2013 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 Category |
Grant-in-Aid for Scientific Research (B)
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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 / multi-photon microscopy / olfactory bulb / smell loss |
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| Research Abstract |
The dysfunction of the blood-brain-barrier (BBB) is the main feature of various central nervous system inflammatory disorders including cerebral malaria; however, little is known how it occurs. Evidences suggest that there is a “cross-talk” between brain and immune system. In this study, we aimed to elaborate immune cells dynamics causing BBB leakage and cerebral malaria by a new approach, bringing together immunology, neuroscience and imaging technologies.
To comprehensively investigate cross-talk between brain and the immune system during cerebral malaria, we used highly advanced powerful imaging techniques such as magnetic resonance imaging (11.7 T ultra-high field MRI) and/or multi-photon microscopy brain imaging. While MRI provides non-invasive whole brain imaging, multi-photon live imaging allows studying single-cell dynamics in living mice.
We’ve visualized brain before and after the cerebral malaria symptoms start. By using ultra-high field MRI, we’ve revealed that olfactory bulb is a special “weak point” to be affected first during cerebral malaria progression. We next visualized this previously un-noticed place with multi-photon intravital microscopy and captured fresh bleedings caused by parasites and/or related events. Our studies concluded that the olfactory bulb is the first place to sense malaria infection and permit “cross-talk” between the brain and the activated immune system. This links the olfactory with loss of smell, high fever, astrocytes, chemokine/chemokine receptor interactions and CD11c+ CD8 T cells.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
In FY2013, we have identified in mice that the olfactory region is a vulnerable location for vascular leakage during experimental cerebral malaria in which this discovery could only be possible by using cutting edge technologies, an ultra-high field MRI in combination with multi-photon live imaging microscopy. The olfactory bulb is the area physically disrupted and damaged functionally (loss of smell) by Plasmodium parasites, followed by high fever. Thus, we identified that there is an early symptom, olfaction loss, before the onset of coma. Olfactory bulb is a very unique organ with special architectural structure, therefore, olfactory easily undergoes parasite accumulation and cell occlusion followed by micro-bleeding. We found that circulating parasites in the olfactory vessels are sensed by astrocytes around olfactory glomeruli at the early stage of infection, and may release CCL21and may have a role for the recruitment of pathological CD8 T cells into brain. We further evaluated this novel understanding into a novel intervention strategy by blocking chemokine-receptor interactions when the early symptom of experimental cerebral malaria, olfaction loss, was evident. 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, cheap and easy diagnosis of cerebral malaria.
Therefore, in a 1 year of time period, we could publish our results in a highly regarded journal Cell Host Microbe (Impact Factor 13).
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| Strategy for Future Research Activity |
We have two main considerations in FY2014: (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 who is expert for the monkey cerebral malaria model, and validate our mice data by using rhesus monkey P. coatneyi infection model. (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. We still do not understand what might be causing fever during CM needs to be further investigated in detail. Chemokine/cytokine storms occur during cerebral malaria locally and systematically, and even in the olfactory bulb. Therefore olfactory could be a future important place for the intervention of cerebral malaria.
Alternatively, we’ll evaluate the reasons of fever responses during mouse malarias in comparison with bacterial products such as LPS and virus infections. Because of the lack of proper devices for the measurement of fever in mice (due to the presence of circadian rhythm), we’ve newly developed thermal camera system for the fever measurement. We’ll need to install this machine in our facilities for further detailed experiments. We’ll try several drugs/compounds which can reduce fever responses via olfactory administration. Although olfactory administration is a challenging model for the administration of bigger drugs-compound in molecular weight, we’ll investigate nanomedical applications.
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| Expenditure Plans for the Next FY Research Funding |
Our paper was almost accepted in March. Therefore we transferred possible publication charges to next fiscal year.
Will be used for publication charges.
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[Journal Article] Olfactory is an overlooked site for the initiation of cerebral malaria2014
Author(s)
Zhao H, Aoshi T, Kawai S, Mori Y, Konishi A, Ozkan M, Fujita Y, Haseda Y, Shimizu M, Kohyama M, Kobiyama K, Eto K, Nabekura J, Horii T, Ishino T, Yuda M, Hemmi H, Kaisho T, Akira S, Kinoshita M, Tohyama K, Yoshioka Y, Ishii KJ, Coban C
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Journal Title
Cell Host Microbe
Volume: in press
Pages: in press
Peer Reviewed
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[Journal Article] Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist2014
Author(s)
Kobiyama K, Aoshi T, Narita H, Kuroda E, Hayashi M, Tetsutani K, Koyama S, Mochizuki S, Sakurai K, Katakai Y, Yasutomi Y, Saijo S, Iwakura Y, Akira S, Coban C, Ishii KJ
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Journal Title
Proc Natl Acad Sci U S A
Volume: 111(8)
Pages: 3086-91
DOI
Peer Reviewed
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