ABSTRACT
Summary: We characterized Mycobacterium bovis BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. Background: We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine). Distinct M. bovis BCG-vaccine derived clinical strains were recovered from the patient's lungs and brain. Methods: BCG strains were phenotypically (growth, antibiotic susceptibility, lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell infection models were used to assess apoptosis, necrosis, cytokine release, autophagy, and JAK-STAT signaling. Results: Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 rpoB mutations conferring high- and low-level rifampin resistance; the latter displayed clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in fadA2, fadE5, and mymA operon genes, respectively. Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and Mycolic acid components in BCG-lung, compared to parent BCG-vaccine. In vitro infected cells showed that the BCG-lung induced a higher cytokine release, necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. Conclusions: During a chronic-disseminated BCG infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.
Subject(s)
BCG Vaccine/adverse effects , BCG Vaccine/immunology , Mycobacterium bovis/immunology , Mycobacterium bovis/pathogenicity , Receptors, Interferon/genetics , Tuberculosis/blood , Tuberculosis/diagnosis , Animals , Anti-Bacterial Agents/pharmacology , BCG Vaccine/administration & dosage , Brain/microbiology , Cattle , Child, Preschool , Drug Resistance, Bacterial , Humans , Lung/microbiology , Male , Mutation , Mycobacterium bovis/drug effects , Mycobacterium bovis/genetics , Receptors, Interferon/deficiency , Vaccination , Virulence , Interferon gamma ReceptorABSTRACT
The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg(2+) causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytotoxicity, Immunologic , Epstein-Barr Virus Infections/immunology , Killer Cells, Natural/immunology , Magnesium Deficiency/immunology , Magnesium/immunology , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Humans , NK Cell Lectin-Like Receptor Subfamily K/genetics , X-Linked Combined Immunodeficiency Diseases/immunologySubject(s)
Ascomycota/isolation & purification , Chromoblastomycosis/microbiology , Chromoblastomycosis/pathology , Thigh , Antifungal Agents/therapeutic use , Chromoblastomycosis/drug therapy , Humans , Male , Middle Aged , National Institutes of Health (U.S.) , Triazoles/therapeutic use , United StatesABSTRACT
Advances in supportive care over the past two decades have decreased the morbidity and mortality attributed to opportunistic infections in immunocompromised patients, including those with hematologic malignancies, hematopoietic stem cell transplantation (HSCT), and aplastic anemia. Despite advances in antiviral therapy, opportunistic viral infections such as influenza, herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) still cause significant morbidity and mortality in patients with compromised host defenses. Antiviral agents are key antimicrobials used for treatment and prophylaxis of viral infections in immunocompromised hosts. Currently, there are more than 40 antiviral agents approved for clinical use, but the majority of these agents are for the treatment of human immunodeficiency virus (HIV) or viral hepatitis. This review will focus on antiviral agents used for the treatment of herpesviruses (HSV, VZV, CMV), community-acquired respiratory viruses (influenza), and adenoviruses. Antiviral agents used for the treatment of HIV and viral hepatitis will not be addressed in this review.
