-
International Immunopharmacology Jun 2024Selenium nanoparticles (SeNPs) enhance the immune response as adjuvants, increasing the efficacy of viral vaccines, including those for COVID-19. However, the efficiency...
Selenium nanoparticles (SeNPs) enhance the immune response as adjuvants, increasing the efficacy of viral vaccines, including those for COVID-19. However, the efficiency of mucosal SeNPs in boosting vaccine-induced protective immunity against tuberculosis remains unclear. Therefore, this study aims to investigate whether the combination of SeNPs with the AH antigen (Ag85A-HspX) can boost respiratory mucosal immunity and thereby enhance the protective effects against tuberculosis. We synthesized SeNPs and assessed their impact on the immune response and protection against Mycobacterium bovis (M. bovis) as a mucosal adjuvant in mice, administered intranasally at a dose of 20 µg. SeNPs outperformed polyinosinic-polycytidylic acid (Poly IC) in stimulating the maturation of bone marrow-derived dendritic cells (BMDCs), which enhanced antigen presentation. SeNPs significantly activated and proliferated tissue-resident memory T cells (T) and effector CD4 T cells in the lungs. The vaccines elicited specific antibody responses in the respiratory tract and stimulated systemic Th1 and Th17 immune responses. Immunization with AH and SeNPs led to higher levels of mucosal secretory IgA in bronchoalveolar lavage fluid (BALF) and secretory IL-17 in splenocytes. Moreover, SeNPs immunized mice showed reduced M. bovis infection loads and inflammatory lesions in the lungs post-challenge. Notably, immunization with AH and SeNPs significantly reduced bacterial load in the lungs, achieving the lowest levels compared to all other tested groups. This study calls for pre-clinical investigation of AHB-SeNPs as an anti-bovine tuberculosis vaccine and for exploring its human vaccine potential, which is anticipated to aid in the development of innovative vaccines or adjuvants.
PubMed: 38878484
DOI: 10.1016/j.intimp.2024.112384 -
BioRxiv : the Preprint Server For... May 2024Previous studies have demonstrated the efficacy and feasibility of an anti-viral vaccine strategy that takes advantage of pre-existing CD4 helper T (Th) cells induced...
Previous studies have demonstrated the efficacy and feasibility of an anti-viral vaccine strategy that takes advantage of pre-existing CD4 helper T (Th) cells induced by bacille Calmette-Guérin (BCG) vaccination. This strategy uses immunization with recombinant fusion proteins comprised of a cell surface expressed viral antigen, such as a viral envelope glycoprotein, engineered to contain well-defined BCG Th cell epitopes, thus rapidly recruiting Th cells induced by prior BCG vaccination to provide intrastructural help to virus-specific B cells. In the current study, we show that Th cells induced by BCG were localized predominantly outside of germinal centers and promoted antibody class switching to isotypes characterized by strong Fc receptor interactions and effector functions. Furthermore, BCG vaccination also upregulated FcγR expression to potentially maximize antibody-dependent effector activities. Using a mouse model of Ebola virus (EBOV) infection, this vaccine strategy provided sustained antibody levels with strong IgG2c bias and protection against lethal challenge. This general approach can be easily adapted to other viruses, and may be a rapid and effective method of immunization against emerging pandemics in populations that routinely receive BCG vaccination.
PubMed: 38853867
DOI: 10.1101/2024.05.28.595735 -
Bioorganic Chemistry Jun 2024The Asp-tRNA/Glu-tRNA amidotransferase (GatCAB) has been proposed as a novel antibacterial drug target due to its indispensability in prominent human pathogens. While...
The Asp-tRNA/Glu-tRNA amidotransferase (GatCAB) has been proposed as a novel antibacterial drug target due to its indispensability in prominent human pathogens. While several inhibitors with in vitro activity have been identified, none have been demonstrated to have potent activity against live bacteria. In this work, seven non-hydrolyzable transition state mimics of GatCAB were synthesized and tested as the transamidase inhibitors against GatCAB from the human pathogen Helicobacter pylori. Notably, the methyl sulfone analog of glutamyl-adenosine significantly reduced GatCAB's transamination rate. Additionally, four lipid-conjugates of these mimics displayed antibacterial activity against Bacillus subtilis, likely due to enhanced cell permeability. Inhibitory activity against GatCAB in live bacteria was confirmed using a sensitive gain-of-function dual luciferase reporter in Mycobacterium bovis-BCG. Only the lipid-conjugated methyl sulfone analog exhibited a significant increase in mistranslation rate, highlighting its cell permeability and inhibitory potential. This study provides insights for developing urgently needed novel antibacterial agents amidst emerging antimicrobial drug resistance.
PubMed: 38852310
DOI: 10.1016/j.bioorg.2024.107530 -
Scientific Reports Jun 2024The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against...
The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against cancer. Here, we describe the biological basis, detailed phenotype and function of long-lived anti-tumour human NK cells (CD56CD16), obtained without cell sorting or feeder cells, after priming of peripheral blood cells with Bacillus Calmette-Guérin (BCG). Further, we demonstrate that survival doses of a cytokine combination, excluding IL18, administered just weekly to BCG-primed NK cells avoids innate lymphocyte exhaustion and leads to specific long-term proliferation of innate cells that exert potent cytotoxic function against a broad range of solid tumours, mainly through NKG2D. Strikingly, a NKG2CCD57FcεRIγ NK cell population expands after BCG and cytokine stimulation, independently of HCMV serology. This strategy was exploited to rescue anti-tumour NK cells even from the suppressor environment of cancer patients' bone marrow, demonstrating that BCG confers durable anti-tumour features to NK cells.
Topics: Killer Cells, Natural; Humans; Cell Proliferation; Neoplasms; BCG Vaccine; Mycobacterium bovis; Lymphocyte Activation; NK Cell Lectin-Like Receptor Subfamily K; Interleukins; CD56 Antigen; NK Cell Lectin-Like Receptor Subfamily C
PubMed: 38849432
DOI: 10.1038/s41598-024-62968-2 -
International Journal of Pharmaceutics Jun 2024Delivering novel antimycobacterial agents through the pulmonary route using nanoparticle-based systems shows promise for treating diseases like tuberculosis. However,...
Delivering novel antimycobacterial agents through the pulmonary route using nanoparticle-based systems shows promise for treating diseases like tuberculosis. However, creating dry powder inhaler (DPI) with suitable aerodynamic characteristics while preserving nanostructure integrity and maintaining bioactivity until the active ingredient travels deeply into the lungs is a difficult challenge. We developed DPI formulations containing levofloxacin-loaded solid lipid nanoparticles (SLNs) via spray-drying technique with tailored aerosolization characteristics for effective inhalation therapy. A range of biophysical techniques, including transmission electron microscopy, confocal microscopy, and scanning electron microscopy were used to measure the morphologies and sizes of the spray-dried microparticles that explored both the geometric and aerodynamic properties. Spray drying substantially reduced the particle sizes of the SLNs while preserving their nanostructural integrity and enhancing aerosol dispersion with efficient mucus penetration. Despite a slower uptake rate compared to plain SLNs, the polyethylene glycol modified formulations exhibited enhanced cellular uptake in both A549 and NR8383 cell lines. The percent viability of Mycobacterium bovis had dropped to nearly 0 % by day 5 for both types of SLNs. Interestingly, the levofloxacin-loaded SLNs demonstrated a lower minimum bactericidal concentration (0.25 µg/mL) compared with pure levofloxacin (1 µg/mL), which indicated the formulations have potential as effective treatments for tuberculosis.
PubMed: 38848797
DOI: 10.1016/j.ijpharm.2024.124309 -
PloS One 2024We have identified an acyl-carrier protein, Rv0100, that is up-regulated in a dormancy model. This protein plays a critical role in the fatty acid biosynthesis pathway,...
We have identified an acyl-carrier protein, Rv0100, that is up-regulated in a dormancy model. This protein plays a critical role in the fatty acid biosynthesis pathway, which is important for energy storage and cell wall synthesis in Mycobacterium tuberculosis (MTB). Knocking out the Rv0100 gene resulted in a significant reduction of growth compared to wild-type MTB in the Wayne model of non-replicating persistence. We have also shown that Rv0100 is essential for the growth and survival of this pathogen during infection in mice and a macrophage model. Furthermore, knocking out Rv0100 disrupted the synthesis of phthiocerol dimycocerosates, the virulence-enhancing lipids produced by MTB and Mycobacterium bovis. We hypothesize that this essential gene contributes to MTB virulence in the state of latent infection. Therefore, inhibitors targeting this gene could prove to be potent antibacterial agents against this pathogen.
Topics: Animals; Mycobacterium tuberculosis; Mice; Bacterial Proteins; Acyl Carrier Protein; Macrophages; Virulence; Gene Expression Regulation, Bacterial; Tuberculosis; Lipids
PubMed: 38848336
DOI: 10.1371/journal.pone.0304876 -
Journal of Clinical Immunology Jun 2024
Topics: Humans; Mycobacterium bovis; BCG Vaccine; Tuberculosis; Male; Infant; Sequence Deletion; Gene Deletion; Female
PubMed: 38847935
DOI: 10.1007/s10875-024-01738-1 -
One Health (Amsterdam, Netherlands) Jun 2024Bovine tuberculosis (bTB), caused by (), is a globally prevalent zoonotic infectious disease. World Organization for Animal Health (WOAH) estimates indicate that up to... (Review)
Review
Bovine tuberculosis (bTB), caused by (), is a globally prevalent zoonotic infectious disease. World Organization for Animal Health (WOAH) estimates indicate that up to 10% of the total human TB cases in developing countries are attributed to . Pakistan ranks 4th in global milk production with a livestock population of over 212 million animals. Over 8 million families are involved in raising these animals as a means of livelihood. To date, there is an absence of national-level data on the prevalence of bTB and an effective control program is still lacking. The multifaceted impacts and substantial economic losses render addressing bTB a daunting, but highly important challenge. In this review, we summarise all the freely available literature on infection from Pakistan using Google scholar and PubMed databases. A total of 40 animal studies were identified using search terms: "bovine tuberculosis in Pakistan, bTB, Pakistan, in Pakistan, in Pakistan"; while seven human studies were identified using the terms: zoonotic tuberculosis in Pakistan', ' in humans Pakistan', 'zTB in TB patients in Pakistan". We have summarized all these studies to identify critical risk factors involved in transmission of bTB among animals and humans. Despite lack of comprehensive and geographically representative studies, the literature suggests a varying prevalence of bTB in animals, ranging from as low as 2% to as high as 19%. Regarding zTB prevalence in humans, estimates range from 1.5% to 13% in high-risk group of farm and abattoir workers, with notably higher percentages in extra-pulmonary TB cases. The review also addresses the challenges that Pakistan faces in formulating an effective policy for the control and eradication of bTB. We conclude with one-health based recommendations as a way forward for controlling TB caused by in cattle and humans.
PubMed: 38846704
DOI: 10.1016/j.onehlt.2024.100763 -
The Journal of Infectious Diseases Jun 2024HIF-1α is a pivotal regulator of metabolic and inflammatory responses. This study investigated the role of HIF-1α in M. bovis infection and its effects on host immune...
HIF-1α is a pivotal regulator of metabolic and inflammatory responses. This study investigated the role of HIF-1α in M. bovis infection and its effects on host immune metabolism and tissue damage. We evaluated the expression of immunometabolism markers and MMPs infected with M. bovis, and following HIF-1α inhibition in vitro. To understand the implications of HIF-1α inhibition on disease progression, mice at different infection stages were treated with the HIF-1α inhibitor, YC-1. Our results revealed an upregulation of the HIF-1α in macrophages post-M. bovis infection, facilitating enhanced M1 macrophage polarization. The blockade of HIF-1α moderated these responses but escalated MMP activity, hindering bacterial control. Consistent with our in vitro results, early-stage treatment of mice with YC-1 aggravated pathological alterations and tissue damage, while late-stage HIF-1α inhibition proved beneficial in managing the disease. Overall, our findings underscored the nuanced role of HIF-1α across varying phases of M. bovis infection.
PubMed: 38843067
DOI: 10.1093/infdis/jiae305 -
Frontiers in Veterinary Science 2024This study aimed to determine the sensitivity (Se) and specificity (Sp) of a circulating pathogen-specific biomarker (polyketide synthetase 5, Pks5)-based enzyme-linked...
This study aimed to determine the sensitivity (Se) and specificity (Sp) of a circulating pathogen-specific biomarker (polyketide synthetase 5, Pks5)-based enzyme-linked immunosorbent assay (ELISA) independently or in conjunction with a caudal fold tuberculin (CFT) test for bovine tuberculosis (bTB) screening in dairy cattle. We enrolled 987 dairy cows from 34 herds in Chiang Mai province, Thailand. A conditionally independent Bayesian model with a single population was inferred from the test results. The percentage of positive results for the Pks5-ELISA using 0.4 OD cutoff test and CFT test were 9.0% (89/987) and 10.5% (104/987), respectively. The median of posterior estimates of Se for the Pks5-ELISA test was 90.2% (95% posterior probability interval [PPI] = 76.6-97.4%), while the estimated Sp was slightly higher (median = 92.9, 95% PPI = 91.0-94.5%). The median estimated Se of the CFT test was 85.9% (95% PPI = 72.4-94.6%), while the estimated Sp was higher, with a median of 90.7% (95% PPI = 88.7-92.5%). The posterior estimate for true disease prevalence was 2.4% (95% PPI = 1.2-3.9%). The Pks5-ELISA test yielded characteristics at or above the acceptable standards for bTB detection. Therefore, the pathogen-specific biomarker, Pks5, is a potential detection system for bTB screening and may be applied as an ancillary test together with the currently applied standard method (CFT test) to reinforce the bTB control and eradication programs.
PubMed: 38840633
DOI: 10.3389/fvets.2024.1384537