayir 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (00397712)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Keywords | Cerebral malaria / imaging / MRI / two-photon microscopy / olfactory bulb / smell loss |
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| Outline of Annual Research Achievements |
Cerebral malaria is a deadly complication of P. falciparum infection in humans and characterized by sudden coma, death or long-term neuro-disability. Studies using a mouse model of experimental cerebral malaria (ECM) have indicated that blood-brain barrier (BBB) disruption and CD8 T cell recruitment contribute to disease, but the spatiotemporal mechanisms are poorly understood. To understand how BBB disruption occurs during ECM, we have approached to the problem by using cutting-edge imaging technologies.We have shown in FY2014 by ultra-high-field MRI and multiphoton microscopy that the olfactory bulb is physically and functionally damaged (loss of smell) by Plasmodium parasites during ECM. The trabecular small capillaries comprising the olfactory bulb show parasite accumulation and cell occlusion followed by microbleeding, events associated with high fever and cytokine storm. Specifically, the olfactory upregulates chemokine CCL21, and loss or functional blockade of its receptors CCR7 and CXCR3 results in decreased CD8 T cell activation and recruitment, respectively, as well as prolonged survival. Thus, early detection of olfaction loss and blockade of pathological cell recruitment may offer potential therapeutic strategies for ECM. Given that even 1 day early detection of malarial coma could increase treatment success dramatically; this previously unnoticed, truly overlooked location and detection of olfaction loss during malaria infection may provide early and easy diagnosis of CM. We published our results in Cell Host Microbe (Zhao et al, 2014,14;15 (5):551-63)
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
In FY2014, we followed our studies on focusing on olfactory bulb and its relation to the fever. One of the factors involved in BBB leakage might be a high fever. Although it is speculated that there should be thermoregulation in mouse models of malaria similar to murine sepsis models, currently there have been no reports of a febrile response in mouse malarias. Moreover, ECM, in contrast to human infection, is considered to cause hypothermia. By using a thermal camera, we detected a distinct fever period occurring 24 hr before the final manifestation of disease, thermal loss, and death. Importantly, the fever period correlated with severe olfaction loss. We concluded that systemic and local cytokine/chemokine storm might cause high fever in mice, similar to human CM cases, and probably had the major role in the loss of BBB integrity. Importantly, lack of high fever in Rag2-/- mice and in lethal and nonlethal Py infections may confirm that fever is associated with ECM and might be related to BBB leakage. However, the mediators causing fever during ECM and their direct role on BBB disruption are currently unknown. There is a lack of information and direct correlation in murine malaria that proinflammatory cytokines would be elevated and cause malarial fever. Because, our current research identified factors that might be involved in preceding the BBB opening from the olfactory bulb, to confirm our findings, we have bred several KO mice deficient in chemokines and or fever-related genes.
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| Strategy for Future Research Activity |
We have two main considerations in FY2015: (1) Are these findings applicable to humans? Since obtaining human samples from endemic areas such as Africa may take several years, instead, we’ll collaborate with Prof S. Kawai (Dokkyo University) who is expert for the monkey cerebral malaria model, and validate our mice data by using rhesus monkey P. coatneyi infection model. Due to lack of enough funding, our studies slowed down in FY2014. We hope to continue our aim during FY2015. (2) Can olfactory bulb be an intervention target for the treatment of cerebral malaria? We found two mechanisms could be reasons for the BBB disruption from olfactory; a chemokine/cytokine storm and fever. The conclusion driven from our studies is that chemokine/cytokine storms occur during cerebral malaria locally and systematically. Therefore olfactory could be a future important location for the intervention of cerebral malaria. Our studies from FY2013 are still ongoing with using other chemokine-deficient mice and/or chemokine blocking strategy for the treatment of CM.
Alternatively, we’ll continue to evaluate the reasons of fever responses during mouse malarias. We’ve confirmed by using genetically KO mice that some mediators involved in the fever in response to bacterial products might be functioning differentially during cerebral malaria fever. We’ll continue to try several drugs/compounds which can reduce fever responses via olfactory administration.
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| Causes of Carryover |
Because obtaining human samples from endemic areas such as Africa may take several years, instead, we’ll collaborate with Prof S. Kawai (Dokkyo University) who is expert for the monkey cerebral malaria model, and validate our mice data by using rhesus monkey P. coatneyi infection model. Due to lack of enough funding, our studies slowed down in FY2014. We hope to continue our aim during FY2015. (2) Can olfactory bulb be an intervention target for the treatment of cerebral malaria? We found two mechanisms could be reasons for the BBB disruption from olfactory; a chemokine/cytokine storm and fever. Therefore olfactory could be a future important location for the intervention of cerebral malaria.
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| Expenditure Plan for Carryover Budget |
1.We'll continue non-human cerebral malaria model with using imaging techniques.
2. We'll use treatments modalities from the olfactory bulb.
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