Eri Ochiai

University of Kentucky, Lexington, Kentucky, United States

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Publications (17)38.03 Total impact

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    ABSTRACT: In vitro studies demonstrated that microglia and astrocytes produce IFN-γ in response to various stimulations, including LPS. However, the physiological role of IFN-γ production by brain-resident cells, including glial cells, in resistance against cerebral infections remains unknown. We analyzed the role of IFN-γ production by brain-resident cells in resistance to reactivation of cerebral infection with Toxoplasma gondii using a murine model. Our study using bone marrow chimeric mice revealed that IFN-γ production by brain-resident cells is essential for upregulating IFN-γ-mediated protective innate immune responses to restrict cerebral T. gondii growth. Studies using a transgenic strain that expresses IFN-γ only in CD11b(+) cells suggested that IFN-γ production by microglia, which is the only CD11b(+) cell population among brain-resident cells, is able to suppress the parasite growth. Furthermore, IFN-γ produced by brain-resident cells is pivotal for recruiting T cells into the brain to control the infection. These results indicate that IFN-γ produced by brain-resident cells is crucial for facilitating both the protective innate and T cell-mediated immune responses to control cerebral infection with T. gondii. Copyright © 2015 by The American Association of Immunologists, Inc.
    No preview · Article · Jun 2015 · The Journal of Immunology
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    ABSTRACT: Histoplasmosis one of the most important mycoses, needs to be diagnosed rapidly and accurately. The main method used to diagnose histoplasmosis is serological detection of antibodies to the Histoplasma capsulatum H and M antigens. Several other protein antigens have been reported in H. capsulatum; however, they have not been used for diagnosis. In this study, we explored novel antigens that were detected during H. capsulatum infection. We obtained a protein mixture from H. capsulatum yeast cells after vigorous mixing in a 0.1% Triton X-100 solution. From the resultant pool, we detected nine spots that reacted with sera from patients with histoplasmosis and identified eight seroactive proteins with mass spectrometry. The seroactive proteins were purified, and their antigenicities were tested with an enzyme-linked immunosorbent assay (ELISA). ELISA revealed that the titer of the patients’ sera to N-acetylated α-linked acidic dipeptidase was significantly higher than those of healthy volunteers (P < 0.01). These data indicate that N-acetylated α-linked acidic dipeptidase of H. capsulatum is recognized as a major antigen during histoplasmosis.
    Preview · Article · Feb 2015 · Biochemical and Biophysical Research Communications
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    ABSTRACT: The incidence of Aspergillus infection has been increasing in the past few years. Also, new Aspergillus fumigatus-related species, namely Aspergillus lentulus, Aspergillus udagawae, and Aspergillus viridinutans, were shown to infect humans. These fungi exhibit marked morphological similarities to A. fumigatus, albeit with different clinical courses and antifungal drug susceptibilities. The present study used liquid chromatography/time-of-flight mass spectrometry to identify the secondary metabolites secreted as virulence factors by these Aspergillus species and compared their antifungal susceptibility. The metabolite profiles varied widely among A. fumigatus, A. lentulus, A. udagawae, and A. viridinutans, producing 27, 13, 8, and 11 substances, respectively. Among the mycotoxins, fumifungin, fumiquinazoline A/B and D, fumitremorgin B, gliotoxin, sphingofungins, pseurotins, and verruculogen were only found in A. fumigatus, whereas auranthine was only found in A. lentulus. The amount of gliotoxin, one of the most abundant mycotoxins in A. fumigatus, was negligible in these related species. In addition, they had decreased susceptibility to antifungal agents such as itraconazole and voriconazole, even though metabolites that were shared in the isolates showing higher minimum inhibitory concentrations than epidemiological cutoff values were not detected. These strikingly different secondary metabolite profiles may lead to the development of more discriminative identification protocols for such closely related Aspergillus species as well as improved treatment outcomes. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
    No preview · Article · Jan 2015 · Journal of Infection and Chemotherapy
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    ABSTRACT: T cells are required to maintain the latency of chronic infection with Toxoplasma gondii in the brain. Here, we examined the role of non-glutamic acid-leucine-arginine CXC chemokine CXCL9 for T-cell recruitment to prevent reactivation of infection with T. gondii. Severe combined immunodeficient mice were infected and treated with sulfadiazine to establish a chronic infection. Immune T cells from infected wild-type mice were transferred into the mice in combination with treatment with anti-CXCL9 or control sera. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Numbers of CD4(+) and CD8(+) T cells isolated from the brains were markedly less in mice treated with anti-CXCL9 serum than in mice treated with control serum at 3 days after sulfadiazine discontinuation. Amounts of tachyzoite (acute stage form of T. gondii)-specific SAG1 mRNA and numbers of foci associated with tachyzoites were significantly greater in the former than the latter at 5 days after sulfadiazine discontinuation. An accumulation of CD3(+) T cells into the areas of tachyzoite growth was significantly less frequent in the mice treated with anti-CXCL9 serum than in mice treated with control serum. These results indicate that CXCL9 is crucial for recruiting immune T cells into the brain and inducing an accumulation of the T cells into the areas where tachyzoites proliferate to prevent reactivation of chronic T. gondii infection. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Nov 2014 · American Journal Of Pathology
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    ABSTRACT: Reactivation of chronic infection with Toxoplasma gondii can cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4β1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild-type mice were treated with anti-α4 integrin or control antibodies and transferred into infected SCID or nude mice, and animals received the same antibody every other day. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Expression of mRNA for CD3δ, CD4, CD8β, IFN-γ, and inducible nitric oxide synthase (NOS2; an effector molecule to inhibit T. gondii growth), and numbers of CD4(+) and CD8(+) T cells in the brain, were significantly less in mice treated with anti-α4 integrin antibody than those treated with control antibody at 3 days after sulfadiazine discontinuation. At 6 days after sulfadiazine discontinuation, cerebral tachyzoite-specific SAG1 mRNA levels and numbers of inflammatory foci associated with tachyzoites were markedly greater in anti-α4 integrin antibody-treated than control antibody-treated animals, even though IFN-γ and NOS2 mRNA levels were higher in the former than the latter. These results indicate that VCAM-1/α4β1 integrin interaction is crucial for prompt recruitment of immune T cells and induction of IFN-γ-mediated protective immune responses during the early stage of reactivation of chronic T. gondii infection to control tachyzoite growth.
    No preview · Article · Apr 2014 · Infection and immunity
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    ABSTRACT: Toxoplasma gondii establishes a chronic infection by forming cysts preferentially in the brain. This chronic infection is one of the most common parasitic infections in humans and can be reactivated to develop life-threatening toxoplasmic encephalitis in immunocompromised patients. Host-pathogen interactions during the chronic infection include growth of the cysts and their removal by both natural rupture and elimination by the immune system. Analyzing these interactions is important for understanding the pathogenesis of this common infection. We developed a differential equation framework of cyst growth and employed Akaike Information Criteria (AIC) to determine the growth and removal functions that best describe the distribution of cyst sizes measured from the brains of chronically infected mice. The AIC strongly support models in which T. gondii cysts grow at a constant rate such that the per capita growth rate of the parasite is inversely proportional to the number of parasites within a cyst, suggesting finely-regulated asynchronous replication of the parasites. Our analyses were also able to reject the models where cyst removal rate increases linearly or quadratically in association with increase in cyst size. The modeling and analysis framework may provide a useful tool for understanding the pathogenesis of infections with other cyst producing parasites.
    Full-text · Article · Nov 2013 · PLoS Computational Biology
  • Y. Suzuki · Q. Sa · E. Ochiai · J. Mullins · R. Yolken · S.K. Halonen
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    ABSTRACT: Following infection with Toxoplasma gondii, tachyzoites proliferate within a variety of nucleated cells in various organs during the acute stage of infection. Interferon-gamma (IFNγ)-dependent cell-mediated immune responses, and humoral immune responses to a lesser extent, control the tachyzoite proliferation, but the parasite establishes a chronic infection by forming tissue cysts, especially in the brain, heart and skeletal muscle. IFNγ can activate microglia, astrocytes, and brain microvascular endothelial cells to prevent tachyzoite growth by using different mechanisms depending on the cell types. T cells are an essential producer of IFNγ to control tachyzoites, and interleukin (IL)-12 plays a crucial role in inducing their IFNγ production. Many other cytokines such as TNF-α and IL-6 are involved in the IFNγ-mediated protective immune responses against tachyzoites in the brain. In addition, multiple cytokines and molecules such as IL-10, IL-27, and lipoxin A4 play important downregulatory roles on the immune responses to prevent development of immunopathology. T. gondii can form cysts in multiple cell types in the brain, including neurons and astrocytes. Recently, CD8+ T cells were revealed to have an activity to remove tissue cysts from the brains of chronically infected mice. This anti-cyst activity of the T cells is does not require their IFNγ but requires perforin. Therefore, the immune system appears to use two different mechanisms, one is mediated by IFNγ and another is mediated by perforin, depending on the stage of the parasite that it targets. Therefore, cerebral infection with T. gondii is controlled by well-organized and orchestrated functions of the immune system. Genetic factors in both the host and the parasite also affect the susceptibility to the cerebral infection. Although chronic infection with T. gondii has been considered as "latent", recent studies indicated a correlation of the infection with cryptogenic epilepsy and neuropsychiatric disorders such as schizophrenia. T. gondii can also cause congenital infection to the fetus, in which the brain is the major organ affected.
    No preview · Article · Sep 2013
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    ABSTRACT: Background Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our envelopment. Methods Microarray assays with ontology and pathway analyses were performed with the lungs of mice. A comparison was made of the expression patterns of biological pathways between our model and those published for IPAH. Results Some pathways in our model showed the same expression patterns in IPAH, which included bone morphogenetic protein (BMP) signaling with down-regulation of BMP receptor type 2, activin-like kinase type 1, and endoglin. On the other hand, both Wnt/planar cell polarity (PCP) signaling and its downstream Rho/ROCK signaling were found alone to be activated in IPAH and not in our model. Conclusions Activation of Wnt/PCP signaling, in upstream positions of the pathway, found alone in lungs from end stage IPAH may play essential roles in the pathogenesis of the disease.
    Full-text · Article · Nov 2012 · Respiratory research
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    Yasuhiro Suzuki · Qila Sa · Marie Gehman · Eri Ochiai
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    ABSTRACT: Toxoplasma gondii is an obligate intracellular protozoan parasite that causes various diseases, including lymphadenitis, congenital infection of fetuses and life-threatening toxoplasmic encephalitis in immunocompromised individuals. Interferon-gamma (IFN-γ)-mediated immune responses are essential for controlling tachyzoite proliferation during both acute acquired infection and reactivation of infection in the brain. Both CD4+ and CD8+ T cells produce this cytokine in response to infection, although the latter has more potent protective activity. IFN-γ can activate microglia, astrocytes and macrophages, and these activated cells control the proliferation of tachyzoites using different molecules, depending on cell type and host species. IFN-γ also has a crucial role in the recruitment of T cells into the brain after infection by inducing expression of the adhesion molecule VCAM-1 on cerebrovascular endothelial cells, and chemokines such as CXCL9, CXCL10 and CCL5. A recent study showed that CD8+ T cells are able to remove T. gondii cysts, which represent the stage of the parasite in chronic infection, from the brain through their perforin-mediated activity. Thus, the resistance to cerebral infection with T. gondii requires a coordinated network using both IFN-γ- and perforin-mediated immune responses. Elucidating how these two protective mechanisms function and collaborate in the brain against T. gondii will be crucial in developing a new method to prevent and eradicate this parasitic infection.
    Preview · Article · Oct 2011 · Expert Reviews in Molecular Medicine
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    ABSTRACT: Stachybotrys chartarum, a ubiquitous fungus in our environment, has been suspected of causing respiratory symptoms in humans, such as acute infant pulmonary hemorrhage and asthma. We previously established a mouse model in which repeated inhalation of Stachybotrys chartarum spores caused pulmonary hypertension. To further investigate the model, particularly in the pulmonary circulation, mice were intra-tracheally injected with spores, 18 times over 12 weeks. Severe muscularization was observed in the small- to medium-sized pulmonary arteries. Bronchoalveolar lavage fluid revealed an increase in eosinophils accompanied by high concentrations of Th2-associated cytokines, IL-4, IL-5, but not Th1-associated IFN-γ. The remodeling was temporary, resolving after cessation of spore inhalation. Chronic inhibition of the RhoA/Rho-kinase pathway by fasudil attenuated pulmonary arterial remodeling. These data suggest that Stachybotrys-mediated remodeling is caused by Th2-associated inflammation and can be resolved by Rho-kinase inhibition, either through direct effects on smooth muscle hypertrophy or through indirect effects on vascular inflammation. These data also show that extensive pulmonary vascular remodeling, often thought of as a fixed lesion, will spontaneously resolve in the absence of underlying molecular etiology.
    No preview · Article · Apr 2011 · Mycopathologia
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    A Watanabe · Y Hashimoto · E Ochiai · A Sato · K Kamei
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    ABSTRACT: Endotracheal intubation in mice is both a common and important technique. However, it is a difficult procedure because of the small orotracheal size and the success rate is variable. There have been many reports of refined techniques that facilitate intubation but only a few reports have proposed how to verify the proper placement of the endotracheal tube. We describe a novel, safe and reliable method to confirm endotracheal intubation in mice using an extension tube for intravenous infusion. One drop of water was instilled in the extension tube and connected to the end of the catheter used as an endotracheal tube. When the catheter was inserted correctly into the trachea, the water in the extension tube oscillated in synchrony with the movement of the mouse's thorax, indicating correct placement of the catheter. This method was simple, reliable and use materials that are routinely available. This method is helpful for experimental mouse models that require airway access.
    Preview · Article · Jul 2009 · Laboratory Animals
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    ABSTRACT: Inhalation of Stachybotrys chartarum, a ubiquitous fungus in our living environment, has been suspected as a cause of acute idiopathic pulmonary haemorrhage in infants, but its relation to human diseases is not yet known. The aim of present study was to investigate the effect of repeated intratracheal injection of the fungus into mice, paying special attention to the pulmonary vascular system. Spores of S. chartarum were injected into the trachea of mice from 6 to 18 times over 4-12 weeks, and the lungs were examined by histopathology, morphometrics and haemodynamics. When 1 x 10(4) spores/mouse were injected, histopathological examination showed the development of pulmonary arterial hypertension (PAH). Symmetrical thickening of the intima and media of the pulmonary arterial walls was seen after six injections over 4 weeks. Right ventricular hypertrophy was also evident after 12 injections. PAH was confirmed by the elevation of right ventricular systolic pressure (20.1 +/- 5.7 mmHg in the injected group vs. 12.0 +/- 2.4 mmHg in the control group, P < 0.01). This study showed that the inhalation of S. chartarum caused PAH in mice, suggesting a potential of S. chartarum as a cause of human health problem such as PAH.
    Full-text · Article · Jun 2008 · International Journal of Experimental Pathology
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    ABSTRACT: Aspergillus fumigatus has been shown to trigger the activation of nuclear factor-kappaB (NF-kappaB), but it remains unclear whether other transcription factors are also induced following infection by this organism. In this study, we demonstrated that A. fumigatus also triggers activator protein 1 (AP-1), a transcription factor that plays an important role during the production of cytokines and chemokines. Swollen conidia strongly induce the activation of AP-1, and more than 80% of these were stained positively with anti-beta-glucan antibodies by fluorescence microscopy. Hyphae were also stained with anti-beta-glucan antibodies, albeit significantly weaker compared with swollen conidia. Furthermore, our present findings also showed that A. fumigatus triggers the activation of AP-1 in a dectin-1 (receptor for beta-glucan)-dependent manner. These data thus suggest that AP-1 is triggered by beta-glucan recognition on the surface of A. fumigatus. We also showed that Syk tyrosine kinase is required for AP-1 induction in this pathway. We therefore speculate that the dectin-1/Syk/AP-1 signaling pathway plays an important role in the host defense response to fungal infection.
    No preview · Article · Mar 2008 · Microbial Pathogenesis
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    ABSTRACT: The number of patients with invasive fungal infection (IFI) has dramatically increased since the beginning of the 1980s. Aspergillus fumigatus, the most common species recovered from aspergillosis, is an important pathogen of IFI. Recently, new antifungal agents have become available in Japan, but mortality from aspergillosis is still high. Early initiation of therapy seems to improve the survival rate. Study of virulence factors of the fungus may lead to the development of novel diagnostic tools or advancements in therapy. Many candidates of the fungal virulence factors have been studied including proteases and mycotoxins. We previously discussed the influence of fungal secondary metabolites such as gliotoxin and other low molecular components on the virulence, and showed that A. fumigatus produces potent cytotoxic substances other than gliotoxin. Studies are in progress to clarify the significance of the unknown substances.
    No preview · Article · Feb 2008 · Nippon Ishinkin Gakkai Zasshi
  • Katsuhiko KAMEI · Eri OCHIAI

    No preview · Article · Jan 2008 · Mycotoxins
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    ABSTRACT: Stachybotrys chartarum is a dematiaceous fungus that is ubiquitous in our living environment. This fungus has long been regarded as non-pathogenic and its inhalation effect on humans has been scarcely studied. Recently, however, epidemiologic studies on acute idiopathic pulmonary hemorrhage in infants suggested that the fungus might be potentially pathogenic to humans. To determine the pathogenicity of this fungus, its interaction with the host defense system was studied using polymorphonuclear leukocytes (PMNs) and macrophages. Histopathological analysis of mice intratracheally injected with this fungus was also performed. The results disclosed that the conidia of S. chartarum were resistant to the antifungal activities of alveolar macrophages in terms of phagocytosis, killing and inhibition of germination. However, the conidia could not survive in the lungs of mice when injected intratracheally. Lavage fluid of mycelia that contained the dark slimy material coating the surface of conidia showed cytotoxic activity against macrophages and PMNs. Intratracheal injection of conidia in mice resulted in intraalveolar infiltration of PMNs. When using multiple injections during a 3-week period, strong eosinophilic infiltration into the proximal alveoli and perivascular tissues was observed. Our results suggest that inhalation of conidia may cause serious damage to the human lung, particularly when repeated.
    Preview · Article · Feb 2005 · Nippon Ishinkin Gakkai Zasshi
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    ABSTRACT: Aspergillus fumigatus often causes serious health problems. The airway of the human body, the most common initial site of damage, is always exposed to an oxygenated condition, and the oxygen concentration may play a critical role in the virulence of A. fumigatus. In this study, oxygen content, fungal growth, the production of cytotoxic substance(s) in the fungal culture, and their relationship were investigated. Two clinical strains of A. fumigatus were cultured under certain oxygen contents (10, 14 and 20%), and cytotoxicity of their culture filtrates on murine macrophages and their fungal growth were evaluated. The components of these filtrates were analyzed by gas chromatography-mass spectrometry. All culture filtrates contained gliotoxin and showed potent cytotoxicity on macrophages at very low concentration. The amount of gliotoxin in the culture filtrate prepared at 10% oxygen was markedly less, but diminutions in fungal growth and cytotoxicity of this culture filtrate were negligible. These results suggest that a well-oxygenated condition is suitable for the production of gliotoxin by A. fumigatus. A significant role of cytotoxic substances(s) other than gliotoxin is also suggested.
    No preview · Article · Aug 2004 · Mycopathologia

Publication Stats

105 Citations
38.03 Total Impact Points


  • 2011-2015
    • University of Kentucky
      • Department of Microbiology, Immunology & Molecular Genetics
      Lexington, Kentucky, United States
  • 2005-2015
    • Chiba University
      • • Medical Mycology Research Center (MMRC)
      • • Graduate School of Science and Technology
      Tiba, Chiba, Japan