Olfactory plays a key role in spatiotemporal pathogenesis of cerebral malaria.
Cerebral malaria is a complication of Plasmodium falciparum infection characterized by sudden coma, death, or neurodisability. Studies using a mouse model of experimental cerebral malaria (ECM) have indicated that blood-brain barrier disruption and CD8 T cell recruitment contribute to disease, but the spatiotemporal mechanisms are poorly understood. We show 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.
Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hong
H
Zhao
Laboratory of Vaccine Science, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Taiki
T
Aoshi
Departments of Tropical Medicine and Parasitology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan.
Satoru
S
Kawai
Laboratory of Biofunctional Imaging, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yuki
Y
Mori
Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Aki
A
Konishi
Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Muge
M
Ozkan
Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yukiko
Y
Fujita
Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Yasunari
Y
Haseda
Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Mikiko
M
Shimizu
Laboratory of Immunochemistry, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Masako
M
Kohyama
Laboratory of Vaccine Science, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Kouji
K
Kobiyama
Division of Homeostatic Development Unit, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585, Japan.
Kei
K
Eto
Division of Homeostatic Development Unit, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585, Japan.
Junichi
J
Nabekura
Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Toshihiro
T
Horii
Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan.
Tomoko
T
Ishino
Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan.
Masao
M
Yuda
Laboratory of Immune Regulation, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hiroaki
H
Hemmi
Laboratory of Immune Regulation, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Tsuneyasu
T
Kaisho
Laboratory of Host Defense, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Shizuo
S
Akira
Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan.
Manabu
M
Kinoshita
Laboratory for Nano-neuroanatomy, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.
Koujiro
K
Tohyama
Laboratory of Biofunctional Imaging, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yoshichika
Y
Yoshioka
Laboratory of Vaccine Science, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Ken J
KJ
Ishii
Laboratory of Malaria Immunology, Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: ccoban@biken.osaka-u.ac.jp.
Cevayir
C
Coban
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054421:Chemokine CCL21 / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009830:Olfactory Bulb / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D010963:Plasmodium falciparum / Q000472:pathogenicity / Q000502:physiology*; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology; D014774:Virulence
C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; C515188:Cxcr3 protein, mouse; D054400:Receptors, CCR7; D054367:Receptors, CXCR3