Mycobacterium tuberculosis Infection is Exacerbated in Mice Lacking Lecithin:Retinol Acyltransferase.
Background: Vitamin A (VA, [ROL]) and its family of metabolites, including all-trans retinoic acid (RA), regulate the transcription of genes vital to innate and adaptive immune responses. In humans VA deficiency (VAD) is associated with increased severity of Mycobacterium tuberculosis (Mtb) infection, however despite this, little is known on the causal relationship between VA and Mtb. Methods: Using wild-type (WT) mice and a genetic VAD model, LRAT-/- mice, that are unable to synthesize retinyl esters (RE), a storage form of retinoids, in lung, liver, and other tissues, we explored the interrelationship among VAD, Mtb infection, and lung pathology over a 56-day Mtb infection period. Results: We first measured Mtb colony forming units (CFUs) and found that at day 56 post-infection, LRAT-/- mice had significantly higher CFUs compared to vitamin A sufficient (VAS) WT mice. Lung histology showed that LRAT-/- mice had more severe lung pathology, marked by greater numbers pulmonary lesions and higher lung levels of macrophage, T-cell and neutrophil markers, F4/80, CD3e and Ly6G respectively compared to WT mice. We also found that lung mRNA levels of TNFα,IL1β, IL6, IL12p40 and IFNγ, pro-inflammatory cytokines were significantly increased in LRAT-/- mice compared to WT mice. We next examined the temporal changes to lung retinoid levels in WT mice and found that, compared to pre-Mtb infection, lung total RE, but not ROL, increased by day 56 post-Mtb infection suggesting increased uptake or decreased mobilization of lung RE pools in response to Mtb. Despite the increases in lung RE, we found that pulmonary RA signaling steadily decreased from pre-infection to day 56 post-Mtb infection in WT mice, marked by reduced mRNA levels of RA-targets genes such as RARβ2, CRBP1, Cyp26A1 and LRAT. We found that compared to WT mice, LRAT-/- mice, which have no pulmonary RE and lower ROL levels, had lower lung mRNA levels of RA-targets genes, suggesting an even greater reduction in pulmonary RA signaling in response to Mtb infection. Conclusion: We showed that mice lacking LRAT are potentially at increased risk for an aggravated response to Mtb infection because of their lower lung VA levels. Further examination of the role of pulmonary VA and LRAT in the host-response to Mtb is warranted.
Steven E. Trasino1,2, Xiao-Han Tang 1, Carolina Trujillo3, Jaclynn Andres3, Sabine Ehrt3, and Lorraine J. Gudas1*
1. Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY.
2. School of Urban Public Health, Nutrition Program, Hunter College, City University of New York, New York, NY.
3. Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY.