MicroRNA-155, a double-blade sword regulator of innate tuberculosis immunity.

Tuberculosis (TB) is a chronic, life-threatening disease caused by unusual facultative intracellular bacteria, Mycobacterium tuberculosis. This bacterium has unique resistance to many antimicrobial agents and has become a major global health concern due to emerging multidrug-resistant strains. Additionally, it has developed multiple schemes to exploit host immune signaling and establish long-term survival within host tissues. Thus, understanding the pathways that govern the crosstalk between the bacterium and the immune system could provide a new avenue for therapeutic interventions. MicroRNAs (miRs) are short, noncoding, and regulator RNA molecules that control the expression of cellular genes by targeting their mRNAs post-transcriptionally. MiR-155 is one of the most crucial miR in shaping the host immune defenses against M. tuberculosis. MiR-155 is remarkably downregulated in patients with clear clinical TB symptoms in comparison with latently infected patients and/or healthy individuals, thereby implicating its role in controlling M. tuberculosis infection. However, functional probing of miR-155 suggests dual effects in regulating the host's innate defenses in response to mycobacterial infection. This review provides comprehensive knowledge and future perspectives regarding complex signaling pathways that mediated miR-155 expression during M. tuberculosis infections. Moreover, miR-155-targeting signaling orchestrates inflammatory mediators' production, apoptosis, and autophagy.

Isatin derivatives as broad-spectrum antiviral agents: the current landscape.

In recent decades, several viruses have resulted in large outbreaks with serious health, economic and social consequences. The current unprecedented outbreak of the new coronavirus, SARS-COV-2, necessitates intensive efforts for delivering effective therapies to eradicate such a deadly virus. Isatin is an opulent heterocycle that has been proven to provide tremendous opportunities in the area of drug discovery. Over the last fifty years, suitably functionalized isatin has shown remarkable and broad-spectrum antiviral properties. The review herein is an attempt to compile all of the reported information about the antiviral activity of isatin derivatives with an emphasis on their structure-activity relationships (SARs) along with mechanistic and molecular modeling studies. In this regard, we are confident that the review will afford the scientific community a valuable platform to generate more potent and cost-effective antiviral therapies based on isatin templates.

l-Serine potentiates fluoroquinolone activity against Escherichia coli by enhancing endogenous reactive oxygen species production.

BACKGROUND: The increase in multiple antimicrobial-resistant bacteria seriously threatens global public health. Novel effective strategies are urgently needed. l-Serine was reported as the most effective amino acid inhibitor against bacterial growth and can sensitize Escherichia coli cells to gentamicin. It is currently unknown whether l-serine affects other type of antibiotics such as ß-lactams and fluoroquinolones. METHODS: Using E. coli, we studied the combination of l-serine with diverse antibiotics against laboratory and clinical E. coli cultures and persisters. The intracellular NAD(+)/NADH level and ROS were determined using kits. Total cellular iron was determined by using a colorimetric ferrozine-based assay. RESULTS: Exogenous l-serine sensitized E. coli ATCC 25922 and clinically isolated fluoroquinolone-resistant E. coli to fluoroquinolones. This potentiation is independent of growth phase. Addition of serine increases the production of NADH. The underlying mechanism of this strategy is that the combination of serine with ofloxacin or moxifloxacin increases the NAD(+)/NADH ratio, disrupts the Fe-S clusters and increases the production of endogenous reactive oxygen species. Furthermore, we used a serine and ofloxacin or moxifloxacin combination in vitro to combat bacterial persister cells, compared with antibiotic treatment alone; combinational treatments of persister cells with antibiotics and l-serine resulted in a significantly greater decrease in cell viability. CONCLUSIONS: To our knowledge, this is the first report that l-serine can potentiate the action of ofloxacin or moxifloxacin against Gram-negative bacteria and could constitute a new strategy for the eradication of bacterial infections.

Phylogenomics of Mycobacterium Nitrate Reductase Operon.

NarGHJI operon encodes a nitrate reductase that can reduce nitrate to nitrite. This process enhances bacterial survival by nitrate respiration under anaerobic conditions. NarGHJI operon exists in many bacteria, especially saprophytic bacteria living in soil which play a key role in the nitrogen cycle. Most actinomycetes, including Mycobacterium tuberculosis, possess NarGHJI operons. M. tuberculosis is a facultative intracellular pathogen that expands in macrophages and has the ability to persist in a non-replicative form in granuloma lifelong. Nitrogen and nitrogen compounds play crucial roles in the struggle between M. tuberculosis and host. M. tuberculosis can use nitrate as a final electron acceptor under anaerobic conditions to enhance its survival. In this article, we reviewed the mechanisms regulating nitrate reductase expression and affecting its activity. Potential genes involved in regulating the nitrate reductase expression in M. tuberculosis were identified. The conserved NarG might be an alternative mycobacterium taxonomic marker.

[The roles of epigenetics and protein post-translational modifications in bacterial antibiotic resistance].

The increasing antibiotic resistance is now threatening to take us back to a pre-antibiotic era. Bacteria have evolved diverse resistance mechanisms, on which in-depth research could help the development of new strategies to control antibiotic-resistant infections. Epigenetic alterations and protein post-translational modifications (PTMs) play important roles in multiple cellular processes such as metabolism, signal transduction, protein degradation, DNA replication regulation and stress response. Recent studies demonstrated that epigenetics and PTMs also play vital roles in bacterial antibiotic resistance. In this review, we summarize the regulatory roles of epigenetic factors including DNA methylation and regulatory RNAs as well as PTMs such as phosphorylation and succinylation in bacterial antibiotic resistance, which may provide innovative perspectives on selecting antibacterial targets and developing antibiotics.

The interleukin-10 family: Major regulators of the immune response against Plasmodium falciparum infections.

Malaria caused by the Plasmodium falciparum strain is more severe because of this protozoan's ability to disrupt the physiology of host cells during the blood stages of development by initiating the production of the interleukin-10 (IL-10) family of cytokines. P. falciparum feeds on hemoglobin and causes host cells to adhere to the walls of blood vessels by remodeling their composition. IL-10 is produced by CD4+ T cells that inhibits antigen-presenting cells' activity to prevent inflammation. This cytokine and its family members are crucial in promoting malarial infection by inhibiting the host's protective immune response, thus initiating Plasmodium parasitemia. IL-10 is also responsible for preventing severe pathology during Plasmodium infection and initiates several signaling pathways to alter the physiology of host cells during malarial infection. This review summarizes the critical aspects of P. falciparum infection, including its role in signaling pathways for cytokine exudation, its effect on microRNA, the human immune response in malaria, and the role played by the liver hormone hepcidin. Moreover, future aspects of vaccine development and therapeutic strategies to combat P. falciparum infections are also discussed in detail.

Rubella Virus Infections: A Bibliometric Analysis of the Scientific Literature from 2000 to 2021.

Rubella virus (RuV) generally causes a mild infection, but it can sometimes lead to systemic abnormalities. This study aimed to conduct a bibliometric analysis of over two decades of RuV research. Medical studies published from 2000 to 2021 were analyzed to gain insights into and identify research trends and outputs in RuV. R and VOSviewer were used to conduct a bibliometric investigation to determine the globally indexed RuV research output. The Dimensions database was searched with RuV selected as the subject, and 2500 published documents from the preceding two decades were reviewed. The number of publications on RuV has increased since 2003, reaching its peak in 2020. There were 12,072 authors and 16,769 author appearances; 88 publications were single-authored and 11,984 were multi-authored. The United States was the most influential contributor to RuV research, in terms of publications and author numbers. The number of RuV-related articles has continued to increase over the past few years due to the significant rubella burden in low-income nations. This study will aid in formulating plans and policies to control and prevent RuV infections.

Xanthone: A Promising Antimycobacterial Scaffold.

BACKGROUND: Tuberculosis (TB) is one of the infectious diseases associated with high rate of morbidity and mortality and still remains one of the top-ten leading causes of human death in the world. The development of new anti-TB drugs is mandatory due to the existence of latent infection as well as the expansion of the resistant Mycobacterium tuberculosis (MBT) strains. Xanthones encompass a wide range of structurally diverse bioactive compounds, obtained either naturally or through chemical synthesis. There is a growing body of literature that recognizes the antitubercular activity of xanthone derivatives. OBJECTIVE: The objective of this review is to highlight the main natural sources along with the critical design elements, structure-activity relationships (SARs), modes of action and pharmacokinetic profiles of xanthone-based anti-TB compounds. METHODS: In the present review, the anti-TB activity of xanthones reported in the literature from 1972 to date is presented and discussed. RESULTS: Exploration of xanthone scaffold led to the identification of several members of this class having superior activity against both sensitive and resistant MBT strains with distinctive mycobacterial membrane disrupting properties. However, studies regarding their modes of action, pharmacokinetic properties and safety are limited. CONCLUSION: Comprehendible data and information are afforded by this review and it would certainly provide scientists with new thoughts and means which will be conducive to design and develop new drugs with excellent anti-TB activity through exploration of xanthone scaffold.

Characterization of a Novel Bacteriophage Henu2 and Evaluation of the Synergistic Antibacterial Activity of Phage-Antibiotics.

Staphylococcus aureus phage Henu2 was isolated from a sewage sample collected in Kaifeng, China, in 2017. In this study, Henu2, a linear double-stranded DNA virus, was sequenced and found to be 43513bp long with 35% G + C content and 63 putative open reading frames (ORFs). Phage Henu2 belongs to the family Siphoviridae and possesses an isometric head (63 nm in diameter). The latent time and burst size of Henu2 were approximately 20 min and 7.8 plaque forming unit (PFU)/infected cells. The Henu2 maintained infectivity over a wide range of temperature (10-60 °C) and pH values (4-12). Phylogenetic and comparative genomic analyses indicate that Staphylococcus aureus phage Henu2 should be a new member of the family of Siphoviridae class-II. In this paper, Phage Henu2 alone exhibited weak inhibitory activity on the growth of S. aureus. However, the combination of phage Henu2 and some antibiotics or oxides could effectively inhibit the growth of S. aureus, with a decrease of more than three logs within 24 h in vitro. These results provide useful information that phage Henu2 can be combined with antibiotics to increase the production of phage Henu2 and thus enhance the efficacy of bacterial killing.

Molecular analysis of blaSHV, blaTEM, and blaCTX-M in extended-spectrum ß-lactamase producing Enterobacteriaceae recovered from fecal specimens of animals.

Colonization of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae as animal gut microbiota is a substantial global threat. This study aimed to determine the molecular characterization of blaSHV, blaTEM, and blaCTX-M variants in animals, as well as to evaluate the antimicrobial resistance conferred by these genes. We prospectively analyzed 1273 fecal specimens of farm and domestic animals for the isolation of enterobacteria that had the ESBL phenotype by using biochemical methods. The extracted genes were amplified by polymerase chain reaction and sequenced for the characterization of blaSHV, blaTEM, and blaCTX-M variants. The drug-resistance spectrum and hierarchical clusters were analyzed against 19 antibacterial agents. Out of 245 (19.2%) ESBL enterobacteria, 180 (75.5%) Escherichia coli and 34 (13.9%) Klebsiella pneumoniae were prevalent species. A total of 73.9% blaCTX-M, 26.1% blaTEM, and 14.2% blaSHV were found among the enterobacteria; however, their association with farm or domestic animals was not statistically significant. The distribution of bla gene variants showed the highest number of blaCTX-M-1 (133; 54.3%), followed by blaCTX-M-15 (28; 11.4%), blaTEM-52 (40; 16.3%), and blaSHV-12 (22; 9%). In addition, 84.5% of the enterobacteria had the integrons intI1. We observed ±100% enterobacteria resistant to cephalosporin, 7 (2.9%) to colistin (minimum inhibitory concentration breakpoint ≥4 µg/mL), 9 (3.7%) to piperacillin-tazobactam, 11 (4.5%) to imipenem, 14 (5.7%) to meropenem, and 18 (7.3%) to cefoperazone-sulbactam, without statistically significant association. Animal gut microbiota contain a considerable number of blaCTX-M, blaTEM, blaSHV, and integrons, which are a potential source of acquired extensive drug resistance in human strains and leaves fewer therapeutic substitutes.

Molecular Epidemiology of Extensively-Drug Resistant Acinetobacter baumannii Sequence Type 2 Co-Harboring bla NDM and bla OXA From Clinical Origin.

BACKGROUND: The therapeutic management of carbapenem-resistant Acinetobacter baumannii (CR-AB) represents a serious challenge to the public health sector because these pathogens are resistant to a wide range of antibiotics, resulting in limited treatment options. The present study was planned to investigate the clonal spread of CR-AB in a clinical setting. METHODOLOGY: A total of 174 A. baumannii clinical isolates were collected from a tertiary care hospitals in Lahore, Pakistan. The isolates were confirmed by VITEK 2 compact system and molecular identification of recA and bla OXA-51. Antimicrobial profile and the screening of carbapenem-resistant genes were carried out using VITEK 2 system and PCR, respectively. The molecular typing of the isolates was performed according to the Pasteur scheme. RESULTS: Of the 174 A. baumannii isolates collected, the majority were isolated from sputum samples (46.5%) and in the intensive care unit (ICU, 75%). Among these, 113/174 (64.9%) were identified as CR-AB, and 49.5% and 24.7% harbored bla OXA-23 and bla NDM-1, respectively. A total of 11 (9.7%) isolates co-harbored bla OXA-51, bla NDM-1, and bla OXA-23. Interestingly, 46.9% of the CR-AB belonged to sequence type 2 (ST2; CC1), whereas 15.9% belonged to ST1 (CC1). All of the CR-AB isolates showed extensive resistance to clinically relevant antibiotics, except colistin. CONCLUSION: The study concluded CR-AB ST2 clone harboring bla OXA-23 and bla NDM-1 are widely distributed in Pakistan's clinical settings, which could result in increased mortality. Strict compliance with the National Action Plan on Antimicrobial Resistance is necessary to reduce the impacts of these strains.

Association of IL28 B and IL10 Polymorphism with HCV Infection and Direct Antiviral Treatment.

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in IL28B and IL10 regions are important in predicting the antiviral response in hepatitis C virus (HCV) patients. In this study, the association of IL28B and IL10 genetic polymorphisms and other clinical factors was assessed as a predictive marker for the sustained virological response (SVR) of HCV patients taking direct-acting antivirals (DAAs). METHODS: We processed 384 serum specimens of HCV serology positive cases for qualitative and quantitative polymerase chain reaction (PCR). Patients were followed up for 12 weeks after the start of antiviral therapy, and the viral load was monitored at each time point. IL28B and IL10 polymorphisms (rs8103142 and rs12980275, rs1800872 and rs3021094, respectively) were detected by real-time PCR, followed by melt curve analysis for genotyping. RESULTS: This study's findings indicate an independent association of SVR with high basal viral load (P=0.005) and an HCV genotype other than 3 (P=0.001). Patients with viral load log10 >6.5 IU/mL required more days to reach an undetectable viral RNA load. The results of the genetic analysis showed a significant association of rs8103142 genotype CC (P<0.01) and rs12980275 genotype AA (P=0.01) with non-SVR. Both SNPs showed an independent association in the multivariate analysis. CONCLUSION: High basal viral load, HCV genotype, and host polymorphisms of rs8103142 and rs12980275 have an independent association in predicting the therapeutic response of HCV patients. The preliminary identification of polymorphisms prior to treatment will help in predicting the outcome of therapy.

A combination therapy of Phages and Antibiotics: Two is better than one.

Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.

Insight into the emerging role of SARS-CoV-2 nonstructural and accessory proteins in modulation of multiple mechanisms of host innate defense.

Coronavirus disease-19 (COVID-19) is an extremely infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has become a major global health concern. The induction of a coordinated immune response is crucial to the elimination of any pathogenic infection. However, SARS-CoV-2 can modulate the host immune system to favor viral adaptation and persistence within the host. The virus can counteract type I interferon (IFN-I) production, attenuating IFN-I signaling pathway activation and disrupting antigen presentation. Simultaneously, SARS-CoV-2 infection can enhance apoptosis and the production of inflammatory mediators, which ultimately results in increased disease severity. SARS-CoV-2 produces an array of effector molecules, including nonstructural proteins (NSPs) and open-reading frames (ORFs) accessory proteins. We describe the complex molecular interplay of SARS-CoV-2 NSPs and accessory proteins with the host's signaling mediating immune evasion in the current review. In addition, the crucial role played by immunomodulation therapy to address immune evasion is discussed. Thus, the current review can provide new directions for the development of vaccines and specific therapies.

Heavy Metal Tolerance Trend in Extended-Spectrum ß-Lactamase Encoding Strains Recovered from Food Samples.

This study evaluates bacteriological profiles in ready-to-eat (RTE) foods and assesses antibiotic resistance, extended-spectrum ß-lactamase (ESBL) production by gram-negative bacteria, and heavy metal tolerance. In total, 436 retail food samples were collected and cultured. The isolates were screened for ESBL production and molecular detection of ESBL-encoding genes. Furthermore, all isolates were evaluated for heavy metal tolerance. From 352 culture-positive samples, 406 g-negative bacteria were identified. Raw food samples were more often contaminated than refined food (84.71% vs. 76.32%). The predominant isolates were Klebsiella pneumoniae (n = 76), Enterobacter cloacae (n = 58), and Escherichia coli (n = 56). Overall, the percentage of ESBL producers was higher in raw food samples, although higher occurrences of ESBL-producing E. coli (p = 0.01) and Pseudomonas aeruginosa (p = 0.02) were observed in processed food samples. However, the prevalence of ESBL-producing Citrobacter freundii in raw food samples was high (p = 0.03). Among the isolates, 55% were blaCTX-M, 26% were blaSHV, and 19% were blaTEM. Notably, heavy metal resistance was highly prevalent in ESBL producers. These findings demonstrate that retail food samples are exposed to contaminants including antibiotics and heavy metals, endangering consumers.

Molecular Epidemiology of Extensively Drug-Resistant mcr Encoded Colistin-Resistant Bacterial Strains Co-Expressing Multifarious ß-Lactamases.

Plasmid-mediated colistin resistance (Col-R) conferred by mcr genes endangers the last therapeutic option for multifarious ß-lactamase-producing bacteria. The current study aimed to explore the mcr gene molecular epidemiology in extensively drug-resistant (XDR) bacteria. Col-R gram-negative bacterial strains were screened using a minimum inhibitory concentration (MIC) breakpoint ≥4 µg/mL. Resistant isolates were examined for mcr variants, extended-spectrum ß-lactamase, AmpC, and carbapenemase genes using polymerase chain reaction (PCR). The MIC breakpoints for mcr-positive strains were determined using broth microdilution and E-test strips. Overall, 19/718 (2.6%) gram-negative rods (GNRs) harboring mcr were identified, particularly in pus (p = 0.01) and tracheal secretions (p = 0.03). Molecular epidemiology data confirmed 18/19 (95%) mcr-1 and 1/19 (5%) mcr-2 genes. Integron detection revealed 15/17 (88%) Int-1 and 2/17 (12%) Int-2. Common co-expressing drug-resistant ß-lactamase genes included 8/16 (50%) blaCTM-1, 3/16 (19%) blaCTM-15, 3/3 (100%) blaCMY-2, 2/8 (25%) blaNDM-1, and 2/8 (25%) blaNDM-5. The MIC50 and MIC90 values (µg/mL) were as follows: Escherichia coli, 12 and 24; Klebsiella pneumoniae, 12 and 32; Acinetobacter baumannii, 8 and 12; and Pseudomonas aeruginosa, 32 and 64, respectively. Treatment of XDR strains has become challenging owing to the co-expression of mcr-1, mcr-2, multifarious ß-lactamase genes, and integrons.

Mycobacterium tuberculosis Rv0341 Promotes Mycobacterium Survival in In Vitro Hostile Environments and within Macrophages and Induces Cytokines Expression.

Mycobacterium tuberculosis represents an ancient deadly human pathogen that can survive and multiply within macrophages. The effectors are key players for the successful pathogenesis of this bacterium. M. tuberculosis open reading frame (ORF) Rv0341, a pathogenic mycobacteria-specific gene, was found to be upregulated in macrophages isolated from human tuberculosis granuloma and inside the macrophages during in vitro infection by M. tuberculosis. To understand the exact role of this gene, we expressed the Rv0341 gene in M. smegmatis, which is a non-pathogenic Mycobacterium. We found that Rv0341 expression can alter colony morphology, reduce the sliding capability, and decrease the cell wall permeability of M. smegmatis. Furthermore, Rv0341 remarkably enhanced M. smegmatis survival within macrophages and under multiple in vitro stress conditions when compared with the control strain. Ms_Rv0341 significantly induced expression of TNF-α, IL-1ß, and IL-10 compared with M. smegmatis harboring an empty vector. In summary, these data suggest that Rv0341 is one of the M. tuberculosis virulence determinants that can promote bacilli survival in harsh conditions and inside macrophages.

Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV.

After the outbreak of the severe acute respiratory syndrome (SARS) in the world in 2003, human coronaviruses (HCoVs) have been reported as pathogens that cause severe symptoms in respiratory tract infections. Recently, a new emerged HCoV isolated from the respiratory epithelium of unexplained pneumonia patients in the Wuhan seafood market caused a major disease outbreak and has been named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes acute lung symptoms, leading to a condition that has been named as "coronavirus disease 2019" (COVID-19). The emergence of SARS-CoV-2 and of SARS-CoV caused widespread fear and concern and has threatened global health security. There are some similarities and differences in the epidemiology and clinical features between these two viruses and diseases that are caused by these viruses. The goal of this work is to systematically review and compare between SARS-CoV and SARS-CoV-2 in the context of their virus incubation, originations, diagnosis and treatment methods, genomic and proteomic sequences, and pathogenic mechanisms.

Human cytomegalovirus-encoded MicroRNAs: A master regulator of latent infection.

Human cytomegalovirus (HCMV) can modulate the host cell microenvironment to cause latent infection and is therefore considered a major health concern in immunocompromised patients. HCMV-encoded microRNAs (miRs) have emerged as a key player in regulating the expression of the host cell and viral genes to induce latent infection. HCMV-encoded miRs can inhibit antiviral immune responses, such as proinflammatory mediators production, antigenic presentation, and apoptosis. In addition, HCMV miRs can reduce viral DNA replication. In this review, we describe the mechanisms underlying HCMV-encoded miR-mediated regulation of latent infection that may be exploited for future designing novel miRs-directed therapies.

Effective Immune Functions of Micronutrients against SARS-CoV-2.

The third coronavirus outbreak in the last two decades has caused significant damage to the world's economy and community health. The highly contagious COVID-19 infection has affected millions of people to date and has led to hundreds of thousands of deaths worldwide. Aside from the highly infectious nature of SARS-CoV-2, the lack of a treatment or vaccine has been the main reason for its spread. Thus, it has become necessary to find alternative methods for controlling SARS-CoV-2. For the present review, we conducted an online search for different available nutrition-based therapies for previously known coronavirus infections and RNA-based virus infections as well as general antiviral therapies. These treatments have promise for combating COVID-19, as various nutrients and minerals play direct and indirect roles in the control and prevention of this newly emerged viral infection. The patients' nutritional status with COVID-19 must be analyzed before administering any treatment, and nutritional supplements should be given to the affected individuals along with routine treatment. We suggest a potential interventional role of nutrients to strengthen the immune system against the emerging infection caused by COVID-19.