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Nature Communications Dec 2023Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity....
Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 in mice yet drives low levels of type-1 IFNs but robust IFNγ. Here we examine the role of ongoing IFNγ responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFNγ receptor expression by non-hematopoietic cells. Importantly, we show that BCG infection prompts pulmonary epithelial cells to upregulate IFN-stimulated genes with reported anti-viral activity in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFNγ by demonstrating that the recombinant cytokine itself provides strong protection against SARS-CoV-2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.
Topics: Animals; Mice; SARS-CoV-2; Interferon-gamma; COVID-19; Lung; Interferon Type I
PubMed: 38086794
DOI: 10.1038/s41467-023-43447-0 -
International Journal of Molecular... Jul 2023Tuberculosis (TB) is a zoonotic infectious disease caused by (Mtb). Mtb is a typical intracellular parasite, and macrophages are its main host cells. NLRP3...
Tuberculosis (TB) is a zoonotic infectious disease caused by (Mtb). Mtb is a typical intracellular parasite, and macrophages are its main host cells. NLRP3 inflammasome-mediated pyroptosis is a form of programmed cell death implicated in the clearance of pathogenic infections. The bidirectional regulatory effect of endoplasmic reticulum stress (ERS) plays a crucial role in determining cell survival and death. Whether ERS is involved in macrophage pyroptosis with Mtb infection remains unclear. This article aims to explore the regulation of the NLRP3 inflammasome and pyroptosis by ERS in THP-1 macrophages infected with (BCG). The results showed that BCG infection induced THP-1 macrophage ERS, NLRP3 inflammasome activation and pyroptosis, which was inhibited by ERS inhibitor TUDCA. NLRP3 inhibitor MCC950 inhibited THP-1 macrophage NLRP3 inflammasome activation and pyroptosis caused by BCG infection. Compared with specific Caspase-1 inhibitor VX-765, pan-Caspase inhibitor Z-VAD-FMK showed a more significant inhibitory effect on BCG infection-induced pyroptosis of THP-1 macrophages. Taken together, this study demonstrates that ERS mediated NLRP3 inflammasome activation and pyroptosis after BCG infection of THP-1 macrophages, and that BCG infection of THP-1 macrophages induces pyroptosis through canonical and noncanonical pathways.
Topics: Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; BCG Vaccine; Mycobacterium bovis; Macrophages; Endoplasmic Reticulum Stress
PubMed: 37511451
DOI: 10.3390/ijms241411692 -
Frontiers in Immunology 2023Tuberculosis (TB) remains a serious public health threat around the world. An effective vaccine is urgently required for cost-effective, long-term control of TB.... (Review)
Review
Tuberculosis (TB) remains a serious public health threat around the world. An effective vaccine is urgently required for cost-effective, long-term control of TB. However, the only licensed vaccine Bacillus Calmette-Guerin (BCG) is limited to prevent TB for its highly variable efficacy. Substantial progress has been made in research and development (R&D) of TB vaccines in the past decades, and a dozen vaccine candidates, including live attenuated mycobacterial vaccines, killed mycobacterial vaccines, adjuvanted subunit vaccines, viral vector vaccines, and messenger RNA (mRNA) vaccines were developed in clinical trials to date. Nevertheless, many challenges to the successful authorization for the use and deployment of an effective tuberculosis vaccine remain. Therefore, it is still necessary and urgent to continue exploring new vaccine construction approaches. Virus-like particles (VLPs) present excellent prospects in the field of vaccine development because of their helpful immunological features such as being safe templates without containing viral nucleic acid, repetitive surface geometry, conformational epitopes similar to natural viruses, and enhancing both innate and adaptive immune responses. The marketization process of VLP vaccines has never stopped despite VLP vaccines face several shortcomings such as their complex and slow development process and high production cost, and several VLP-based vaccines, including vaccines against Human papillomavirus (HPV), Hepatitis B Virus (HBV) and malaria, are successfully licensed for use at the market. In this review, we provide an update on the current progress regarding the development of TB vaccines in clinical trials and seek to give an overview of VLP-based TB vaccine candidates.
Topics: Humans; Mycobacterium bovis; Tuberculosis; Tuberculosis Vaccines; Vaccines, Attenuated; Vaccines, Virus-Like Particle; Viral Vaccines; Clinical Trials as Topic
PubMed: 38022657
DOI: 10.3389/fimmu.2023.1238649 -
Frontiers in Microbiology 2023complex (MAC) bacteria are the most prominent etiological agents of lymphadenitis in pigs. subspecies (MAH) is a member of MAC and has been reported in many parts of...
INTRODUCTION
complex (MAC) bacteria are the most prominent etiological agents of lymphadenitis in pigs. subspecies (MAH) is a member of MAC and has been reported in many parts of the world to be the most prevalent non-tuberculous mycobacteria (NTM) to cause mycobacteriosis in humans, mainly in children. Thus, the economic and zoonotic impact of MAC species are increasingly being recognized. In South Africa, little is known about the distribution of NTM and the molecular epidemiology of in pigs.
MATERIALS AND METHODS
In this study, lymph nodes including mandibular, mesenteric, submandibular, and retropharyngeal, with tuberculosis-like lesions were collected during routine meat inspection of slaughter pigs with no disease symptoms ( = 132), between 1991 and 2002. These pigs were slaughtered at 44 abattoirs distributed across seven of the nine South African provinces. Mycobacterial culture, polymerase chain reaction (PCR), and sequencing of the specific 577 bp 16S rRNA gene fragment were performed for species and subspecies identification.
RESULTS
The majority of the isolates (each per sample); 114 (86.4%) were identified as MAH, 8 (6%) as MAA subsp. , 4 (3%) were , 2 (1.5%) as , and 1 (0.75%) as The other isolates were identified as (0.75%), (0.75%), and a spp. (0.75%). Using an eight-marker MLVA typing tool, we deciphered at least nine MIRU VNTR INMV types of MAH and MAA.
DISCUSSION
Identification of known zoonotic mycobacteria, including MAH, MAA, , and , from slaughter pigs has a potential public health impact and also strengthens recognition of the potential economic impact of MAC. This study has also for the first time in South Africa, revealed MAC MIRU VNTR INMV genotypes which will aid in the future epidemiological investigation of MAC in South Africa.
PubMed: 38033580
DOI: 10.3389/fmicb.2023.1284906 -
One Health (Amsterdam, Netherlands) Jun 2024This study investigated the presence of () DNA in archived human sputum samples previously collected from residents who reside adjacent to the -endemic...
This study investigated the presence of () DNA in archived human sputum samples previously collected from residents who reside adjacent to the -endemic Hluhluwe-iMfolozi wildlife park, South Africa (SA). Sixty-eight sputum samples were GeneXpert MTB/RIF Ultra-positive for complex (MTBC) DNA but culture negative for . Amplification and Sanger sequencing of and genes from DNA extracted from stored heat-inactivated sputum samples confirmed the presence of detectable amounts of MTBC from 20 out of the 68 sputum samples. Region of difference PCR, spoligotyping and long-read amplicon deep sequencing identified ( = 10) and ( = 7). Notably, spoligotypes and were identified in 4 samples, with previously identified in local cattle and wildlife and exclusively in African buffaloes in the adjacent park. DNA in sputum, from people living near the park, underscores zoonotic transmission potential in SA. Identification of spoligotypes specifically associated with wildlife only and spoligotypes found in livestock as well as wildlife, highlights the complexity of TB epidemiology at wildlife-livestock-human interfaces. These findings support the need for integrated surveillance and control strategies to curb potential spillover and for the consideration of human infection in SA patients with positive Ultra results.
PubMed: 38487729
DOI: 10.1016/j.onehlt.2024.100702 -
Pathogens (Basel, Switzerland) Aug 2023Metabolic dysregulation in results in increased macrophage apoptosis or pyroptosis. However, mechanistic links between virulence and bacterial metabolic plasticity...
Metabolic dysregulation in results in increased macrophage apoptosis or pyroptosis. However, mechanistic links between virulence and bacterial metabolic plasticity remain ill defined. In this study, we screened random transposon insertions of BCG to identify mutants that induce pyroptotic death of the infected macrophage. Analysis of the transposon insertion sites identified a panel of (unctioning eath epressor) genes, which were shown in some cases to encode functions central to metabolism. In-depth studies of one gene, (BCG3787/Rv3727), demonstrated its important role in the maintenance of and BCG redox balance in reductive stress conditions in the host. Our studies expand the subset of known genes linking bacterial metabolic plasticity to virulence and also reveal that the broad induction of pyroptosis by an intracellular bacterial pathogen is linked to enhanced cellular immunity in vivo.
PubMed: 37764917
DOI: 10.3390/pathogens12091109 -
RSC Advances Oct 2023Bovine tuberculosis (bTB) is considered a worldwide infectious zoonotic disease. causes bTB disease. It is one of the complex (MTBC) members. MTBC is a clonal complex... (Review)
Review
Bovine tuberculosis (bTB) is considered a worldwide infectious zoonotic disease. causes bTB disease. It is one of the complex (MTBC) members. MTBC is a clonal complex of close relatives with approximately 99.95% similarity. is a spillover pathogen that can transmit from animals to humans and rarely from humans to animals with contact. Genotyping techniques are important to discriminate and differentiate between MTBC species. Spoligotyping and mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) are widely used but they have some limitations. As an alternative, whole genome sequencing approaches have been utilized due to their high-resolution power. They are employed in typing and explain the evolutionary and phylogenetic relationships between isolates. The control of bTB disease has attracted a large amount of attention. Rapid and proper diagnosis is necessary for monitoring the disease as an initial step for its control and treatment. Nanotechnology has a potential impact on the rapid diagnosis and treatment of bTB through the use of nanocarrier and metal nanoparticles (NPs). Special attention has been paid to voltammetric and impedimetric electrochemical strategies as facile, sensitive, and selective methods for the efficient detection of tuberculosis. The efficacy of these sensors is enhanced in the presence of NPs, which act as recognition and/or redox probes. Gold, silver, copper, cobalt, graphene, and magnetic NPs, as well as polypyrrole nanowires and multiwalled carbon nanotubes have been employed for detecting tuberculosis. Overall, NP-based electrochemical sensors represent a promising tool for the diagnosis of bTB.
PubMed: 37908649
DOI: 10.1039/d3ra05606f -
PLoS Pathogens Nov 2023Despite widespread immunization with Bacille-Calmette-Guérin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality...
Despite widespread immunization with Bacille-Calmette-Guérin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a reduction in lung bacterial burdens that is more durable than that observed after conventional dose challenge, curbs Mtb dissemination to the contralateral lung, and, in a small percentage of mice, prevents detectable infection. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing.
Topics: Animals; Mice; Humans; Mycobacterium tuberculosis; BCG Vaccine; Disease Models, Animal; Tuberculosis Vaccines; Vaccination; Mycobacterium bovis
PubMed: 38011264
DOI: 10.1371/journal.ppat.1011825 -
PloS One 2023Even in the face of the COVID-19 pandemic, Tuberculosis (TB) continues to be a major public health problem and the 2nd biggest infectious cause of death worldwide. There...
Even in the face of the COVID-19 pandemic, Tuberculosis (TB) continues to be a major public health problem and the 2nd biggest infectious cause of death worldwide. There is, therefore, an urgent need to develop effective TB diagnostic methods, which are cheap, portable, sensitive and specific. Raman spectroscopy is a potential spectroscopic technique for this purpose, however, so far, research efforts have focused primarily on the characterisation of Mycobacterium tuberculosis and other Mycobacteria, neglecting bacteria within the microbiome and thus, failing to consider the bigger picture. It is paramount to characterise relevant Mycobacteriales and develop suitable analytical tools to discriminate them from each other. Herein, through the combined use of Raman spectroscopy and the self-optimising Kohonen index network and further multivariate tools, we have successfully undertaken the spectral analysis of Mycobacterium bovis BCG, Corynebacterium glutamicum and Rhodoccocus erythropolis. This has led to development of a useful tool set, which can readily discern spectral differences between these three closely related bacteria as well as generate a unique spectral barcode for each species. Further optimisation and refinement of the developed method will enable its application to other bacteria inhabiting the microbiome and ultimately lead to advanced diagnostic technologies, which can save many lives.
Topics: Humans; Mycobacterium bovis; Spectrum Analysis, Raman; Pandemics; Tuberculosis; Mycobacterium tuberculosis; Actinomycetales; Neural Networks, Computer; BCG Vaccine
PubMed: 38079400
DOI: 10.1371/journal.pone.0293093 -
International Journal of Molecular... Jun 2024() is the causative agent of bovine tuberculosis (bTb). Genetic selection aiming to identify less susceptible animals has been proposed as a complementary measure in...
Genome-Wide Association Study Reveals Quantitative Trait Loci and Candidate Genes Associated with High Interferon-gamma Production in Holstein Cattle Naturally Infected with .
() is the causative agent of bovine tuberculosis (bTb). Genetic selection aiming to identify less susceptible animals has been proposed as a complementary measure in ongoing programs toward controlling infection. However, individual animal phenotypes for bTb based on interferon-gamma (IFNɣ) and its use in bovine selective breeding programs have not been explored. In the current study, IFNɣ production was measured using a specific IFNɣ ELISA kit in bovine purified protein derivative (bPPD)-stimulated blood samples collected from Holstein cattle. DNA isolated from the peripheral blood samples collected from the animals included in the study was genotyped with the EuroG Medium Density bead Chip, and the genotypes were imputed to whole-genome sequences. A genome-wide association analysis (GWAS) revealed that the IFNɣ in response to bPPD was associated with a specific genetic profile (heritability = 0.23) and allowed the identification of 163 SNPs, 72 quantitative trait loci (QTLs), 197 candidate genes, and 8 microRNAs (miRNAs) associated with this phenotype. No negative correlations between this phenotype and other phenotypes and traits included in the Spanish breeding program were observed. Taken together, our results define a heritable and distinct immunogenetic profile associated with strong production of IFNɣ in response to .
Topics: Animals; Cattle; Quantitative Trait Loci; Mycobacterium bovis; Genome-Wide Association Study; Interferon-gamma; Tuberculosis, Bovine; Polymorphism, Single Nucleotide; Phenotype; Genotype
PubMed: 38892353
DOI: 10.3390/ijms25116165