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Pathogenesis AND Tuberculosis

Monika Linke, Ha Thi Thanh Pham, Karl Katholnig, Thomas Schnöller, Anne Miller, Florian Demel, Birgit Schütz, Margit Rosner, Boris Kovacic, Nyamdelger Sukhbaatar, Birgit Niederreiter, Stephan Blüml, Peter Kuess, Veronika Sexl, Mathias Müller, Mario Mikula, Wolfram Weckwerth, Arvand Haschemi, Martin Susani, Markus Hengstschläger, Michael J Gambello, Thomas Weichhart
The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo...
January 16, 2017: Nature Immunology
Wilhelmina Maria Cornelia Timmermans, Jan Alexander Michael van Laar, Petrus Martinus van Hagen, Menno Cornelis van Zelm
Granulomas are clusters of immune cells. These structures can be formed in reaction to infection and display signs of necrosis, such as in tuberculosis. Alternatively, in several immune disorders, such as sarcoidosis, Crohn's disease and common variable immunodeficiency, non-caseating granulomas are formed without an obvious infectious trigger. Despite advances in our understanding of the human immune system, the pathogenesis underlying these non-caseating granulomas in chronic inflammatory diseases is still poorly understood...
December 2016: Clinical & Translational Immunology
Haipeng Liu, Ruijuan Zheng, Peng Wang, Hua Yang, Xin He, Qun Ji, Wenjuan Bai, Hao Chen, Jianxia Chen, Wenxia Peng, Siyu Liu, Zhonghua Liu, Baoxue Ge
Interleukin-37 (IL-37), a novel member of the IL-1 family, plays fundamental immunosuppressive roles by broadly reducing both innate inflammation and acquired immunity, but whether it is involved in the pathogenesis of tuberculosis (TB) has not been clearly elucidated. In this study, single nucleotide polymorphism (SNP) analysis demonstrated an association of the genetic variant rs3811047 of IL-37 with TB susceptibility. In line with previous report, a significant elevated IL-37 abundance in the sera and increased expression of IL-37 protein in the peripheral blood mononuclear cells (PBMC) were observed in TB patients in comparison to healthy controls...
2017: PloS One
Garima Khare, Prachi Nangpal, Anil K Tyagi
Ferritins and bacterioferritins are iron storage proteins that represent key players in iron homeostasis. Several organisms possess both forms of ferritins, however, their relative physiological roles are less understood. Mycobacterium tuberculosis possesses both ferritin (BfrB) and bacterioferritin (BfrA), playing an essential role in its pathogenesis as reported by us earlier. This study provides insights into the role of these two proteins in iron homeostasis by employing M. tuberculosis bfr mutants. Our data suggests that BfrA is required for efficient utilization of stored iron under low iron conditions while BfrB plays a crucial role as the major defense protein under excessive iron conditions...
2017: PloS One
Theodore R Mellors, Lionel Blanchet, JoAnne L Flynn, Jaime Tomko, Melanie O'Malley, Charles A Scanga, Philana L Lin, Jane E Hill
Breath is hypothesized to contain clinically relevant information, useful for the diagnosis and monitoring of disease, as well as understanding underlying pathogenesis. Non-human primates, such as the cynomolgus macaque, serve as an important model for the study of human disease, including over 70 different human infections. In this feasibility study, exhaled breath was successfully collected in less than five minutes under Biosafety Level 3 conditions from five anesthetized, intubated cynomolgus and rhesus macaques, before and after lung infection with M...
January 5, 2017: Journal of Applied Physiology
Faramarz Valafar
No abstract text is available yet for this article.
December 2016: International Journal of Mycobacteriology
Umesh Datta Gupta, Ali Abbas, Raj Pal Singh Kashyap, Pushpa Gupta
BACKGROUND: Central nervous system (CNS) infections caused by Mycobacterium tuberculosis (MTB) are the most severe forms of extrapulmonary TB (EPTB) due to high levels of mortality and neurological morbidity. Limited studies are available on CNS-TB animal-model development, despite the steady rise in cerebral-TB cases in India over the past decade. This study describes the development of a murine model of CNS-TB using a clinical strain (C3) isolated from the cerebrospinal fluid (CSF) of CNS-TB patients...
December 2016: International Journal of Mycobacteriology
Wenmin Yang, Wanyan Deng, Jie Zeng, Sai Ren, Md Kaisar Ali, Yinzhong Gu, Yangyuling Li, Jianping Xie
Mycobacterium tuberculosis PE/PPE family proteins, named after the presence of conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains at N-terminal, are prevalent in M. tuberculosis genome. The function of most PE/PPE family proteins remains elusive. To characterize the function of PE_PGRS18, the encoding gene was heterologously expressed in M. smegmatis, a nonpathogenic mycobacterium. The recombinant PE_PGRS18 is cell wall associated. M. smegmatis PE_PGRS18 recombinant showed differential response to stresses and altered the production of host cytokines IL-6, IL-1β, IL-12p40 and IL-10, as well as enhanced survival within macrophages largely via attenuating the apoptosis of macrophages...
December 16, 2016: Apoptosis: An International Journal on Programmed Cell Death
Alimuddin Zumla, Isaac Darko Otchere, Gloria Ivy Mensah, Adwoa Asante-Poku, Florian Gehre, Markus Maeurer, Matthew Bates, Peter Mwaba, Francine Ntoumi, Dorothy Yeboah-Manu
Mycobacterium africanum comprises two phylogenetic lineages within the Mycobacterium tuberculosis complex (MTBC). M. africanum was first described and isolated in 1968 from the sputum of a Senegalese patient with pulmonary tuberculosis (TB) and it has been identified increasingly as an important cause of human TB, particularly prevalent in West Africa. The restricted geographical distribution of M. africanum, in contrast to the widespread global distribution of other species of MTBC, requires explanation. Available data indicate that M...
December 12, 2016: International Journal of Infectious Diseases: IJID
Xiaofan Yang, Jiahui Yang, Jinli Wang, Qian Wen, Hui Wang, Jianchun He, Shengfeng Hu, Wenting He, Xialin Du, Sudong Liu, Li Ma
Macrophages play a crucial role in the control and elimination of invading Mycobacterium tuberculosis (Mtb), and also serve as the major residence for Mtb. However, the interaction between macrophages and Mtb remains to be clearly determined. Although long noncoding RNAs (lncRNAs) have emerged as key regulators in many biological processes, their roles in anti-mycobacterial responses of macrophages remain to be elucidated. Here, we applied microarray analysis to examine lncRNA and mRNA expression profiles in human primary macrophages after 72 h of infection with H37Ra or H37Rv...
December 14, 2016: Scientific Reports
Kimberly M Sogi, Cynthia M Holsclaw, Gabriela K Fragiadakis, Daniel K Nomura, Julie A Leary, Carolyn R Bertozzi
Sulfomenaquinone (SMK) is a recently identified metabolite that is unique to the Mycobacterium tuberculosis (M. tuberculosis) complex and is shown to modulate its virulence. Here, we report the identification of the SMK biosynthetic operon that, in addition to a previously identified sulfotransferase stf3, includes a putative cytochrome P450 gene (cyp128) and a gene of unknown function, rv2269c. We demonstrate that cyp128 and stf3 are sufficient for the biosynthesis of SMK from menaquinone and rv2269c exhibits promoter activity in M...
November 11, 2016: ACS Infectious Diseases
Suzaan Marais, Rachel P J Lai, Katalin A Wilkinson, Graeme Meintjes, Anne O'Garra, Robert J Wilkinson
Tuberculosis meningitis (TBM) is a frequent cause of meningitis in HIV-infected individuals, resulting in death in ~ 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological TB-immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole blood microarray analysis of HIV-infected TBM patients and reflected the findings at the protein level...
December 8, 2016: Journal of Infectious Diseases
Ashley L Garner, Jayan Rammohan, Jeremy P Huynh, Lucas M Onder, James Chen, Brian Bae, Drake Jensen, Leslie A Weiss, Ana Ruiz Manzano, Seth A Darst, Elizabeth A Campbell, Bryce E Nickels, Eric A Galburt, Christina L Stallings
: CarD is an essential RNA polymerase (RNAP) interacting protein in Mycobacterium tuberculosis (Mtb) that stimulates formation of RNAP-promoter open complexes. CarD plays a complex role in Mtb growth and virulence that is not fully understood. Therefore, to gain further insight into the role of CarD in Mtb growth and virulence we determined the effect of increasing the affinity of CarD for RNAP. Using site-directed mutagenesis guided by crystal structures of CarD bound to RNAP, we identified amino acid substitutions that increase the affinity of CarD for RNAP...
December 5, 2016: Journal of Bacteriology
Julia Lienard, Fredric Carlsson
Mycobacteria are a major human health problem globally. Regarding tuberculosis the situation is worsened by the poor efficacy of current vaccine regimens and by emergence of drug-resistant strains (Manjelievskaia J et al, Trans R Soc Trop Med Hyg 110: 110, 2016; Pereira et al., Lancet Infect Dis 12:300-306, 2012; undermining both disease-prevention and available treatments. Thus, increased basic understanding of mycobacterial-and particularly Mycobacterium tuberculosis-virulence strategies and pathogenesis is of great importance...
2017: Methods in Molecular Biology
Mitchell V Palmer, Tyler C Thacker, W Ray Waters
The hallmark lesion of tuberculosis in humans and animals is the granuloma. The granuloma represents a distinct host cellular immune response composed of epithelioid macrophages, lymphocytes, and multinucleated giant cells, often surrounding a caseous necrotic core. Within the granuloma, host-pathogen interactions determine disease outcome. Factors within the granulomas such as cytokines and chemokines drive cell recruitment, activity, function and ultimately the success or failure of the host's ability to control infection...
2016: PloS One
Katerina S Jurkoshek, Ying Wang, Jaffre J Athman, Marian R Barton, Pamela A Wearsch
The production of extracellular vesicles is a universal mechanism for intercellular communication that is conserved across kingdoms. Prokaryotes secrete 50-250 nm membrane vesicles (MVs) in a manner that is regulated by environmental stress and is thought to promote survival. Since many types of host-derived stress are encountered during infection, this implies an important role for MV secretion in bacterial pathogenesis. Accordingly, MVs produced by gram-positive and gram-negative pathogens contain toxins, virulence factors, and other molecules that promote survival in the host...
2016: Frontiers in Cell and Developmental Biology
Monoranjan Boro, Vikas Singh, Kithiganahalli Narayanaswamy Balaji
Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20-like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner...
November 24, 2016: Scientific Reports
C Seshadri, N T T Thuong, N T H Mai, N D Bang, T T H Chau, D M Lewinsohn, G E Thwaites, S J Dunstan, T R Hawn
The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis...
November 24, 2016: Genes and Immunity
Monu, Laxman S Meena
OBJECTIVES: The periodic binding of protein expressed by Mycobacterium tuberculosis H37Rv with the host cell receptor molecules i.e. fibronectin (Fn) is gaining significance because of its adhesive properties. The genome sequencing of M. tuberculosis H37Rv revealed that the proline-glutamic (PE) proteins contain polymorphic GC-rich repetitive sequences (PGRS) which have clinical importance in pathogenesis events when the host encounters M. tuberculosis H37Rv. The functional parts of PE_PGRS family proteins, have not been extensively studied in tuberculosis biology...
October 2016: Iranian Journal of Basic Medical Sciences
Lei Shen, Hong Shi, Yan Gao, Qinfang Ou, Qianqian Liu, Yuanyuan Liu, Jing Wu, Wenhong Zhang, Lin Fan, Lingyun Shao
PD-1 is a cell surface receptor of activated T and B lymphocytes and it's role in tuberculosis is controversial because of lack of congruence between clinical study and animal model. To investigate the immunological pathogenesis mechanisms of tuberculosis and to develop the immune therapy target essential for controlling tuberculosis, here we explored the expression characteristics and dynamic changes of PD-1/PD-L1 pathway in different CD4+T cell subsets. We enrolled 24 human subjects including 15 active tuberculosis (ATB) patients and 9 healthy donors (HD)...
December 2016: Tuberculosis
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