To treat or not to treat tuberculosis -clinical decision making in patients with previous pulmonary tuberculosis using 18F-FDG PET/CT.

Post-tuberculosis (TB) radiological changes and symptoms can mimic TB. PCR-based diagnostic tests can show positive results, suggesting the presence of Mycobacterium tuberculosis DNA in the absence of viable bacteria. We present a case with two episodes of previous TB. Despite workup including trace to low positive PCR results, after performing sputum analysis, bronchoalveolar lavage analysis, cyto-brush and 18F-FDG PET/CT guided transthoracic biopsy, no culturable mycobacteria were detected. 18F-FDG PET/CT showed a high metabolic activity of the biopsied lesions. More accurate strategies and tools in patients with previous TB and positive PCR results are required to make appropriate treatment decisions.

Antisense Therapy for Infectious Diseases.

Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.

COVID-19Base v3: Update of the knowledgebase for drugs and biomedical entities linked to COVID-19.

COVID-19 has taken a huge toll on our lives over the last 3 years. Global initiatives put forward by all stakeholders are still in place to combat this pandemic and help us learn lessons for future ones. While the vaccine rollout was not able to curb the spread of the disease for all strains, the research community is still trying to develop effective therapeutics for COVID-19. Although Paxlovid and remdesivir have been approved by the FDA against COVID-19, they are not free of side effects. Therefore, the search for a therapeutic solution with high efficacy continues in the research community. To support this effort, in this latest version (v3) of COVID-19Base, we have summarized the biomedical entities linked to COVID-19 that have been highlighted in the scientific literature after the vaccine rollout. Eight different topic-specific dictionaries, i.e., gene, miRNA, lncRNA, PDB entries, disease, alternative medicines registered under clinical trials, drugs, and the side effects of drugs, were used to build this knowledgebase. We have introduced a BLSTM-based deep-learning model to predict the drug-disease associations that outperforms the existing model for the same purpose proposed in the earlier version of COVID-19Base. For the very first time, we have incorporated disease-gene, disease-miRNA, disease-lncRNA, and drug-PDB associations covering the largest number of biomedical entities related to COVID-19. We have provided examples of and insights into different biomedical entities covered in COVID-19Base to support the research community by incorporating all of these entities under a single platform to provide evidence-based support from the literature. COVID-19Base v3 can be accessed from: https://covidbase-v3.vercel.app/. The GitHub repository for the source code and data dictionaries is available to the community from: https://github.com/91Abdullah/covidbasev3.0.

Lyl1-deficiency promotes inflammatory responses and increases mycobacterial burden in response to Mycobacterium tuberculosis infection in mice.

Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential in various forms of leukemia with pivotal roles in hematopoietic stem cell biology. While its role in early hematopoiesis is well established, its function in mature innate cells is less explored. Here, we identified Lyl1 as a drastically perturbed gene in the Mycobacterium tuberculosis (Mtb) infected mouse macrophage transcriptome. We report that Lyl1 downregulation upon immune stimulation is a host-driven process regulated by NFκB and MAP kinase pathways. Interestingly, Lyl1-deficient macrophages have decreased bacterial killing potential with reduced nitric oxide (NO) levels while expressing increased levels of pro-inflammatory interleukin-1 and CXCL1. Lyl1-deficient mice show reduced survival to Mtb HN878 infection with increased bacterial burden and exacerbated inflammatory responses in chronic stages. We observed that increased susceptibility to infection was accompanied by increased neutrophil recruitment and IL-1, CXCL1, and CXCL5 levels in the lung homogenates. Collectively, these results suggest that Lyl1 controls Mtb growth, reduces neutrophilic inflammation and reveals an underappreciated role for Lyl1 in innate immune responses.

Host-Directed Targeting of LincRNA-MIR99AHG Suppresses Intracellular Growth of Mycobacterium tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills 1.6 million people worldwide every year, and there is an urgent need for targeting host-pathogen interactions as a strategy to reduce mycobacterial resistance to current antimicrobials. Noncoding RNAs are emerging as important regulators of numerous biological processes and avenues for exploitation in host-directed therapeutics. Although long noncoding RNAs (lncRNAs) are abundantly expressed in immune cells, their functional role in gene regulation and bacterial infections remains understudied. In this study, we identify an immunoregulatory long intergenic noncoding RNA, lincRNA-MIR99AHG, which is upregulated in mouse and human macrophages upon IL-4/IL-13 stimulation and downregulated after clinical Mtb HN878 strain infection and in peripheral blood mononuclear cells from active TB patients. To evaluate the functional role of lincRNA-MIR99AHG, we used antisense locked nucleic acid (LNA) GapmeR-mediated antisense oligonucleotide (ASO) lncRNA knockdown experiments. Knockdown of lincRNA-MIR99AHG with ASOs significantly reduced intracellular Mtb growth in mouse and human macrophages and reduced pro-inflammatory cytokine production. In addition, in vivo treatment of mice with MIR99AHG ASOs reduced the mycobacterial burden in the lung and spleen. Furthermore, in macrophages, lincRNA-MIR99AHG is translocated to the nucleus and interacts with high affinity to hnRNPA2/B1 following IL-4/IL-13 stimulation and Mtb HN878 infection. Together, these findings identify lincRNA-MIR99AHG as a positive regulator of inflammation and macrophage polarization to promote Mtb growth and a possible target for adjunctive host-directed therapy against TB.

Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to Mycobacterium tuberculosis infection.

BACKGROUND: Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. OBJECTIVES: To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364. METHODS: The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. RESULTS: S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared with DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low γ-H2AX expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a ∼1 log cfu reduction in mycobacterial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. CONCLUSIONS: Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.

Evaluation of Berberine as an Adjunct to TB Treatment.

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis.

Globally, more than 10 million people developed active tuberculosis (TB), with 1.4 million deaths in 2020. In addition, the emergence of drug-resistant strains in many regions of the world threatens national TB control programs. This requires an understanding of host-pathogen interactions and finding novel treatments including host-directed therapies (HDTs) is of utter importance to tackle the TB epidemic. Mycobacterium tuberculosis (Mtb), the causative agent for TB, mainly infects the lungs causing inflammatory processes leading to immune activation and the development and formation of granulomas. During TB disease progression, the mononuclear inflammatory cell infiltrates which form the central structure of granulomas undergo cellular changes to form epithelioid cells, multinucleated giant cells and foamy macrophages. Granulomas further contain neutrophils, NK cells, dendritic cells and an outer layer composed of T and B lymphocytes and fibroblasts. This complex granulomatous host response can be modulated by Mtb to induce pathological changes damaging host lung tissues ultimately benefiting the persistence and survival of Mtb within host macrophages. The development of cavities is likely to enhance inter-host transmission and caseum could facilitate the dissemination of Mtb to other organs inducing disease progression. This review explores host targets and molecular pathways in the inflammatory granuloma host immune response that may be beneficial as target candidates for HDTs against TB.

IL-4i1 Regulation of Immune Protection During Mycobacterium tuberculosis Infection.

BACKGROUND: Interleukin 4 (IL-4i1)-induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied. METHODS: We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and proinflammatory responses were measured in vitro and in vivo. Histopathological analysis, lung immune cell recruitment, and macrophage activation were assessed at the early and chronic stages of Mtb infection. RESULTS: IL-4i1-deficient (IL-4i1-/-) mice displayed increased protection against acute H37Rv, HN878 and chronic HN878 Mt infections, with reduced lung bacterial burdens and altered APC responses compared with wild-type mice. Moreover, "M1-like" interstitial macrophage numbers, and nitrite and Interferon-γ production were significantly increased in IL-4i1-/- mice compared with wild-type mice during acute Mtb HN878 infection. CONCLUSIONS: Together, these data suggest that IL-4i1 regulates APC-mediated inflammatory responses during acute and chronic Mtb infection. Hence, IL-4i1 targeting has potential as an immunomodulatory target for host-directed therapy.

MIREyA: a computational approach to detect miRNA-directed gene activation.

Emerging studies demonstrate the ability of microRNAs (miRNAs) to activate genes via different mechanisms. Specifically, miRNAs may trigger an enhancer promoting chromatin remodelling in the enhancer region, thus activating the enhancer and its target genes. Here we present MIREyA, a pipeline developed to predict such miRNA-gene-enhancer trios based on an expression dataset which obviates the need to write custom scripts. We applied our pipeline to primary murine macrophages infected by Mycobacterium tuberculosis (HN878 strain) and detected Mir22, Mir221, Mir222, Mir155 and Mir1956, which could up-regulate genes related to immune responses. We believe that MIREyA is a useful tool for detecting putative miRNA-directed gene activation cases. MIREyA is available from:  https://github.com/veania/MIREyA.

IL-4-Responsive B Cells Are Detrimental During Chronic Tuberculosis Infection in Mice.

In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4Rα) expression in murine B cells. To better understand the role of IL4Rα signalling in B cells, we compared wild type mice with B cell-specific IL4Rα deficient mice (mb1creIL-4Rα-/lox mice). Chronic Mtb aerosol infection in mb1creIL-4Rα-/lox mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4Rα-/lox) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1creIL-4Rα-/lox mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4Rα deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1creIL-4Rα-/lox mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1creIL-4Rα-/lox mice also increased the ability of macrophages to produce nitric oxide, IL-1ß, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.

Deletion of N-acetylmuramyl-L-alanine amidases alters the host immune response to Mycobacterium tuberculosis infection.

Peptidoglycan (PG), a heteropolysaccharide component of the mycobacterial cell wall can be shed during tuberculosis infection with immunomodulatory consequences. As such, changes in PG structure are expected to have important implications on disease progression and host responses during infection with Mycobacterium tuberculosis. Mycobacterial amidases have important roles in remodeling of PG during cell division and are implicated in susceptibility to antibiotics. However, their role in modulating host immunity remains unknown. We assessed the bacterial burden and host immune responses to M. tuberculosis mutants defective for either one of two PG N-acetylmuramyl-L-alanine amidases, Ami1 and Ami4, in bone marrow-derived macrophages (BMDM) and C57BL/6 mice. In infected BMDM, the single deletion of both genes resulted in increased proinflammatory cytokine responses. In mice, infection with the Δami1 mutant led to differential induction of pro-inflammatory cytokines and chemokines, decreased cellular recruitment and reduced lung pathology during the acute phase of the infection. While increased proinflammatory cytokines production was observed in BMDM infected with the Δami4 mutant, these effects did not prevail in mice. Infection using the Δami1 and Δami4 Mtb mutants showed that these genes are dispensable for intracellular mycobacterial growth in macrophages and mycobacterial burden in mice. These findings suggest that both Ami1 and Ami4 in M. tuberculosis are not essential for mycobacterial growth within the host. In summary, we show that amidases are important for modulating host immunity during Mtb infection in murine macrophages and mice.

Toward Preparing a Knowledge Base to Explore Potential Drugs and Biomedical Entities Related to COVID-19: Automated Computational Approach.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is taking a huge toll on public health. Along with the non-therapeutic preventive measurements, scientific efforts are currently focused, mainly, on the development of vaccines and pharmacological treatment with existing drugs. Summarizing evidences from scientific literatures on the discovery of treatment plan of COVID-19 under a platform would help the scientific community to explore the opportunities in a systematic fashion. OBJECTIVE: The aim of this study is to explore the potential drugs and biomedical entities related to coronavirus related diseases, including COVID-19, that are mentioned on scientific literature through an automated computational approach. METHODS: We mined the information from publicly available scientific literature and related public resources. Six topic-specific dictionaries, including human genes, human miRNAs, diseases, Protein Databank, drugs, and drug side effects, were integrated to mine all scientific evidence related to COVID-19. We employed an automated literature mining and labeling system through a novel approach to measure the effectiveness of drugs against diseases based on natural language processing, sentiment analysis, and deep learning. We also applied the concept of cosine similarity to confidently infer the associations between diseases and genes. RESULTS: Based on the literature mining, we identified 1805 diseases, 2454 drugs, 1910 genes that are related to coronavirus related diseases including COVID-19. Integrating the extracted information, we developed the first knowledgebase platform dedicated to COVID-19, which highlights potential list of drugs and related biomedical entities. For COVID-19, we highlighted multiple case studies on existing drugs along with a confidence score for their applicability in the treatment plan. Based on our computational method, we found Remdesivir, Statins, Dexamethasone, and Ivermectin could be considered as potential effective drugs to improve clinical status and lower mortality in patients hospitalized with COVID-19. We also found that Hydroxychloroquine could not be considered as an effective drug for COVID-19. The resulting knowledgebase is made available as an open source tool, named COVID-19Base. CONCLUSIONS: Proper investigation of the mined biomedical entities along with the identified interactions among those would help the research community to discover possible ways for the therapeutic treatment of COVID-19.

Protocol for systematic review and meta-analysis: impact of statins as immune-modulatory agents on inflammatory markers in adults with chronic diseases.

INTRODUCTION: Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, are lipid-lowering agents that are central in preventing or reducing the complications of atherosclerotic cardiovascular disease. Because statins have anti-inflammatory properties, there is considerable interest in their therapeutic potential in other chronic inflammatory conditions. We aim to identify the statin with the greatest ability to reduce systemic inflammation, independent of the underlying disease entity. METHODS AND ANALYSIS: We aim to conduct a comprehensive search of published and peer-reviewed randomised controlled clinical trials, with at least one intervention arm of a Food & Drug Administration-licensed or European Medicines Agency-licensed statin and a minimum treatment duration of 12 weeks. Our objective is to investigate the effect of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) on lipid profile, particularly, cholesterol low-density lipoprotein and inflammation markers such as high-sensitive C reactive protein (hsCRP), CRP, tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8, soluble cluster of differentiation 14 (sCD14) or sCD16 in adults, published in the last 20 years (between January 1999 and December 2019). We aim to identify the most potent statin to reduce systemic inflammation and optimal dosing. The following databases will be searched: Medline, Scopus, Web of Science and Cochrane Library of Systematic Reviews. The risk of bias of included studies will be assessed by Cochrane Risk of Bias Tool and Quality Assessment Tool for Quantitative Studies. The quality of studies will be assessed, to show uncertainty, by the Jadad Score. If sufficient evidence is identified, a meta-analysis will be conducted with risk ratios or ORs with 95% CIs in addition to mean differences. ETHICS AND DISSEMINATION: Ethics approval is not required as no primary data will be collected. Results will be presented at conferences and published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020169919.

Functional annotation of human long noncoding RNAs via molecular phenotyping.

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.

The gut microbiome in tuberculosis susceptibility and treatment response: guilty or not guilty?

Although tuberculosis (TB) is a curable disease, it remains the foremost cause of death from a single pathogen. Globally, approximately 1.6 million people died of TB in 2017. Many predisposing factors related to host immunity, genetics and the environment have been linked to TB. However, recent evidence suggests a relationship between dysbiosis in the gut microbiome and TB disease development. The underlying mechanism(s) whereby dysbiosis in the gut microbiota may impact the different stages in TB disease progression, are, however, not fully explained. In the wake of recently emerging literature, the gut microbiome could represent a potential modifiable host factor to improve TB immunity and treatment response. Herein, we summarize early data detailing (1) possible association between gut microbiome dysbiosis and TB (2) the potential for the use of microbiota biosignatures to discriminate active TB disease from healthy individuals (3) the adverse effect of protracted anti-TB antibiotics treatment on gut microbiota balance, and possible link to increased susceptibility to Mycobacterium tuberculosis re-infection or TB recrudescence following successful cure. We also discuss immune pathways whereby the gut microbiome could impact TB disease and serve as target for clinical manipulation.

Differential Targeting of c-Maf, Bach-1, and Elmo-1 by microRNA-143 and microRNA-365 Promotes the Intracellular Growth of Mycobacterium tuberculosis in Alternatively IL-4/IL-13 Activated Macrophages.

Mycobacterium tuberculosis (Mtb) can subvert the host defense by skewing macrophage activation toward a less microbicidal alternative activated state to avoid classical effector killing functions. Investigating the molecular basis of this evasion mechanism could uncover potential candidates for host directed therapy against tuberculosis (TB). A limited number of miRNAs have recently been shown to regulate host-mycobacterial interactions. Here, we performed time course kinetics experiments on bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages (MDMs) alternatively activated with IL-4, IL-13, or a combination of IL-4/IL-13, followed by infection with Mtb clinical Beijing strain HN878. MiR-143 and miR-365 were highly induced in Mtb-infected M(IL-4/IL-13) BMDMs and MDMs. Knockdown of miR-143 and miR-365 using antagomiRs decreased the intracellular growth of Mtb HN878, reduced the production of IL-6 and CCL5 and promoted the apoptotic death of Mtb HN878-infected M(IL-4/IL-13) BMDMs. Computational target prediction identified c-Maf, Bach-1 and Elmo-1 as potential targets for both miR-143 and miR-365. Functional validation using luciferase assay, RNA-pulldown assay and Western blotting revealed that c-Maf and Bach-1 are directly targeted by miR-143 while c-Maf, Bach-1, and Elmo-1 are direct targets of miR-365. Knockdown of c-Maf using GapmeRs promoted intracellular Mtb growth when compared to control treated M(IL-4/IL-13) macrophages. Meanwhile, the blocking of Bach-1 had no effect and blocking Elmo-1 resulted in decreased Mtb growth. Combination treatment of M(IL-4/IL-13) macrophages with miR-143 mimics or miR-365 mimics and c-Maf, Bach-1, or Elmo-1 gene-specific GapmeRs restored Mtb growth in miR-143 mimic-treated groups and enhanced Mtb growth in miR-365 mimics-treated groups, thus suggesting the Mtb growth-promoting activities of miR-143 and miR-365 are mediated at least partially through interaction with c-Maf, Bach-1, and Elmo-1. We further show that knockdown of miR-143 and miR-365 in M(IL-4/IL-13) BMDMs decreased the expression of HO-1 and IL-10 which are known targets of Bach-1 and c-Maf, respectively, with Mtb growth-promoting activities in macrophages. Altogether, our work reports a host detrimental role of miR-143 and miR-365 during Mtb infection and highlights for the first time the role and miRNA-mediated regulation of c-Maf, Bach-1, and Elmo-1 in Mtb-infected M(IL-4/IL-13) macrophages.

Transcriptionally induced enhancers in the macrophage immune response to Mycobacterium tuberculosis infection.

BACKGROUND: Tuberculosis is a life-threatening infectious disease caused by Mycobacterium tuberculosis (M.tb). M.tb subverts host immune responses to build a favourable niche and survive inside of host macrophages. Macrophages can control or eliminate the infection, if acquire appropriate functional phenotypes. Transcriptional regulation is a key process that governs the activation and maintenance of these phenotypes. Among the factors orchestrating transcriptional regulation during M.tb infection, transcriptional enhancers still remain unexplored. RESULTS: We analysed transcribed enhancers in M.tb-infected mouse bone marrow-derived macrophages. We established a link between known M.tb-responsive transcription factors and transcriptional activation of enhancers and their target genes. Our data suggest that enhancers might drive macrophage response via transcriptional activation of key immune genes, such as Tnf, Tnfrsf1b, Irg1, Hilpda, Ccl3, and Ccl4. We report enhancers acquiring transcription de novo upon infection. Finally, we link highly transcriptionally induced enhancers to activation of genes with previously unappreciated roles in M.tb infection, such as Fbxl3, Tapt1, Edn1, and Hivep1. CONCLUSIONS: Our findings suggest the importance of macrophage host transcriptional enhancers during M.tb infection. Our study extends current knowledge of the regulation of macrophage responses to M.tb infection and provides a basis for future functional studies on enhancer-gene interactions in this process.

Intervening along the spectrum of tuberculosis: meeting report from the World TB Day nanosymposium in the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town.

Tuberculosis (TB), caused by the highly infectious  Mycobacterium tuberculosis, remains a leading cause of death worldwide, with an estimated 1.6 million associated deaths reported in 2017. In South Africa, an estimated 322,000 (range 230,000-428,000) people were infected with TB in 2017, and a quarter of them lost their lives due to the disease. Bacille Calmette-Guérin (BCG) remains the only effective vaccine against disseminated TB, but its inability to confer complete protection against pulmonary TB in adolescents and adults calls for an urgent need to develop new and better vaccines. There is also a need to identify markers of disease protection and develop novel drugs. It is within this backdrop that we convened a nanosymposium at the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town to commemorate World TB Day and showcase recent findings generated by early career scientists in the institute. The speakers spoke on four broad topics: identification of novel drug targets, development of host-directed drug therapies, transmission of TB and immunology of TB/HIV co-infections.

Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases.

Basic leucine zipper transcription factor 2 (Batf2) activation is detrimental in Type 1-controlled infectious diseases, demonstrated during infection with Mycobacterium tuberculosis (Mtb) and Listeria monocytogenes Lm. In Batf2-deficient mice (Batf2-/-), infected with Mtb or Lm, mice survived and displayed reduced tissue pathology compared to infected control mice. Indeed, pulmonary inflammatory macrophage recruitment, pro-inflammatory cytokines and immune effectors were also decreased during tuberculosis. This explains that batf2 mRNA predictive early biomarker found in active TB patients is increased in peripheral blood. Similarly, Lm infection in human macrophages and mouse spleen and liver also increased Batf2 expression. In striking contrast, Type 2-controlled schistosomiasis exacerbates during infected Batf2-/- mice with increased intestinal fibro-granulomatous inflammation, pro-fibrotic immune cells, and elevated cytokine production leading to wasting disease and early death. Together, these data strongly indicate that Batf2 differentially regulates Type 1 and Type 2 immunity in infectious diseases.