Details of a Researcher - Nishimura, Tomoyasu

Papers - Nishimura, Tomoyasu

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Natural history of Mycobacterium fortuitum pulmonary infection presenting with migratory infiltrates

Okamori Satoshi, Asakura Takanori, Nishimura Tomoyasu, Tamizu Eiko, Ishii Makoto, Yoshida Mitsunori, Fukano Hanako, Hayashi Yuichiro, Fujita Masaki, Hoshino Yoshihiko, Betsuyaku Tomoko, Hasegawa Naoki

BMC Infectious Diseases 18 ( 1 ) 2018.01

ISSN 1471-2334

Background: Presence of Mycobacterium fortuitum in respiratory tracts usually indicates mere colonization or transient infection, whereas true pulmonary infection occurs in patients with gastroesophageal disease. However, little is known about the diagnostic indications for true M. fortuitum pulmonary infection and the natural history of the disease. Case presentation: A 59-year-old man was referred to our hospital for treatment against M. fortuitum pulmonary infection. Fifteen years before the referral, he underwent total gastrectomy, after which he experienced esophageal reflux symptoms. After the referral, the patient was closely monitored without antimicrobial therapy because of mild symptoms and no pathological evidence of M. fortuitum pulmonary infection. During the observation, chest imaging showed migratory infiltrates. Two years after the referral, his lung biopsy specimen revealed foamy macrophages and multinucleated giant cells, indicating lipoid pneumonia. However, he was continually monitored without any treatment because there was no evidence of nontuberculous mycobacterial infection. Four years after the referral, he developed refractory pneumonia despite receiving adequate antibiotic therapy. After confirmation of granulomatous lesions, multiple antimicrobial therapy for M. fortuitum resulted in a remarkable improvement with no exacerbation for over 5 years. Random amplified polymorphic DNA polymerase chain reaction analysis revealed identical M. fortuitum strains in seven isolates from six sputum and one intestinal fluid specimens obtained during the course of the disease. Conclusions: We have described a patient with M. fortuitum pulmonary infection who presented with migratory infiltrates. The pathological evidence and microbiological analysis suggested that M. fortuitum pulmonary infection was associated with lipoid pneumonia and chronic exposure to gastrointestinal fluid. Therefore, physicians should carefully monitor patients with M. fortuitum detected from lower respiratory tract specimens and consider antimicrobial therapy for M. fortuitum infection when the patient does not respond to adequate antibiotic therapy against common pneumonia pathogens.

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Risk of tuberculosis infection among health care workers and nursing students in Japan

Nishimura Tomoyasu, Ota Masaki, Mori Masaaki, Fujiwara Hiroshi, Takano Yaoko, Kato Seiya, Kawabe Hiroshi, Hasegawa Naoki

Journal of Infection and Chemotherapy 2018.01

ISSN 1341-321X

It is important to evaluate the risk of tuberculosis (TB) infection among health care workers (HCWs) and nursing students in Japan to propose the optimal countermeasure against new TB infection for them. To estimate the annual incidence of TB infection in HCWs at a Japanese university hospital without TB wards and in nursing students at a Japanese university using interferon-gamma release assay (IGRA). Serial IGRAs were prospectively conducted on the HCWs between August 2010 and December 2015. For nursing students, two IGRA tests were conducted before commencement of clinical training and at employment as nurses between April 2007 and December 2015. A total of 328 HCWs and 298 nursing students were followed for 670.15 and 1212.80 person-years, respectively. Assuming IGRA-positive conversions were all attributable to true infection, the incidence of TB infection in HCWs and nursing students was 0.149/100 and 0.0825/100 person-years, respectively. At a Japanese university hospital without TB wards and a Japanese university, the annual incidence of TB infection among HCWs and nursing students estimated from serial IGRA results was low, but continued vigilance for the prevention of TB infection is essential.

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Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease

Kamata Hirofumi, Asakura Takanori, Suzuki Shoji, Namkoong Ho, Yagi Kazuma, Funatsu Yohei, Okamori Satoshi, Uno Shunsuke, Uwamino Yoshifumi, Fujiwara Hiroshi, Nishimura Tomoyasu, Ishii Makoto, Betsuyaku Tomoko, Hasegawa Naoki

BMC Pulmonary Medicine 17 ( 1 ) 2017.12

ISSN 1471-2466

Background: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. Methods: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. Results: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P=0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P=0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P=0.043 and 0.021, respectively). Conclusions: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

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Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

Zhao X., Khan N., Gan H., Tzelepis F., Nishimura T., Park S. Y., Divangahi M., Remold H. G.

Mucosal Immunology 10 ( 6 ) 1553 - 1568 2017.11

ISSN 1933-0219

Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host M •, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected M • is dependent on the action of the cytosolic Receptor Interacting Protein Kinase 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphoma - extra large (Bcl-x L). RIPK3-deficient M • are able to better control bacterial growth in vitro and in vivo. Mechanistically, cytosolic RIPK3 translocates to the mitochondria where it promotes necrosis and blocks caspase 8-activation and apoptosis via Bcl-x L. Furthermore, necrosis is associated with stabilization of hexokinase II on the mitochondria as well as cyclophilin D-dependent mitochondrial permeability transition. Collectively, these events upregulate the level of reactive oxygen species to induce necrosis. Thus, in Mtb-infected M •, mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8-activation.

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The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases

Yagi Kazuma, Ishii Makoto, Namkoong Ho, Asami Takahiro, Iketani Osamu, Asakura Takanori, Suzuki Shoji, Sugiura Hiroaki, Yamada Yoshitake, Nishimura Tomoyasu, Fujiwara Hiroshi, Funatsu Yohei, Uwamino Yoshifumi, Kamo Tetsuro, Tasaka Sadatomo, Betsuyaku Tomoko, Hasegawa Naoki

BMC Infectious Diseases 17 ( 1 ) 2017.08

ISSN 1471-2334

Background: In multidrug regimens, including an intravenous aminoglycoside (e.g. amikacin [AMK]) is recommended for difficult-to-treat non-tuberculous mycobacterial (NTM) lung diseases. We aimed to evaluate the efficacy, safety, and feasibility of inhaled AMK therapy in patients with difficult-to-treat NTM lung diseases in a retrospective chart review. Methods: The study population consisted of patients with NTM lung diseases who received combination therapy, including inhaled AMK therapy, at Keio University Hospital (Tokyo, Japan), from January 2014 through May 2016. A total of 26 cases, consisting of 23 Mycobacterium avium complex (MAC) and three Mycobacterium abscessus complex (MABC) infections cases, were included in this study. The efficacy, safety, and feasibility of inhaled AMK therapy were retrospectively investigated. The Research Ethics Committee of Keio University Hospital approved this study, and informed consent was obtained from all patients. Results: All 26 patients were culture-positive at enrolment. Twenty-three of the 26 patients (88.5%), including 21/23 MAC patients (91.3%) and 2/3 MABC patients (66.7%), were administered inhaled AMK therapy for >3months. The proportion of patients who had clinical symptoms, including, cough and sputum, declined after inhalation AMK therapy. Ten of the 23 patients (43.5%) who received AMK inhalation, including 8/21 MAC (38.1%) and 2/2 MABC patients (100%), showed sputum conversion, defined as at least three consecutive negative sputum cultures. Seven of the 23 patients, including, 5/21 MAC and 2/2 MABC patients, showed improvements in high-resolution computed tomography imaging of the chest. In addition, the serum AMK trough levels before the second inhalation were <1.2μg/mL in all 26 patients, with no occurrence of severe adverse events, such as renal toxicity. One patient (3.8%) experienced auditory toxicity, in the form of tinnitus. However, this symptom was reversible, after temporary interruption of AMK, the patient was able to safely resume the therapy. Conclusions: Inhaled AMK therapy is an effective and feasible therapy for difficult-to-treat NTM lung disease.

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Hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity

Nishimura Tomoyasu, Tamizu Eiko, Uno Shunsuke, Uwamino Yoshifumi, Fujiwara Hiroshi, Nishio Kazumi, Nakano Yasushi, Shiono Hirofumi, Namkoong Ho, Hoshino Yoshihiko, Iwata Satoshi, Hasegawa Naoki

Journal of Infection and Chemotherapy 2017

ISSN 1341-321X

MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity.

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The first case report of acute cholangitis and bacteremia due to Neisseria subflava

Uwamino Yoshifumi, Sugita Kayoko, Iwasaki Eisuke, Fujiwara Hiroshi, Nishimura Tomoyasu, Hasegawa Naoki, Iwata Satoshi

Internal Medicine 56 ( 2 ) 221 - 223 2017

ISSN 0918-2918

We herein report a case of acute cholangitis and bacteremia caused by a commensal Neisseria species, Neisseria subflava, in an 82-year-old man with cholangiocarcinoma. Emergency endoscopic nasobiliary drainage and cefoperazone/sulbactam therapy were effective. Gram negative coccobacilli were isolated from both blood and bile cultures on 5% sheep blood agar. The isolate was identified as N. subflava biovar perflava by mass spectrometry, a sequence analysis of the 16S rRNA, and biochemical testing. Although biliary infections due to commensal Neisseria are extremely rare, this case demonstrates the possibility of its occurrence in patients undergoing bile duct treatment.

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Rapid detection and typing of carbapenemase genes from carbapenem-resistant enterobacteriaceae isolates collected in a Japanese hospital using the Xpert Carba-R assay

Uwamino Yoshifumi, Sugita Kayoko, Hasegawa Naoki, Nishimura Tomoyasu, Fujiwara Hiroshi, Iwata Satoshi

Japanese Journal of Infectious Diseases 70 ( 1 ) 124 - 125 2017

ISSN 1344-6304

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Macrolide-resistant mycobacterium avium complex lung disease

Morimoto Kozo, Namkoong Ho, Hasegawa Naoki, Nakagawa Taku, Morino Eriko, Shiraishi Yuji, Ogawa Kenji, Izumi Kiyohiko, Takasaki Jin, Yoshiyama Takashi, Hoshino Yoshihiko, Matsuda Shuichi, Hayashi Yuta, Sasaki Yuka, Ishii Makoto, Kurashima Atsuyuki, Nishimura Tomoyasu, Betsuyaku Tomoko, Goto Hajime

Annals of the American Thoracic Society 13 ( 11 ) 1904 - 1911 2016.11

ISSN 2325-6621

Rationale: The management of macrolide-resistant Mycobacterium aviumcomplex (MR-MAC)pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). Objectives: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. Methods: The medical records of 102 consecutive cases with MR-MACpulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014were reviewed.The data of 311 consecutive caseswith MDR-TB were extracted from the medical data at Fukujuji Hospital. Measurements and Main Results: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. Conclusions: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

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Clinical characteristics of pulmonary Mycobacterium scrofulaceum disease in 2001–2011

Suzuki Shoji, Morino Eriko, Ishii Makoto, Namkoong Ho, Yagi Kazuma, Asakura Takanori, Asami Takahiro, Fujiwara Hiroshi, Uwamino Yoshifumi, Nishimura Tomoyasu, Tasaka Sadatomo, Betsuyaku Tomoko, Takasaki Jin, Iwata Satoshi, Hasegawa Naoki

Journal of Infection and Chemotherapy 22 ( 9 ) 611 - 616 2016.09

ISSN 1341-321X

Background Mycobacterium scrofulaceum is a well-known pathogen associated with cervical lymphadenitis in children. However, pulmonary M. scrofulaceum disease is a rare condition with unknown clinical features. The present study aimed to clarify the clinical features of pulmonary M. scrofulaceum disease described in recent cases and reports. Methods We reviewed the medical records of all adult patients with pulmonary M. scrofulaceum disease at Keio University Hospital and the National Center for Global Health and Medicine Center Hospital between 2001 and 2011. We also conducted a review of the PubMed database to identify additional cases of pulmonary M. scrofulaceum disease in adults. Results Our study identified 8 cases of pulmonary M. scrofulaceum disease at the 2 identified institutions during our study period. Most cases were diagnosed in middle-aged and elderly men with underlying pulmonary diseases such as chronic obstructive pulmonary disease and Mycobacterium avium complex lung disease, as well as those with a history of pulmonary tuberculosis. In contrast, most previously reported cases identified through our literature review had a history of dust inhalation or underlying silicosis. Three of 8 cases at our institutions and 20 of 23 cases from the literature were treated with combination therapies. Conclusions We conclude that in the recent histories of our institutions, pulmonary M. scrofulaceum disease has mainly occurred in patients with chronic pulmonary diseases. We further conclude that combination therapies that include clarithromycin might yield better patient outcomes.

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Clinical efficacy and safety of multidrug therapy including thrice weekly intravenous amikacin administration for Mycobacterium abscessus pulmonary disease in outpatient settings

Namkoong Ho, Morimoto Kozo, Nishimura Tomoyasu, Tanaka Hiromu, Sugiura Hiroaki, Yamada Yoshitake, Kurosaki Atsuko, Asakura Takanori, Suzuki Shoji, Fujiwara Hiroshi, Yagi Kazuma, Ishii Makoto, Tasaka Sadatomo, Betsuyaku Tomoko, Hoshino Yoshihiko, Kurashima Atsuyuki, Hasegawa Naoki

BMC Infectious Diseases 16 ( 1 ) 2016.08

ISSN 1471-2334

Background: Mycobacterium abscessus (M. abscessus) pulmonary disease is a refractory chronic infectious disease. Options for treating M. abscessus pulmonary disease are limited, especially in outpatient settings. Among parenteral antibiotics against M. abscessus, intravenous amikacin (AMK) is expected to be an effective outpatient antimicrobial therapy. This study evaluated the clinical efficacy and safety of intravenous AMK therapy in outpatients with M. abscessus pulmonary disease. Methods: This retrospective chart review of cases of M. abscessus pulmonary disease evaluated patient background data, AMK dosage and duration, sputum conversion, clinical symptoms radiological findings, and adverse events. M. massiliense was excluded on the basis of multiplex PCR assay. Results: Thirteen patients (2 men and 11 women) with M. abscessus pulmonary disease were enrolled at 2 hospitals. The median age at the initiation of intravenous AMK treatment was 65 years (range: 50-86 years). Patients received a median AMK dose of 12.5 mg/kg (range: 8.3-16.2 mg/kg) for a median duration of 4 months (range: 3-9 months). The addition of intravenous AMK led to sputum conversion in 10 of 13 patients, and 8 patients continued to have negative sputum status 1 year after treatment. Approximately half of the patients showed improvement on chest high-resolution computed tomography. There were no severe adverse events such as ototoxicity, vestibular toxicity, and renal toxicity. Conclusions: Thrice weekly intravenous AMK administration in outpatient settings is effective and safe for patients with M. abscessus pulmonary disease.

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Middle-aged to elderly women have a higher asymptomatic infection rate with Mycobacterium avium complex, regardless of body habitus

Nishimura Tomoyasu, Fujita-Suzuki Yukiko, Mori Masaaki, Carpenter Stephen M., Fujiwara Hiroshi, Uwamino Yoshifumi, Tamizu Eiko, Yano Ikuya, Kawabe Hiroshi, Hasegawa Naoki

Respirology 21 ( 3 ) 553 - 555 2016.04

ISSN 1323-7799

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Pharmacokinetics of intravenous peramivir in the airway epithelial lining fluid of healthy volunteers

Funatsu Yohei, Tasaka Sadatomo, Asami Takahiro, Namkoong Ho, Fujiwara Hiroshi, Iketani Osamu, Yagi Kazuma, Kimizuka Yoshifumi, Ishii Makoto, Nishimura Tomoyasu, Ogata Haruhiko, Iwata Satoshi, Betsuyaku Tomoko, Hasegawa Naoki

Antiviral Therapy 21 ( 7 ) 621 - 625 2016

ISSN 1359-6535

Background: Some subtypes of influenza virus, such as H5N1 and H7N9, cause severe viral pneumonia, for which the intraluminal concentration of the anti-influenza agent in the airway is critical. However, the pharmacokinetics of peramivir, the only available injectable neuraminidase inhibitor formulation, in the airway epithelial lining fluid (ELF) remains unclear. In this study, we aimed to determine the time course of peramivir in the pharyngeal ELF, bronchial ELF and plasma of healthy volunteers using bronchoscopic microsampling technique. Methods: Six healthy volunteers were studied. After baseline plasma sampling, 0.3 g peramivir was intravenously injected over 0.5 h. ELF was obtained from the upper and lower airways using bronchoscopic microsampling at the end of the infusion (0.5 h) and after 1.0, 1.5, 2.0, 2.5, 3.0, 4.0 and 5.0 h. The concentrations of peramivir in the ELFs and in the plasma were quantified by LC/MS/MS analysis. Results: The mean maximum concentration (C_max) in pharyngeal ELF, bronchial ELF and plasma was 1.20 ±0.42, 9.60 ±2.30 and 50.52 ±17.51 ng/ml, respectively. The penetration ratio at C_max in pharyngeal and bronchial ELFs was 2.4 and 19.0, respectively. The ratio of the area under the curve from 0 to infinity in pharyngeal and bronchial ELFs was 4.8 and 39.1 mg•min/l, respectively. Conclusions: The time course of peramivir concentration in the ELFs revealed that concentrations above the 50% inhibitory concentration value of influenza were achieved in the upper and lower airways. Therefore, peramivir could be an important treatment option for influenza viral pneumonia.

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Health-related quality of life is inversely correlated with C-reactive protein and age in Mycobacterium avium complex lung disease

Asakura Takanori, Funatsu Yohei, Ishii Makoto, Namkoong Ho, Yagi Kazuma, Suzuki Shoji, Asami Takahiro, Kamo Tetsuro, Fujiwara Hiroshi, Uwamino Yoshifumi, Nishimura Tomoyasu, Tasaka Sadatomo, Betsuyaku Tomoko, Hasegawa Naoki

Respiratory Research 2015.12

ISSN 1465-9921

Background: Mycobacterium avium complex (MAC) lung diseases generally cause chronic disease in immunocompetent hosts. Although a few studies have examined health-related quality of life (HRQL) in patients with MAC lung disease, there have been no large studies. This study aimed to evaluate HRQL and its correlation with clinical outcomes in MAC lung disease. Methods: A cross-sectional study was conducted at Keio University Hospital to investigate the factors associated with HRQL in pulmonary nontuberculous mycobacterial diseases. MAC lung diseases were diagnosed according to the 2007 ATS/IDSA guidelines for nontuberculous mycobacterial diseases. The 36-item short form health survey (SF-36) was administered to assess clinical outcomes. Clinical variables included treatment status, latest haematological data, and bacterial smear and culture results. Results: The SF-36 scores for the 235 patients (median age, 69 years; 45 men and 190 women) with MAC lung disease, except for the bodily pain and mental health subscale scores, were significantly lower than the Japanese population norms. In the multivariable analyses, current treatment for MAC and a positive sputum smear or culture within the past year were significantly associated with lower SF-36 scores. C-reactive protein (CRP) and age showed stronger inverse correlations with SF-36 scores. Conclusions: HRQL, especially the physical component, was impaired in patients with MAC lung diseases; this appears to be related with current treatment status, positive sputum smear or culture within the previous year, and particularly CRP and age. Further studies including qualitative assessments are needed to investigate the efficacy of CRP as a marker for progression or treatment response in MAC lung disease. Trial registration: Clinical trial registered with UMIN ( UMIN000007964).

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Recurrence of disseminated Mycobacterium avium complex disease in a patient with anti-gamma interferon autoantibodies by reinfection

Nishimura Tomoyasu, Fujita-Suzuki Yukiko, Yonemaru Makoto, Ohkusu Kiyofumi, Sakagami Takuro, Carpenter Stephen M., Otsuka Yoshihito, Namkoong Ho, Yano Ikuya, Hasegawa Naoki

Journal of Clinical Microbiology 53 ( 4 ) 1436 - 1438 2015.04

ISSN 0095-1137

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Pulmonary nocardiosis caused by Nocardia cyriacigeorgica in patients with Mycobacterium avium complex lung disease

Yagi Kazuma, Ishii Makoto, Namkoong Ho, Asami Takahiro, Fujiwara Hiroshi, Nishimura Tomoyasu, Saito Fumitake, Kimizuka Yoshifumi, Asakura Takanori, Suzuki Shoji, Kamo Tetsuro, Tasaka Sadatomo, Gonoi Tohru, Kamei Katsuhiko, Betsuyaku Tomoko, Hasegawa Naoki

BMC Infectious Diseases 14 684 2014

BACKGROUND: Pulmonary nocardiosis frequently occurs in immunocompromised hosts and in some immunocompetent hosts with chronic lung disease; however, few reports have described pulmonary nocardiosis with nontuberculous mycobacterial lung infection. Here we report for the first time two cases of pulmonary nocardiosis caused by Nocardia cyriacigeorgica associated with Mycobacterium avium complex (MAC) lung disease caused by M. avium.CASE PRESENTATION: Case 1 is that of a 72-year-old Japanese man with untreated MAC lung disease, who was diagnosed with rheumatoid arthritis and initiated on methotrexate. After 3 years of methotrexate therapy, the patient remained smear-negative and culture-positive for MAC, but also became smear-positive for Nocardia species. He received trimethoprim/sulfamethoxazole, and his symptoms and lung infiltrates improved. Case 2 is that of an immunocompetent 53-year-old Japanese woman with MAC lung disease, who was treated with a combined therapy of clarithromycin, rifampicin, ethambutol, and levofloxacin. MAC sputum culture was negative after 1 year of combined treatment, which was maintained for 2 years. After four treatment-free years, Nocardia species were occasionally isolated from her sputum, although MAC was rarely isolated from sputum cultures over the same period. In both cases, the Nocardia species were identified as the recently defined N. cyriacigeorgica by 16S ribosomal RNA gene sequencing.CONCLUSION: We report two cases of pulmonary nocardiosis caused by N. cyriacigeorgica associated with MAC lung disease caused by M. avium and suggest that N. cyriacigeorgica may be a major infective agent associated with MAC lung disease.

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The prostaglandin E₂ receptor EP4 is integral to a positive feedback loop for prostaglandin E₂ production in human macrophages infected with Mycobacterium tuberculosis

Nishimura Tomoyasu, Zhao Xiaomin, Gan Huixian, Koyasu Shigeo, Remold Heinz G.

FASEB Journal 27 ( 9 ) 3827 - 3836 2013.09

ISSN 0892-6638

Prostaglandin E₂ (PGE₂) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mφs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE₂ receptor EP2. However, human Mφs also express EP4, a PGE₂ receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mφs have been unclear. EP4 antagonist addition to H37Rainfected Mφs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase- 1 (mPGES-1), which are involved in PGE₂ production. Moreover, H37Ra infection induced PGE₂ production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected Mφs, PGE₂ production induced by pathogen recognition receptors/p38 MAPK signaling is upregulated by EP4-triggered signaling to maintain an effective PGE₂ concentration.-Nishimura, T., Zhao, X., Gan, H., Koyasu, S., and Remold, H. G. The prostaglandin E ₂ receptor EP4 is integral to a positive feedback loop for prostaglandin E₂ production in human macrophages infected with Mycobacterium tuberculosis.

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IL-1β promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation

Jayaraman Pushpa, Sada-Ovalle Isabel, Nishimura Tomoyasu, Anderson Ana C., Kuchroo Vijay K., Remold Heinz G., Behar Samuel M.

Journal of Immunology 190 ( 8 ) 4196 - 4204 2013.04

ISSN 0022-1767

In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effector Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to down-regulate Th1 responses, we recently described that its interaction with Galectin-9 expressed by M. tuberculosis-infected macrophages stimulates IL-1β secretion, which is essential for survival in the mouse model. Why IL-1β is required for host resistance to M. tuberculosis infection is unknown. In this article, we show that IL-1β directly kills M. tuberculosis in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1β and downstream TNF production lead to caspase-dependent restriction of intracellular M. tuberculosis growth.

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Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis

Behar S. M., Martin C. J., Booty M. G., Nishimura T., Zhao X., Gan H. X., Divangahi M., Remold H. G.

Mucosal Immunology 4 ( 3 ) 279 - 287 2011.05

ISSN 1933-0219

Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E 2 (proapoptotic) and lipoxin (LX)A 4 (pronecrotic). Although PGE 2 protects against necrosis, virulent Mtb induces LXA 4 and inhibits PGE 2 production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.

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Elevated serum adiponectin level in patients with mycobacterium avium-intracellulare complex pulmonary disease

Tasaka Sadatomo, Hasegawa Naoki, Nishimura Tomoyasu, Yamasawa Wakako, Kamata Hirofumi, Shinoda Hiromi, Kimizuka Yoshifumi, Fujiwara Hiroshi, Hirose Hiroshi, Ishizaka Akitoshi

Respiration 79 ( 5 ) 383 - 387 2010.04

ISSN 0025-7931

Background: Patients with Mycobacterium avium-intracellulare complex (MAC) pulmonary disease often suffer from weight loss. Adipokines are factors secreted by adipocytes, including leptin and adiponectin, as well as some inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). Body mass index (BMI) is known to be inversely correlated with adiponectin and positively with leptin, TNF-α, and IL-6. Objective: We aimed to evaluate the levels of serum adipokines, including adiponectin, leptin, TNF-α, and IL-6 in patients with MAC pulmonary disease. Methods: Forty consecutive patients with MAC pulmonary disease (8 males; median age 62 years; median BMI 18.1) were examined. Serum levels of adiponectin, leptin, TNF-α, and IL-6 were measured with ELISA. Age-, sex- and BMI-matched healthy subjects served as controls. Results: Serum adiponectin was significantly elevated in patients with MAC pulmonary disease compared with the controls (p < 0.01). In both the patients and controls, serum adiponectin levels were inversely correlated with BMI (p < 0.05). No significant correlation was observed between serum adiponectin levels and C-reactive protein or lung function. Serum leptin levels, which were positively correlated with BMI, did not differ between patients and controls. Serum levels of TNF-α and IL-6 were significantly greater in patients with MAC pulmonary disease than in controls. The levels of TNF-α and IL-6 were not correlated with BMI and other adipokines examined. Conclusion: The results of the present study indicate that, in patients with MAC pulmonary disease, adiponectin is inappropriately secreted and may play a role in the pathophysiology of the disease.

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