TCA metabolism regulates DNA hypermethylation in LPS and -induced immune tolerance.

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance.

Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection.

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2000 deaths in the U.S.

Antiviral Effect of Antimicrobial Peptoid TM9 and Murine Model of Respiratory Coronavirus Infection.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo--substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2.

Peptide-mimetic treatment of in a mouse model of respiratory infection.

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2,000 deaths annually. While the emergence of resistant bacteria has become concerningly common, identification of useful new drug classes has been limited over the past 40+ years.

Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS): a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses.

Background: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19.

Recent Developments in Drug Delivery for Treatment of Tuberculosis by Targeting Macrophages.

Tuberculosis (TB) is among the greatest public health and safety concerns in the 21 century, which causes TB, infects alveolar macrophages and uses these cells as one of its primary sites of replication. The current TB treatment regimen, which consist of chemotherapy involving a combination of 3-4 antimicrobials for a duration of 6-12 months, is marked with significant side effects, toxicity, and poor compliance. Targeted drug delivery offers a strategy that could overcome many of the problems of current TB treatment by specifically targeting infected macrophages.

Stabilization of Tuberculosis Reporter Enzyme Fluorescence (REFtb) Diagnostic Reagents for Use at the Point of Care.

Tuberculosis is one of the most frequent causes of death in humans worldwide. One of the primary reasons tuberculosis remains a public health threat is that diagnosis can take weeks to months, is often not very sensitive and cannot be accomplished in many remote environments. A rapid, sensitive and inexpensive point-of-care (POC) diagnostic would have a major impact on tuberculosis eradication efforts.

Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression May Prevent Severe COVID-19 Inflammatory Responses and Reduce Microthrombosis.

COVID-19 is characterized by hyperactivation by inflammatory cytokines and recruitment of macrophages, neutrophils, and other immune cells, all hallmarks of a strong inflammatory response that can lead to severe complications and multi-organ damage. Mortality in COVID-19 patients is associated with a high prevalence of neutrophil extracellular trap (NET) formation and microthrombosis that are exacerbated by hyperglycemia, diabetes, and old age. SARS-CoV-2 infection in humans and non-human primates have revealed long-term neurological consequences of COVID-19, possibly concomitant with the formation of Lewy bodies in the brain and invasion of the nervous system the olfactory bulb.

Efficacy of Cathelicidin-Mimetic Antimicrobial Peptoids against Staphylococcus aureus.

Staphylococcus aureus is one of the most common pathogens associated with infection in wounds. The current standard of care uses a combination of disinfection and drainage followed by conventional antibiotics such as methicillin. Methicillin and vancomycin resistance has rendered these treatments ineffective, often causing the reemergence of infection.

Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis.

Background: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death.

Methods: Guinea pigs were infected with () for 45 days, followed by RRBS DNA methylation analysis.

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes.

Background: , animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.

Methods: A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes.

Tuberculosis endotypes to guide stratified host-directed therapy.

There is hope that host-directed therapy (HDT) for Tuberculosis (TB) can either shorten treatment duration, help cure drug resistant disease or limit the immunopathology. Many candidate HDT drugs have been proposed, however solid evidence only exists for a few select patient groups. The clinical presentation of TB is variable, with differences in severity, tissue pathology, and bacillary burden.

COVID-19 and Beyond: Exploring Public Health Benefits from Non-Specific Effects of BCG Vaccination.

Bacille Calmette-Guérin (BCG) vaccination, widely used throughout the world to protect against infant tuberculous meningitis and miliary tuberculosis (TB), can provide broad non-specific protection against infectious respiratory diseases in certain groups. Interest in BCG has seen a resurgence within the scientific community as the mechanisms for non-specific protection have begun to be elucidated. The impact of the COVID-19 pandemic on nearly every aspect of society has profoundly illustrated the pressure that respiratory infections can place on a national healthcare system, further renewing interest in BCG vaccination as a public health policy to reduce the burden of those illnesses.

Phage-encoded cationic antimicrobial peptide required for lysis.

Most phages of Gram-negative hosts encode spanins for disruption of the outer membrane, the last step in host lysis. However, bioinformatic analysis indicates that ∼15% of these phages lack a spanin gene, suggesting they have an alternate way of disrupting the OM. Here, we show that the T7-like coliphage phiKT causes the explosive cell lysis associated with spanin activity despite not encoding spanins.

100 years of Bacillus Calmette-Guérin immunotherapy: from cattle to COVID-19.

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections.

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) has complex and dynamic interactions with the human host, and subpopulations of Mtb that emerge during infection can influence disease outcomes. This study implicates zinc ion (Zn2+) availability as a likely driver of bacterial phenotypic heterogeneity in vivo. Zn2+ sequestration is part of "nutritional immunity", where the immune system limits micronutrients to control pathogen growth, but this defense mechanism seems to be ineffective in controlling Mtb infection.

Enhancing sensitivity of lateral flow assay with application to SARS-CoV-2.

Lateral flow assay (LFA) has long been used as a biomarker detection technique. It has advantages such as low cost, rapid readout, portability, and ease of use. However, its qualitative readout process and lack of sensitivity are limiting factors.

Safety and delivery efficiency of a photodynamic treatment of the lungs using indocyanine green and extracorporeal near infrared illumination.

Photodynamic inactivation (PDI) is a promising alternative for combating infections caused by antimicrobial resistant bacteria. Pneumonias are among the most worrisome infections because of their high-mortality rate. Previous studies have demonstrated the feasibility of using PDI with extracorporeal light to treat pneumonia.

Dissemination Plays a Critical Role in Pathogenesis.

is primarily a respiratory pathogen. However, 15% of infections worldwide occur at extrapulmonary sites causing additional complications for diagnosis and treatment of the disease. In addition, dissemination of out of the lungs is thought to be more than just a rare event leading to extrapulmonary tuberculosis, but rather a prerequisite step that occurs during all infections, producing secondary lesions that can become latent or productive.

DNA hypermethylation during tuberculosis dampens host immune responsiveness.

Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited.

Molecular Nanomachines Can Destroy Tissue or Kill Multicellular Eukaryotes.

Light-activated molecular nanomachines (MNMs) can be used to drill holes into prokaryotic (bacterial) cell walls and the membrane of eukaryotic cells, including mammalian cancer cells, by their fast rotational movement, leading to cell death. We examined how these MNMs function in multicellular organisms and investigated their use for treatment and eradication of specific diseases by causing damage to certain tissues and small organisms. Three model eukaryotic species, , , and (mouse), were evaluated.

Molecular Nanomachines Disrupt Bacterial Cell Wall, Increasing Sensitivity of Extensively Drug-Resistant to Meropenem.

Multidrug resistance in pathogenic bacteria is an increasing problem in patient care and public health. Molecular nanomachines (MNMs) have the ability to open cell membranes using nanomechanical action. We hypothesized that MNMs could be used as antibacterial agents by drilling into bacterial cell walls and increasing susceptibility of drug-resistant bacteria to recently ineffective antibiotics.

Fluorescence modeling of optical detection of .

Tuberculosis is one of the deadliest infectious diseases worldwide. New tools to study pathogenesis and monitor subjects in pre-clinical studies to develop treatment regimens are critical for progress. We developed an improved optical system for detecting bacteria in lungs of mice using internal illumination.