Olfactory plays a key role in spatiotemporal pathogenesis of cerebral malaria-Early diagnosis and new treatment modalities are expected-SummaryA special and truly overlooked spot that is vulnerable to Plasmodium parasites during experimental cerebral
malaria has been discovered using highly sensitive ultra-high field MRI and multi-photon live imaging, by theOsaka University Immunology Frontier Research Center(IFReC) Laboratory of Malaria Immunology

Research Group (headed by Associate Professor Cevayir COBAN) and colleagues Prof Ken J Ishii and Dr
Taiki Aoshi from the National Institute for Biomedical Innovation (NIBIO), Prof. Yoshichika Yoshioka and Dr
Yuki Mori from the Osaka University IFReC Biological Functional Imaging Laboratory. The discovery wasmade by a joint research team with researchers from Dokkyo Medical University, the National Institute forPhysiological Sciences, Mie University, Iwate Medical University, and the Osaka Medical Center for Cancerand Cardiovascular Diseases.

The significance of these results to society
Cerebral malaria is a severe complication of malaria infection in humans caused by P. falciparum parasites andcharacterized by sudden onset of clinical symptoms such as convulsions and coma with high rates of death orlong-term disabilities. Diagnosis of CM is not easy as it presents with non-specific symptoms, often resulting in
manifestation of the disease at a time-point when the treatment is less effective. Therefore, the requirement has
been for early, quick and cheap diagnosis of cerebral malaria that permits timely intervention.
Studies using a mouse model of experimental cerebral malaria have indicated that blood brain barrier
disruption and CD8 T cell recruitment contribute to the disease, but the spatiotemporal mechanisms are poorly
understood.
The collaborative group in this study discovered, by ultra-high field MRI and multi-photon microscopy, thatthe olfactory bulb is physically and functionally damaged (loss of smell) by Plasmodium parasites during
cerebral malaria. The trabecular small capillaries comprising the olfactory bulb show parasite accumulation andcell occlusion followed by microbleeding, events associated with high fever and cytokine storm. Specifically,
the olfactory bulb upregulates chemokine CCL21 and the loss or functional blockade of the CCL21 receptors
CCR7 and CXCR3 respectively results in decreased CD8 T cell activation and recruitment as well as prolonged
survival. Thus, the early detection of olfaction loss and blockade of pathological cell recruitment may offer
potential therapeutic strategies for cerebral malaria.

1Specific points made clear by this study:
1. The exact location of where and how the brain is disrupted during cerebral malaria is poorly understood.
The current study has identified in mice that the olfactory region is a vulnerable location for vascularleakage during cerebral malaria. This discovery could only be made possible using an ultra-high field MRI
in combination with multi-photon live imaging microscopy (Fig. 1 A and B).
2. Importantly, there is an early symptom, olfaction loss, before the onset of a coma. Given that early
detection of even one day of malarial coma could dramatically increase treatment success; this previously
unnoticed, truly overlooked location and detection of olfaction loss during malaria infection may provide
early, cheap and easy diagnosis of ECM.
3. In searching for the underlying mechanism(s) of pathology of cerebral malaria via the olfactory region, theCoban group found that CCL21, possibly secreted from OLF astrocytes, might have a role for therecruitment of pathological CD11c+ CD8 T cells into the brain. The group also showed the potential
therapeutic function of CCL21 as a strategy for blocking chemokine-receptor interactions when the early
symptom of cerebral malaria, olfaction loss, is evident (Figure 2).

Article information
Zhao et al. Olfactory plays a key role in spatiotemporal pathogenesis of cerebral malaria.
Cell Host & Microbe 2014 (Online: 12:00 pm, May 14th EST; 4:00 am, May 15th Japan)

Contact
Cevayir Coban
Laboratory of Malaria Immunology, Immunology Frontier Research Center (WPI-IFReC)
Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, JapanTEL+81-6-6879-4805

FAX+81-6-6879-4812

URL

http://malimm.ifrec.osaka-u.ac.jp/

2

A

Ultra-high Field 11.7 T MRI

BMulti-photon Live Imaging

50 μm

CD8 T cells/GFP-PbA/Vessels

Figure 1

Figure 23