Publications by authors named "Olle Stendahl"

43 Publications

Helminth species specific expansion and increased TNF-alpha production of non-classical monocytes during active tuberculosis.

PLoS Negl Trop Dis 2021 Mar 2;15(3):e0009194. Epub 2021 Mar 2.

Department of Biomedical and Clinical Sciences, Linköping University, Sweden.

Both Mycobacterium tuberculosis infection and helminths may affect innate immune mechanisms such as differential effects on monocytes towards the non-classical and intermediate subsets that favor bacterial persistence. Our aim, was to investigate helminth species specific effects on the frequency and functional activity of monocyte subsets in patients with active tuberculosis and healthy subjects. HIV-negative patients with active pulmonary tuberculosis (PTB) and community controls (CCs) in Gondar, Ethiopia were screened for helminth infection by stool microscopy. Flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and ex vivo stimulation with purified protein derivative (PPD) and helminth antigens were used to characterize the distribution of monocyte subsets and their function. A total of 74 PTB patients and 57 CCs with and without helminth infection were included. Non-classical monocytes were increased in PTB patients with Ascaris and hookworm infection but not in Schistosoma-infected patients. Ascaris had the strongest effect in increasing the frequency of non-classical monocytes in both PTB patients and CCs, whereas PTB without helminth infection did not affect the frequency of monocyte subsets. There was a helminth specific increase in the frequency of TNF-α producing non-classical monocytes in hookworm infected PTB patients, both with and without PPD-stimulation. Low-to-intermediate TB disease severity associated with increased frequency of non-classical monocytes only for helminth-positive PTB patients, and the frequency of TNF-α producing monocytes were significantly higher in intermediate and non-classical monocytes of helminth positive PTB patients with an intermediate disease score. Helminth infection affected the frequency of monocyte subsets and function both in TB patients and controls which was helminth species dependent in TB patients. The clinical role of this potential immunomodulatory effect needs further study and may affect the response and protection to tuberculosis in areas where helminth infections are endemic.
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http://dx.doi.org/10.1371/journal.pntd.0009194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954301PMC
March 2021

Helminth Antigen Exposure Enhances Early Immune Control of Mycobacterium tuberculosis in Monocytes and Macrophages.

J Innate Immun 2020 Dec 17:1-16. Epub 2020 Dec 17.

Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden,

Helminth and Mycobacterium tuberculosis (Mtb) coinfection is common and suggested to influence the risk of developing active tuberculosis (TB). It is known that helminths in contrast to TB induce a strong Th2 response in the host. However, the direct impact of helminth antigen exposure on host immunity against TB is largely unknown. Our aim was to explore the effects of helminth antigen exposure on the early immune control of Mtb in monocytes and macrophages. Ascaris lumbricoides (ASC) and Schistosoma mansoni (SM) protein antigens were used to study the immediate effect of helminth antigen exposure in monocytes, on monocyte-to-macrophage differentiation, or mature macrophages, in the control of virulent Mtb H37Rv. Pre-exposure of peripheral blood mononuclear cells reduced Mtb growth in monocytes, especially with SM, but no Th1/Th2 cytokines or activation markers indicated involvement of T cells. Monocytes exposed before maturing into macrophages reduced Mtb growth in macrophages (ASC), and pre-exposure of mature macrophages reduced (ASC) or kept Mtb growth at control levels (SM). This in vitro model shows how helminth infection directly affects the monocyte-macrophage axis at an early stage before cell-mediated immunity develops. During acute helminth coinfection or when helminth antigen concentration is elevated at the site of Mtb infection, these helminths provide an enhanced control and killing of Mtb owing to the direct stimulatory effect of helminth antigens on phagocytic cells.
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http://dx.doi.org/10.1159/000512279DOI Listing
December 2020

Efferocytosis of Apoptotic Neutrophils Enhances Control of Mycobacterium tuberculosis in HIV-Coinfected Macrophages in a Myeloperoxidase-Dependent Manner.

J Innate Immun 2020 27;12(3):235-247. Epub 2019 Jun 27.

Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden,

Tuberculosis remains a big threat, with 1.6 million deaths in 2017, including 0.3 million deaths among patients with HIV. The risk of developing active disease increases considerably during an HIV coinfection. Alveolar macrophages are the first immune cells to encounter the causative agent Mycobacterium tuberculosis, but during the granuloma formation other cells are recruited in order to combat the bacteria. Here, we have investigated the effect of efferocytosis of apoptotic neutrophils by M. tuberculosis and HIV-coinfected macrophages in a human in vitro system. We found that the apo-ptotic neutrophils enhanced the control of M. tuberculosis in single and HIV-coinfected macrophages, and that this was dependent on myeloperoxidase (MPO) and reactive oxygen species in an autophagy-independent manner. We show that MPO remains active in the apoptotic neutrophils and can be harnessed by infected macrophages. In addition, MPO inhibition removed the suppression in M. tuberculosis growth caused by the apoptotic neutrophils. Antimycobacterial components from apoptotic neutrophils could thus increase the microbicidal activity of macrophages during an M. tuberculosis/HIV coinfection. This cooperation between innate immune cells could thereby be a way to compensate for the impaired adaptive immunity against M. tuberculosis seen during a concurrent HIV infection.
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http://dx.doi.org/10.1159/000500861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267674PMC
June 2019

Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia.

Sci Rep 2019 02 28;9(1):3126. Epub 2019 Feb 28.

Division of Microbiology Infection and Inflammation, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.
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http://dx.doi.org/10.1038/s41598-019-40121-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395648PMC
February 2019

HIV Interferes with the Dendritic Cell-T Cell Axis of Macrophage Activation by Shifting -Specific CD4 T Cells into a Dysfunctional Phenotype.

J Immunol 2019 02 28;202(3):816-826. Epub 2018 Dec 28.

Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, 581 85 Linköping, Sweden;

HIV coinfection is the greatest risk factor for transition of latent infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of -specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. -specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV--infected (coinfected) human DCs can dysregulate the -specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control infection in macrophages. After coculture with coinfected DCs, Ag-specific CD4 T cells lost their ability to enhance control of infection in infected macrophages. Coinfection of DCs reduced proliferation of Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-β and IL-10, was also significantly increased by coinfection compared with single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of -specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.
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http://dx.doi.org/10.4049/jimmunol.1800523DOI Listing
February 2019

Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages.

PLoS One 2017 13;12(7):e0181221. Epub 2017 Jul 13.

Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Background: Drugs such as isoniazid (INH) and pretomanid (PRT), used against Mycobacterium tuberculosis are active partly through generation of reactive nitrogen species (RNS). The aim of this study was to explore variability in intracellular susceptibility to nitric oxide (NO) in clinical strains of M. tuberculosis.

Method: Luciferase-expressing clinical M. tuberculosis strains with or without INH resistance were exposed to RNS donors (DETA/NO and SIN-1) in broth cultures and bacterial survival was analysed by luminometry. NO-dependent intracellular killing in a selection of strains was assessed in interferon gamma/lipopolysaccharide-activated murine macrophages using the NO inhibitor L-NMMA.

Results: When M. tuberculosis H37Rv was compared to six clinical isolates and CDC1551, three isolates with inhA mediated INH resistance showed significantly reduced NO-susceptibility in broth culture. All strains showed a variable but dose-dependent susceptibility to RNS donors. Two clinical isolates with increased susceptibility to NO exposure in broth compared to H37Rv were significantly inhibited by activated macrophages whereas there was no effect on growth inhibition when activated macrophages were infected by clinical strains with higher survival to NO exposure in broth. Furthermore, the most NO-tolerant clinical isolate showed increased resistance to PRT both in broth culture and the macrophage model compared to H37Rv in the absence of mutational resistance in genes associated to reduced susceptibility against PRT or NO.

Conclusion: In a limited number of clinical M. tuberculosis isolates we found a significant difference in susceptibility to NO between clinical isolates, both in broth cultures and in macrophages. Our results indicate that mycobacterial susceptibility to cellular host defence mechanisms such as NO need to be taken into consideration when designing new therapeutic strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181221PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509328PMC
September 2017

Vitamin D deficiency among newly diagnosed tuberculosis patients and their household contacts: a comparative cross-sectional study.

Arch Public Health 2017 19;75:25. Epub 2017 Jun 19.

Department of Immunology & Molecular Biology, School of Biomedical and Laboratory Sciences, University of Gondar, Gondar, Ethiopia.

Background: Recent studies suggest that the incidence and severity of tuberculosis is associated with low levels of vitamin D. Even though individuals living in Ethiopia have a high exposure to sunlight which is a source of vitamin D, tuberculosis is still one of the major causes of morbidity and mortality in the country. Therefore, this study aimed to determine the prevalence and associated factors of vitamin D deficiency in newly diagnosed tuberculosis patients, household contacts and community controls in Gondar, Ethiopia.

Methods: A comparative cross-sectional study design was conducted. Blood samples were collected from newly diagnosed smear positive pulmonary TB patients, their household contacts and community controls. Serum 25(OH)-vitamin D was determined by an Enzyme Linked Immunosorbent Assay. A serum level of 25(OH)-vitamin D below < 50 nmol/L was defined as vitamin D deficiency and <25 nmol/L as severe vitamin D deficiency.

Results: A total of 126 newly diagnosed smear positive TB patients, 57 house hold contacts and 70 apparently community controls were included in the study. The mean ± SD age (years) of TB patients, house hold contacts and community controls was 29.8 ± 11.9, 24.3 ± 14.7 and 27.3 ± 7.6 respectively. Ninety out of 126 (71.4%) TB patients were underweight with a BMI of < 18.5 kg/m. The mean 25(OH)-vitamin D level of TB patients (30.1 ± 19.3 nmol/L) was significantly lower than community controls (38.5 ± 20.9 nmol/L,  = 0.005 and household contacts (37.7 ± 12.8 nmol/L, =0.031).). The prevalence of vitamin D deficiency was higher in TB patients (83.3%) than in community controls (67.1%,  = 0.009). The prevalence of vitamin D deficiency was also found higher in household contacts (80.7%). Severe vitamin D deficiency was observed in 53%(67/126), 30% (21/70), 19.3%(11/57) of TB patients, community controls and household contacts respectively. Low BMI (AOR = 2.13; 95%CI: 1.02, 3.28) and being positive for tuberculosis (AOR = 1.93; 95%CI: 1.06, 2.86) were significant predictors of severe vitamin D deficiency.

Conclusion: High prevalence of vitamin D deficiency was found among newly diagnosed TB patients and in their household contacts. The present study warrants further studies to determine the role of vitamin D supplementation in the prevention and treatment of tuberculosis in Ethiopia.
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http://dx.doi.org/10.1186/s13690-017-0195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474861PMC
June 2017

HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells.

Am J Pathol 2016 12 13;186(12):3083-3093. Epub 2016 Oct 13.

Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address:

HIV coinfection is the most prominent risk factor for progression of Mycobacterium tuberculosis (Mtb) infection into active tuberculosis (TB) disease. The mechanisms behind the increased transition from latent to active TB in coinfected individuals have not been well elucidated at the cellular level. We hypothesized that HIV infection contributes to Mtb pathogenesis by interfering with the dendritic cell (DC)-mediated immune control. Mtb-antigen processing and presentation are key events in the immune response against TB. Human immature DCs coinfected with HIV/Mtb had decreased expression of human leukocyte antigen antigen D related and the costimulatory molecules CD40, CD80, and CD86. In addition, Mtb-infected DCs triggered a significant release of the proinflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-α, whereas coinfected DCs did not. To assess the DC antigen presentation capacity, we measured interferon-γ from co-cultures of DCs and autologous Mtb antigen-specific CD4 T cells. Interferon-γ release was significantly reduced when purified protein derivative- and Ag85B-specific CD4 T cells had been activated with coinfected DCs compared to Mtb-infected DCs, and this effect was attributed to Mtb antigen processing rather than peptide-major histocompatibility complex class II loading. Evaluating autophagy as a measure of vesicular processing and maturation further revealed that HIV efficiently blocks initiation of this pathway during coinfection. Overall, our results demonstrate that HIV impairs Mtb antigen presentation in DCs, thereby suppressing an important cell linking innate and adaptive immune response in TB.
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http://dx.doi.org/10.1016/j.ajpath.2016.08.003DOI Listing
December 2016

Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity.

PLoS Negl Trop Dis 2015 Aug 6;9(8):e0003994. Epub 2015 Aug 6.

Department of Medical Microbiology, Linköping University, Linköping, Sweden; Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.

Background: The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB.

Methodology: Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively.

Results: A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/μl versus 2.4 (1.1-4.0) cells/μl; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients.

Conclusions: Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients.
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http://dx.doi.org/10.1371/journal.pntd.0003994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527760PMC
August 2015

Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages.

PLoS One 2014 7;9(7):e101514. Epub 2014 Jul 7.

Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages. We show that Mtb infection exerts a potent proinflammatory activation of human macrophages with enhanced gene activation and release of proinflammatory cytokines and that this response was augmented by apoptotic neutrophils. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response contributing to the early control of Mtb infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101514PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084802PMC
February 2015

Human gene variants linked to enhanced NLRP3 activity limit intramacrophage growth of Mycobacterium tuberculosis.

J Infect Dis 2014 Mar 24;209(5):749-53. Epub 2013 Oct 24.

Division of Microbiology and Molecular Medicine.

Activation of the NLRP3 inflammasome and subsequent generation of interleukin 1β is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequent infection of the cells with virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.
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http://dx.doi.org/10.1093/infdis/jit572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923544PMC
March 2014

Mycobacterium tuberculosis- induced neutrophil extracellular traps activate human macrophages.

J Innate Immun 2013 26;5(6):591-602. Epub 2013 Apr 26.

Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

Neutrophils activated by Mycobacterium tuberculosis (Mtb) form neutrophil extracellular traps (NETs), containing DNA and several biologically active cytosolic and granular proteins. These NETs may assist in the innate immune defense against different pathogens. We investigated whether the NET-forming neutrophils mediate an activating signal to macrophages during the early multicellular inflammatory reaction and granuloma formation. Mtb-induced NETs were found to be reactive oxygen species dependent and phagocytosis dependent. A neutrophil elastase inhibitor also delayed NET formation. However, NET formation occurred independently of Mtb-induced apoptosis. We observed close interactions between macrophages and Mtb-activated neutrophils, where macrophages bound and phagocytosed NETs. Significant secretion of the cytokines interleukin (IL)-6, tumor necrosis factor-α, IL-1β and IL-10 were detected from macrophages cocultured with NETs from Mtb-activated but not phorbol myristate acetate-activated neutrophils. NETs binding heat shock protein 72 (Hsp72) or recombinant Hsp72 were able to trigger cytokine release from macrophages. Only Mtb-induced NETs contained Hsp72, suggesting that these NETs can transfer this danger signal to adjacent macrophages. We propose that Hsp72 sequestered in NETs plays an important role in the interaction between neutrophils and macrophages during the early innate immune phase of an Mtb infection. The immunomodulatory role of NETs and proteins derived from them may influence not only chronic inflammation during tuberculosis but also immune regulation and autoimmunity.
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http://dx.doi.org/10.1159/000348676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741595PMC
July 2014

Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients.

Int J Mycobacteriol 2013 Mar 20;2(1):18-25. Epub 2012 Dec 20.

Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden; Center for Infectious Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden. Electronic address:

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB), the bacterium responsible for tuberculosis (TB), has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs) from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL)-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha) and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth.
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http://dx.doi.org/10.1016/j.ijmyco.2012.11.001DOI Listing
March 2013

[Researching physicians provide better care].

Authors:
Olle Stendahl

Lakartidningen 2012 Sep 19-26;109(38):1661

Institutionen för klinisk och experimentell medicin, Hälsouniversitetet, Linköpings universitet.

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November 2012

The impact of asymptomatic helminth co-infection in patients with newly diagnosed tuberculosis in north-west Ethiopia.

PLoS One 2012 29;7(8):e42901. Epub 2012 Aug 29.

Department of Immunology and Molecular Biology, University of Gondar, Gondar, Ethiopia.

Background: Areas endemic of helminth infection, tuberculosis (TB) and HIV are to a large extent overlapping. The aim of this study was to assess the impact of asymptomatic helminth infection on the immunological response among TB patients with and without HIV, their house hold contacts and community controls.

Methodology: Consecutive smear positive TB patients (n = 112), their household contacts (n = 71) and community controls (n = 112) were recruited in Gondar town, Ethiopia. Stool microscopy, HIV serology, serum IgE level, eosinophil and CD4 counts were performed and tuberculosis patients were followed up for 3 months after initiation of anti-TB treatment.

Results: Helminth co-infection rate was 29% in TB patients and 21% in both community control and household contacts (p = 0.3) where Ascaris lumbricoides was the most prevalent parasite. In TB patients the seroprevalence of HIV was 47% (53/112). Eosinophilia and elevated IgE level were significantly associated with asymptomatic helminth infection. During TB treatment, the worm infection rate of HIV+/TB patients declined from 31% (10/32) at week 0 to 9% (3/32) at week 2 of TB treatment, whereas HIV-/TB patients showed no change from baseline to week 2, 29% (13/45) vs. 22.2% (10/45). This trend was stable at week 8 and 12 as well.

Conclusion: One third of smear positive TB patients were infected with helminths. Eosinophilia and elevated IgE level correlated with asymptomatic worm infection, indicating an effect on host immunity. The rate of worm infection declined during TB treatment in HIV+/TB co-infected patients whereas no decline was seen in HIV-/TB group.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042901PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430660PMC
February 2013

Early treatment response evaluated by a clinical scoring system correlates with the prognosis of pulmonary tuberculosis patients in Ethiopia: a prospective follow-up study.

Scand J Infect Dis 2012 Nov 19;44(11):828-34. Epub 2012 Jul 19.

Department of Clinical Sciences, Section for Infectious Diseases, Skåne University Hospital, Lund University, Malmö, Sweden.

Background: In resource-limited settings the monitoring of tuberculosis (TB) patients is challenging, and early identification of TB patients with a high mortality risk is important. The aim of this study was to investigate prospectively whether early changes in a clinical scoring system (TB score) can predict treatment outcome in Ethiopian patients with pulmonary tuberculosis.

Method: TB patients (n = 250) and blood donors (n = 82) were recruited prospectively at Gondar University Hospital, Ethiopia. Clinical scoring was performed using an interview-based questionnaire and clinical examination.

Results: Among TB patients (53.6% of whom were HIV co-infected) the median TB score declined from week 0 to week 2 (8 (interquartile range (IQR) 6-9) vs 4 (IQR 2-6)) and dropped to a low level at week 8, which was still significantly higher than that found in blood donors (2 (IQR 1-4) vs 0 (IQR 0-1), p < 0.0001). Patients who died had a significantly higher TB score at week 0, week 2, and week 8 than survivors. Mortality was associated with a failure to achieve a decrease greater than 25% in the TB score at 2 weeks. Baseline CD4 + cell counts (< 200 cells/mm³) were associated with mortality but not with initial TB score results.

Conclusions: The TB score was increased during the first 2 months of treatment among patients who died. Failure to achieve a greater than 25% decrease in TB score after 2 weeks of treatment was associated with increased mortality. Repeated clinical scoring during the intensive phase of TB treatment could be useful to identify high-risk patients.
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http://dx.doi.org/10.3109/00365548.2012.694468DOI Listing
November 2012

Resistance to first-line anti-TB drugs is associated with reduced nitric oxide susceptibility in Mycobacterium tuberculosis.

PLoS One 2012 29;7(6):e39891. Epub 2012 Jun 29.

Division of Microbiology and Molecular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

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 susceptibility 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 1 mM 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, independent of antibiotic resistance.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039891PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387217PMC
November 2012

Common genetic variations in the NALP3 inflammasome are associated with delayed apoptosis of human neutrophils.

PLoS One 2012 5;7(3):e31326. Epub 2012 Mar 5.

Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1β production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages.

Methods And Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients' neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response.

Conclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293864PMC
July 2012

[Swedish clinical research can be better].

Authors:
Olle Stendahl

Lakartidningen 2011 May 11-18;108(19):1061

Hälsouniversitetet, Linköpings universitet.

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August 2011

Human macrophages infected with a high burden of ESAT-6-expressing M. tuberculosis undergo caspase-1- and cathepsin B-independent necrosis.

PLoS One 2011 26;6(5):e20302. Epub 2011 May 26.

Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated through caspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1β, while a low MOI gave no IL-1β response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, and HMGB1 release. Although we observed plasma membrane permeabilization and IL-1β release from infected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102687PMC
September 2011

Importance of phagosomal functionality for growth restriction of Mycobacterium tuberculosis in primary human macrophages.

J Innate Immun 2011 11;3(5):508-18. Epub 2011 May 11.

Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Mail amanda.welin @ liu.se

The best characterized survival mechanism of Mycobacterium tuberculosis inside the macrophage is the inhibition of phagosomal maturation. Phagosomal maturation involves several steps including fusion with lysosomes and acidification. However, it has not been elucidated which components of phagosomal maturation correlate with growth restriction of virulent mycobacteria in human macrophages, and we aimed to study this. We infected human monocyte-derived macrophages with M. tuberculosis and assessed bacterial replication, translocation of CD63 to the phagosome, and phagosomal acidification. We found that unstimulated human macrophages were able to control infection with M. tuberculosis upon inoculation at a low multiplicity of infection (MOI) of 1, but not at a high MOI of 10. The low MOI resulted in a macrophage-controlled balance between host cells and bacteria. Both H37Rv and H37Ra infection, at high and low MOI, led to equally ineffective translocation of CD63 to the phagosome. On the other hand, acidification of mycobacterial phagosomes was more efficient at MOI 1 than 10 with both mycobacterial strains, consistent with a direct or indirect role for phagosomal acidification in restricting M. tuberculosis growth. Furthermore, inhibition of the vacuolar H(+)-ATPase as well as of cathepsin D led to enhanced mycobacterial replication inside the macrophage. This again shows the importance of phagosomal acidification for control of mycobacterial growth, through the activation of lysosomal hydrolases. We conclude that acidification and related functional aspects of the mature phagosome are important factors for restriction of M. tuberculosis replication in human macrophages.
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http://dx.doi.org/10.1159/000325297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696374PMC
December 2011

Identification of drug susceptibility pattern and mycobacterial species in sputum smear positive pulmonary tuberculosis patients with and without HIV co-infection in north west Ethiopia.

Ethiop Med J 2010 Jul;48(3):203-10

Department of Medical Laboratory Technology, Jimma University, Ethiopia.

Background: Ethiopia is among the high-burden countries of tuberculosis (TB) in the world Since mycobacterial culture and susceptibility testing are not routinely performed in Ethiopia, recent data on susceptibility patterns and the mycobacterial species cultured from sputum smear positive patients are limited.

Objectives: The aim was to determine first line anti-TB drug susceptibility of Mycobacterium tuberculosis isolates obtained from consecutive newly diagnosed smear positive pulmonary TB patients in north west Ethiopia.

Methodology: A retrospective cross sectional study was conducted using previously collected sputum samples (n=180) kept at the referral hospital of the University of Gondar at -20 degrees C. Sputum samples were cultured on Lowenstein Jensen (LJ) medium. Conventional Polymerase Chain Reaction (PCR) using RD4 primers to identify the M. tuberculosis complex was performed on cultured isolates. Ninety eight (84.4%) of the 116 isolates identified as M. tuberculosis were tested for their drug susceptibility pattern using the proportion method Clinical baseline data including body mass index, body temperature, clinical symptoms and erythrocyte sedimentation rate were obtained.

Results: The culture retrieval rate of previously frozen sputum samples was 64.4% (116/180). All the isolated mycobacterial species (n=116) were confirmed as belonging to the M. tuberculosis complex by PCR. Of 98 isolates for which the drug susceptibility test was done, 15.3% (15/98) were found to be resistant to one or more antimycobacterial drugs, and resistance to isoniazid and streptomycin was most common with 8.2% (8/98) and 6.1% (6/98) respectively. TB patients co infected with HIV had increased erythrocyte sedimentation rate, higher age and lower sputum smear grade than HIV negative TB patients.

Conclusions: No mycobacteria other than M. tuberculosis were detected in sputum smear positive TB-patients. Although no multi drug resistant strain was observed, relatively high rates of INH resistance were found in this region. Culture facilities are urgently needed in regional centers to increase diagnostic sensitivity and monitor developing trends of drug resistance in Ethiopia.
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July 2010

[Sweden (and Europe) need a treatment research foundation!].

Lakartidningen 2010 Apr 21-27;107(16):1087-8

SBU, Statens beredning för medicinsk utvärdering; Stockholm.

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May 2010

Kinetics of the QuantiFERON-TB Gold In-Tube test during treatment of patients with sputum smear-positive tuberculosis in relation to initial TST result and severity of disease.

Scand J Infect Dis 2010 Sep;42(9):650-7

Department of Medical Microbiology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

The QuantiFERON-TB Gold In-Tube test (QFN) measures interferon-gamma production in response to Mycobacterium tuberculosis antigens. Our aim was to assess the kinetics of the QFN and initial tuberculin skin test (TST) result in relation to severity of disease in a tuberculosis (TB) endemic area. Smear-positive TB patients (n = 71) were recruited at Gondar University Hospital, Ethiopia. The TST, QFN, CD4+ cell count and clinical symptoms (TB score) were assessed and followed up during treatment. From baseline to 7 months after treatment, there was a significant decrease in QFN reactivity (93.8% to 62.5% in HIV-negative/TB; 70.3% to 33.3% in HIV-positive/TB patients) down to a level comparable to a control group of blood donors (51.2%). The agreement between TST and QFN was poor in TB patients compared to healthy controls. A negative TST correlated to more advanced TB in contrast to a negative QFN test. We conclude that the QFN reactivity is significantly reduced at the end of treatment against active TB to the background level of healthy blood donors, and that the agreement between TST and QFN is poor including correlation to the severity of disease.
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http://dx.doi.org/10.3109/00365548.2010.482942DOI Listing
September 2010

Dendritic cell activation by sensing Mycobacterium tuberculosis-induced apoptotic neutrophils via DC-SIGN.

Hum Immunol 2010 Jun 11;71(6):535-40. Epub 2010 Mar 11.

Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Linköping University, Sweden.

Mycobacterium tuberculosis (Mtb) manipulates cells of the innate immune system to provide the bacteria with a sustainable intracellular niche. Mtb spread through aerosol carrying them deep into the lungs, where they are internalized by phagocytic cells, such as neutrophils (PMNs), dendritic cells (DCs), and macrophages. PMNs undergo accelerated apoptosis after interaction with the bacterium, and apoptotic cells are sequestered by neighboring phagocytes. Removal of aged apoptotic cells because of natural tissue turnover is described as an immunologically silent process facilitating resolution of inflammation and inhibition of DC maturation. Silencing of immune cells could be favorable for intracellular bacteria. The aim of this study was to clarify the interaction between Mtb-induced apoptotic PMNs and DCs, and evaluate whether this interaction follows the proposed anti-inflammatory pathway. In contrast to aged apoptotic cells, Mtb-induced apoptotic PMNs induced functional DC maturation. We found that the cell fraction from Mtb-induced apoptotic PMNs contained almost all stimulatory capacity, suggesting that cell-cell interaction is crucial for DC activation. Inhibitory studies showed that this cell contact-dependent activation required binding of the PMN Mac-1 (CD11b/CD18) to the DC via DC-SIGN and endocytic activity involving the alpha(v)beta(5) but did not involve the scavenger receptor CD36. Taken together, this study demonstrates that the DCs can distinguish between normal and infected apoptotic PMNs via cellular crosstalk, where the DCs can sense the presence of danger on the Mtb-infected PMNs and modulate their response accordingly.
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http://dx.doi.org/10.1016/j.humimm.2010.02.022DOI Listing
June 2010

Validation of a medium-throughput method for evaluation of intracellular growth of Mycobacterium tuberculosis.

Clin Vaccine Immunol 2010 Apr 27;17(4):513-7. Epub 2010 Jan 27.

Division of Medical Microbiology, Linköping University, 58185 Linköping, Sweden

Intracellular pathogens such as Mycobacterium tuberculosis have adapted to a life inside host cells, in which they utilize host nutrients to replicate and spread. Ineffective methods for the evaluation of growth of intracellular pathogens in their true environment pose an obstacle for basic research and drug screening. Here we present the validation of a luminometry-based method for the analysis of intramacrophage growth of M. tuberculosis. The method, which is performed in a medium-throughput format, can easily be adapted for studies of other intracellular pathogens and cell types. The use of host cells in drug-screening assays dedicated to find antimicrobials effective against intracellular pathogens permits the discovery of not only novel antibiotics but also compounds with immunomodulatory and virulence-impairing activities, which may be future alternatives or complements to antibiotics.
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http://dx.doi.org/10.1128/CVI.00446-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849333PMC
April 2010

[Clinical research must attract the young. Universities and health care can together show possibilities of research].

Authors:
Olle Stendahl

Lakartidningen 2009 Nov 11-17;106(46):3066

Institutionen för klinisk och experimentell medicin, Linköpings universitet.

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February 2010

Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins.

Microb Pathog 2009 Sep 6;47(3):143-50. Epub 2009 Jun 6.

Department of Molecular and Clinical Medicine, Linköping University, Sweden.

Modulation of immune cell apoptosis is a key evasion strategy utilized by Mycobacterium tuberculosis (Mtb). To be able to multiply within macrophages, the bacterium delays apoptosis and down-regulates pro-inflammatory activation in these cells, whereas apoptosis is rapidly induced in the potently bactericidal neutrophils. Initial host-pathogen interactions between neutrophils and Mtb, subsequently leading to apoptosis, need to be investigated to understand the early features during Mtb infections. Opsonized Mtb were readily phagocytosed, and the immuno-mediated phagocytosis triggered early activation of anti-apoptotic Akt in the neutrophils but the bacteria still induced apoptosis to the same extent as non-phagocytosed Mtb. Mtb-induced apoptosis was strictly dependent on NADPH oxidase-generated reactive oxygen species, compounds shown to damage lysosomal granules. Despite this, we found no involvement of damaged azurophilic granules in Mtb-induced apoptosis in human neutrophils. Instead, the Mtb-induced apoptosis was p38 MAPK dependent and induced through the mitochondrial pathway. Moreover, Mtb deficient of mature lipoproteins lacked the determinants required for induction of neutrophil apoptosis. These results show that Mtb exert a strong intrinsic capacity to induce apoptosis in neutrophils that is capable of overcoming the anti-apoptotic signaling in the cell.
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http://dx.doi.org/10.1016/j.micpath.2009.05.006DOI Listing
September 2009

Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection.

BMC Infect Dis 2008 Oct 24;8:146. Epub 2008 Oct 24.

Department of Medical Microbiology, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.

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.
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http://dx.doi.org/10.1186/1471-2334-8-146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596154PMC
October 2008

Incorporation of Mycobacterium tuberculosis lipoarabinomannan into macrophage membrane rafts is a prerequisite for the phagosomal maturation block.

Infect Immun 2008 Jul 21;76(7):2882-7. Epub 2008 Apr 21.

Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden.

Lipoarabinomannan (LAM) is one of the key virulence factors for Mycobacterium tuberculosis, the etiological agent of tuberculosis. During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage and can be detected throughout the cell upon infection. LAM can inhibit phagosomal maturation as well as induce a proinflammatory response in bystander cells. The aim of this study was to investigate how LAM exerts its action on human macrophages. We show that LAM is incorporated into membrane rafts of the macrophage cell membrane via its glycosylphosphatidylinositol anchor and that incorporation of mannose-capped LAM from M. tuberculosis results in reduced phagosomal maturation. This is dependent on successful insertion of the glycosylphosphatidylinositol anchor. LAM does not, however, induce the phagosomal maturation block through activation of p38 mitogen-activated protein kinase, contradicting some previous suggestions.
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http://dx.doi.org/10.1128/IAI.01549-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2446741PMC
July 2008