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.

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.

Epitope-Based Peptide Vaccine Against Fructose-Bisphosphate Aldolase of Madurella mycetomatis Using Immunoinformatics Approaches.

BACKGROUND: Mycetoma is a distinct body tissue destructive and neglected tropical disease. It is endemic in many tropical and subtropical countries. Mycetoma is caused by bacterial infections (actinomycetoma) such as Streptomyces somaliensis and Nocardiae or true fungi (eumycetoma) such as Madurella mycetomatis. To date, treatments fail to cure the infection and the available marketed drugs are expensive and toxic upon prolonged usage. Moreover, no vaccine was prepared yet against mycetoma. AIM: The aim of this study is to predict effective epitope-based vaccine against fructose-bisphosphate aldolase enzymes of M. mycetomatis using immunoinformatics approaches. METHODS AND MATERIALS: Fructose-bisphosphate aldolase of M. mycetomatis sequence was retrieved from NCBI. Different prediction tools were used to analyze the nominee's epitopes in Immune Epitope Database for B-cell, T-cell MHC class II and class I. Then the proposed peptides were docked using Autodock 4.0 software program. RESULTS AND CONCLUSIONS: The proposed and promising peptides KYLQ show a potent binding affinity to B-cell, FEYARKHAF with a very strong binding affinity to MHC I alleles and FFKEHGVPL that shows a very strong binding affinity to MHC II and MHC I alleles. This indicates a strong potential to formulate a new vaccine, especially with the peptide FFKEHGVPL which is likely to be the first proposed epitope-based vaccine against fructose-bisphosphate aldolase of M. mycetomatis. This study recommends an in vivo assessment for the most promising peptides especially FFKEHGVPL.

Phenotypic and Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates from Sudanese Patients.

Background. Currently, mutations in rpoB, KatG, and rrs genes and inhA promoter were considered to be involved in conferring resistance to rifampicin, isoniazid, and streptomycin in Mycobacterium tuberculosis (MTB). Objective. The aims of this study were to detect the prevalence of first-line tuberculosis (TB) drug resistance among a group of previously treated and newly detected TB patients, to determine the association between prevalence of multidrug resistance (MDR) and demographic information (age and sex), to explain genes correlated with MDR Mycobacterium tuberculosis, and to characterize MTB via 16S ribosomal RNA (16S rRNA) analysis. Methods. A hundred MTB isolates from Sudanese pulmonary TB patients were included in the study. The proportional method of drug susceptibility test was carried out on Löwenstein-Jensen media. Multiplex PCR of rpoB and KatG genes and inhA promoter was conducted; then rrs genes were amplified by conventional PCR and were sequenced. The sequences of the PCR product were compared with known rrs gene sequences in the GenBank database by multiple sequence alignment tools. Result. The prevalence of MDR was 14.7% among old cases and 5.3% among newly diagnosed cases. Conclusion. Mutations in rrs could be considered as a diagnostic marker.