2 research outputs found
BCG Vaccination Induces M. avium and M. abscessus Cross-Protective Immunity
Pulmonary non-tuberculous mycobacterial (NTM) infections particularly caused by Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are becoming major health problems in the U.S. New therapies or vaccines which will help prevent the disease, shorten treatment duration and/or increase treatment success rates are urgently needed. This study was conducted with the objective of testing the hypothesis that Bacillus Calmette Guerin (BCG), a vaccine used for prevention of serious forms of tuberculosis (TB) in children and adolescents in tuberculosis hyperendemic countries, induces cross-protective T cell immunity against Mycobacterium avium (MAV) and MAB. Human TB and NTM cross-protective T cells were quantified using flow cytometric assays. The ability of BCG expanded T cells to inhibit the intracellular growth of MAV and MAB was assessed in co-cultures with infected autologous macrophages. In both BCG-vaccinated and M. tuberculosis (Mtb)-infected mice, NTM cross-reactive immunity was measured using IFN-γ ELISPOT assays. Our results demonstrate the following key findings: (i) peripheral blood mononuclear cells from TB skin test-positive individuals contain MAV and MAB cross-reactive T cells, (ii) both BCG vaccination and Mtb infection of mice induce MAV and MAB cross-reactive splenic cells, (iii) BCG-expanded T cells inhibit intracellular MAV and MAB, (iv) CD4, CD8, and γδ T cells play important roles in inhibition of intracellular MAV and MAB and (v) BCG vaccination of healthy volunteers induces TB and NTM cross-reactive T cells. In conclusion, BCG-vaccination induces NTM cross-reactive immunity, and has the potential for use as a vaccine or immunotherapy to prevent and/or treat pulmonary NTM disease
Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis
Efflux pumps are considered a major
potential contributor to the development of various forms of resistance
in Mycobacterium tuberculosis leading
to the emergence of multidrug-resistant tuberculosis (TB). Verapamil
(VER) and tricyclic chemosensitizers such as the phenothiazines are
known to possess efflux pump inhibition properties and have demonstrated
significant efficacy in various TB disease models. Novel hybrid molecules
based on fusion of the VER substructure with various tricyclic, as
well as nontricyclic, chemosensitizer cores or their structural motifs
are described. These hybrid compounds were evaluated in vitro and
ex vivo individually for their intrinsic activity and in combination
for their potentiating potential with the frontline anti-TB drugs,
rifampin and isoniazid. In addition, efflux pump inhibition was assessed
in an ethidium bromide assay. This study led to the identification
of novel compounds, termed hybrid efflux pump inhibitors, with intrinsic
antimycobacterial activities (MIC<sub>90</sub> ≤ 3.17 μg/mL)
and intracellular activity in macrophages at a low concentration (≤6.25
μg/mL)