Effect of Mycobacterium tuberculosis Enhancement of Macrophage P-Glycoprotein Expression and Activity on Intracellular Survival During Antituberculosis Drug Treatment.

BACKGROUND: Tuberculosis is caused by Mycobacterium tuberculosis. Recent emergence of multidrug-resistant (MDR) tuberculosis strains seriously threatens tuberculosis control and prevention. However, the role of macrophage multidrug resistance gene MDR1 on intracellular M. tuberculosis survival during antituberculosis drug treatment is not known. METHODS: We used the human monocyte-derived macrophages to study the role of M. tuberculosis in regulation of MDR1 and drug resistance. RESULTS: We discovered that M. tuberculosis infection increases the expression of macrophage MDR1 to extrude various chemical substances, including tuberculosis drugs, resulting in enhanced survival of intracellular M. tuberculosis. The pathway of regulation involves M. tuberculosis infection of macrophages and suppression of heat shock factor 1, a transcriptional regulator of MDR1 through the up-regulation of miR-431. Notably, nonpathogenic Mycobacterium smegmatis did not increase MDR1 expression, indicating active secretion of virulence factors in pathogenic M. tuberculosis contributing to this phenotype. Finally, inhibition of MDR1 improves antibiotic-mediated killing of M. tuberculosis. CONCLUSION: We report a novel finding that M. tuberculosis up-regulates MDR1 during infection, which limits the exposure of M. tuberculosis to sublethal concentrations of antimicrobials. This condition promotes M. tuberculosis survival and potentially enhances the emergence of resistant variants.

Aging influences the cardiac macrophage phenotype and function during steady state and during inflammation.

Aging-mediated immune dysregulation affects the normal cardiac immune cell phenotypes and functions, resulting in cardiac distress. During cardiac inflammation, immune activation is critical for mounting the regenerative responses to maintain normal heart function. We investigated the impact of aging on myeloid cell phenotype and function during cardiac inflammation induced by a sub-lethal dose of LPS. Our data show that hearts of old mice contain more myeloid cells than the hearts of young mice. However, while the number of monocytic-derived suppressor cells did not differ between young and old mice, monocytic-derived suppressor cells from old mice were less able to suppress T-cell proliferation. Since cardiac resident macrophages (CRMs) are important for immune surveillance, clearance of dead cells, and tissue repair, we focused our studies on CRMs phenotype and function during steady state and LPS treatment. In the steady state, we observed significantly more MHC-IIlow and MHC-IIhigh CRMs in the hearts of old mice; however, these populations were decreased in both young and aged mice upon LPS treatment and the decrease in CRM populations correlated with defects in cardiac electrical activity. Notably, mice treated with a liver X receptor (LXR) agonist showed an increase in MerTK expression in CRMs of both young and old mice, which resulted in the reversal of cardiac electrical dysfunction caused by lipopolysaccharide (LPS). We conclude that aging alters the phenotype of CRMs, which contributes to the dysregulation of cardiac electrical dysfunction during infection in aged mice.

Nontuberculous mycobacterium M. avium infection predisposes aged mice to cardiac abnormalities and inflammation.

Biological aging dynamically alters normal immune and cardiac function, favoring the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and increased instances of cardiac distress. Cardiac failure is the primary reason for hospitalization of the elderly (65+ years). The elderly are also increasingly susceptible to developing chronic bacterial infections due to aging associated immune abnormalities. Since bacterial infections compound the rates of cardiac failure in the elderly, and this phenomenon is not entirely understood, the interplay between the immune system and cardiovascular function in the elderly is of great interest. Using Mycobacterium avium, an opportunistic pathogen, we investigated the effect of mycobacteria on cardiac function in aged mice. Young (2-3 months) and old (18-20 months) C57BL/6 mice were intranasally infected with M. avium strain 104, and we compared the bacterial burden, immune status, cardiac electrical activity, pathology, and function of infected mice against uninfected age-matched controls. Herein, we show that biological aging may predispose old mice infected with M. avium to mycobacterial dissemination into the heart tissue and this leads to cardiac dysfunction. M. avium infected old mice had significant dysrhythmia, cardiac hypertrophy, increased recruitment of CD45+ leukocytes, cardiac fibrosis, and increased expression of inflammatory genes in isolated heart tissue. This is the first study to report the effect of mycobacteria on cardiac function in an aged model. Our findings are critical to understanding how nontuberculous mycobacterium (NTM) and other mycobacterial infections contribute to cardiac dysfunction in the elderly population.