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The Role of Nitric Oxide in Host Defence Against Mycobacterium tuberculosis: Clinical and Experimental Studies
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), responsible for significant morbidity and mortality worldwide, especially in low-income countries. Considering aggravating factors, such as HIV co-infection and emerging drug resistance, new therapeutic interventions are urgently needed. Following exposure to M. tuberculosis, surprisingly few individuals will actually develop active disease, indicating effective defence mechanisms. One such candidate is nitric oxide (NO). The role of NO in human TB is not fully elucidated, but has been shown to have a vital role in controlling TB in animal models.

The general aim of this thesis was to investigate the role of NO in the immune defence against M. tuberculosis, by combining clinical and experimental studies. In pulmonary TB patients, we found low levels of NO in exhaled air, and low levels of NO metabolites in urine. HIV coinfection decreased levels of exhaled NO even further, reflecting a locally impaired NO production in the lung. Low levels of exhaled NO were associated with a decreased cure rate in HIV-positive TB patients. Household contacts to sputum smear positive TB patient presented the highest levels of both urinary NO metabolites and exhaled NO. Malnutrition, a common condition in TB, may lead to deficiencies of important nutrients such as the amino acid L-arginine, essential for NO production. We therefore assessed the effect of an argininerich food supplement (peanuts) in a clinical trial including pulmonary TB patients, and found that peanut supplementation increased cure rate in HIV-positive TB patients.

We also investigated NO susceptibility of clinical strains of M. tuberculosis, and its association to clinical outcome and antibiotic resistance. Patients infected with strains of M. tuberculosis with reduced susceptibility to NO in vitro, showed a tendency towards lower rate of weight gain during treatment. Moreover, there was a clear variability between strains in the susceptibility to NO, and in intracellular survival within NO-producing macrophages. A novel finding, that can be of importance in understanding drug resistance and for drug development, was that reduced susceptibility to NO was associated with resistance to firstline TB drugs, in particular isoniazid and mutations in inhA.

Taken together, the data presented here show that NO plays a vital role  in human immune defence against TB, and although larger multicentre studies are warranted, arginine-rich food supplementation can be recommended to malnourished HIV co-infected patients on TB treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 86 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1304
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-77145ISBN: 978-91-7519-911-5 (print)OAI: oai:DiVA.org:liu-77145DiVA: diva2:525183
Public defence
2012-06-07, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2012-05-14Bibliographically approved
List of papers
1. Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection
Open this publication in new window or tab >>Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection
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2008 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 8, no 146Article in journal (Refereed) Published
Abstract [en]

Background: Nitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO).

Methods: In a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia.

Results: The proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate.

Conclusion: In both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16238 (URN)10.1186/1471-2334-8-146 (DOI)
Note
Original Publication: Jonna Idh, Anna Westman, Daniel Elias, Feleke Moges, Assefa Getachew, Aschalew Gelaw, Tommy Sundqvist, Tony Forslund, Addis Alemu, Belete Ayele, Ermias Diro, Endalkachew Melese, Yared Wondmikun, Sven Britton, Olle Stendahl and Thomas Schoen, Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection, 2008, BMC INFECTIOUS DISEASES, (8), 146. http://dx.doi.org/10.1186/1471-2334-8-146 Publisher: BioMed Central http://www.biomedcentral.com/Available from: 2009-01-16 Created: 2009-01-09 Last updated: 2017-12-14Bibliographically approved
2. Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial
Open this publication in new window or tab >>Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial
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2011 (English)In: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 91, no 5, 370-377 p.Article in journal (Refereed) Published
Abstract [en]

In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X-ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p andlt; 0.01). A low baseline eNO (andlt; 10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Nitric oxide, Arginine, Nutritional supplementation, Tuberculosis, Interleukin 10
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71556 (URN)10.1016/j.tube.2011.06.002 (DOI)000295462300004 ()
Note
Funding Agencies|Swedish Heart and Lung Foundation||Swedish SAREC/SIDA foundation||Swedish Research Council||Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-12-08Bibliographically approved
3. Resistance to First-Line Anti-TB Drugs is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis
Open this publication in new window or tab >>Resistance to First-Line Anti-TB Drugs is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, e39891- p.Article in journal (Refereed) Published
Abstract [en]

Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known.

Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO.

Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment.

Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77129 (URN)10.1371/journal.pone.0039891 (DOI)000305892100124 ()
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2017-12-07Bibliographically approved
4. Susceptibility of Clinical Strains of Mycobacterium tuberculosis to Reactive Nitrogen Species in Activated Macrophages
Open this publication in new window or tab >>Susceptibility of Clinical Strains of Mycobacterium tuberculosis to Reactive Nitrogen Species in Activated Macrophages
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Nitric oxide (NO) is produced in macrophages by the inducible NO synthase (iNOS) upon activation by pro-inflammatory cytokines. NO has been shown to be essential for the control of Mycobacterium tuberculosis infection in murine models whereas its importance in man is not as clear. There is a lack of studies regarding the susceptibility to reactive nitrogen species (RNS) in clinical strains of M. tuberculosis and the relation to first-line drug resistance, such as to isoniazid (INH). The aim of this study was to explore susceptibility to RNS and intracellular survival of clinical strains of M. tuberculosis, with or without INH resistance.

Method: Seven clinical strains of M. tuberculosis were transformed with the pSMT1-plasmid encoding Vibrio harveyi luciferase. Survival was analysed by luminometry following exposure to the NO donor DETA/NO or peroxynitrite (SIN-1). Intracellular killing was studied in murine macrophages (RAW 264.7) activated with interferon gamma (IFN-γ) and lipopolysaccharide (LPS).

Results: There was a significant effect on growth control of M. tuberculosis strains upon macrophage activation, which showed variability among clinical isolates. In the cell-free system, all strains showed a dose-dependent susceptibility to DETA/NO and SIN-1, and clinical strains were in general more resistant than H37Rv to DETA/NO. INH-resistant strains with an inhA mutation were significantly more tolerant to DETA/NO than inhA wild type.

Conclusion: Reactive nitrogen species inhibited growth of clinical M. tuberculosis isolates both in an intra- and extracellular model with significant difference between strains. Increased tolerance to NO was associated with isoniazid resistance mediated by inhA.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77131 (URN)
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2012-05-07Bibliographically approved

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