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Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosol-challenged mice.

ABSTRACT: Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), kills over 1.6 million people each year despite availability of antibiotics. The increase in drug resistant Mtb strains is a major public health emergency and host-directed therapy as adjunct to antibiotic treatment has gained increased interest. Cyclooxygenase inhibitors (COXi) are frequently used drugs to alleviate tuberculosis related symptoms. Mouse studies of acute intravenous Mtb infection have suggested a potential benefit of COXi for host-directed therapy. Here we show that COXi treatment (ibuprofen and celecoxib) is detrimental to Mtb control in different mouse models of respiratory infection. This effect links to impairments of the Type-1 helper (Th1) T-cell response as CD4 T-cells in COXi-treated animals have significantly decreased Th1 differentiation, reduced IFN? expression and decreased protective capacity upon adoptive transfer. If confirmed in clinical trials, these findings could have major impact on global health and question the use of COXi for host-directed therapy.

SUBMITTER: Mortensen R

PROVIDER: S-EPMC6683187 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate <i>Mycobacterium tuberculosis</i> infection in aerosol-challenged mice.

Mortensen Rasmus R Clemmensen Helena Strand HS Woodworth Joshua S JS Therkelsen Marie Louise ML Mustafa Tehmina T Tonby Kristian K Jenum Synne S Agger Else Marie EM Dyrhol-Riise Anne Ma AM Andersen Peter P

Communications biology 20190805

Tuberculosis, caused by infection with <i>Mycobacterium tuberculosis</i> (Mtb), kills over 1.6 million people each year despite availability of antibiotics. The increase in drug resistant Mtb strains is a major public health emergency and host-directed therapy as adjunct to antibiotic treatment has gained increased interest. Cyclooxygenase inhibitors (COXi) are frequently used drugs to alleviate tuberculosis related symptoms. Mouse studies of acute intravenous Mtb infection have suggested a pote ...[more]

PMID: 31396568

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Project description:Mycobacterium tuberculosis infects approximately one-third of the world's population, causing active tuberculosis (TB) in ~10 million people and death in ~1.5 million people annually. A potent vaccine is needed to boost the level of immunity conferred by the current Mycobacterium bovis BCG vaccine that provides moderate protection against childhood TB but variable protection against adult pulmonary TB. Previously, we developed a recombinant attenuated Listeria monocytogenes (rLm)-vectored M. tuberculosis vaccine expressing the M. tuberculosis 30-kDa major secretory protein (r30/Ag85B), recombinant attenuated L. monocytogenes ΔactA ΔinlB prfA*30 (rLm30), and showed that boosting BCG-primed mice and guinea pigs with rLm30 enhances immunoprotection against challenge with aerosolized M. tuberculosis Erdman strain. To broaden the antigen repertoire and robustness of rLm30, we constructed 16 recombinant attenuated L. monocytogenes vaccine candidates expressing 3, 4, or 5 among 15 selected M. tuberculosis antigens, verified their protein expression, genetic stability, and growth kinetics in macrophages, and evaluated them for capacity to boost protective efficacy in BCG-primed mice. We found that boosting BCG-primed C57BL/6 and BALB/c mice with recombinant attenuated L. monocytogenes multiantigenic M. tuberculosis vaccines, especially the rLm5Ag(30) vaccine expressing a fusion protein of 23.5/Mpt64, TB10.4/EsxH, ESAT6/EsxA, CFP10/EsxB, and r30, enhances BCG-induced protective immunity against M. tuberculosis aerosol challenge. In immunogenicity studies, rLm5Ag(30) strongly boosts M. tuberculosis antigen-specific CD4-positive (CD4+) and CD8+ T cell-mediated TH1-type immune responses in the spleens and lungs of BCG-primed C57BL/6 mice but does so only weakly in BCG-primed BALB/c mice. Hence, rLm5Ag(30) boosts BCG-primed immunoprotection against M. tuberculosis aerosol challenge in both C57BL/6 and BALB/c mice despite major differences in the magnitude of the vaccine-induced Th1 response in these mouse strains. Given the consistency with which recombinant attenuated L. monocytogenes vaccines expressing the 5 M. tuberculosis antigens in rLm5Ag(30) are able to boost the already high level of protection conferred by BCG alone in two rigorous mouse models of pulmonary TB and the broad CD4+ and CD8+ T cell immunity induced by rLm5Ag(30), this vaccine holds considerable promise as a new vaccine to combat the TB pandemic, especially for the majority of the world's population immunized with BCG in infancy. IMPORTANCE TB, one of the world's most important infectious diseases, afflicts approximately 10 million people and kills approximately 1.5 million people annually. The current vaccine, BCG, developed over a century ago, has been administered to about 5 billion people, mostly in infancy, but is only modestly protective. Hence, a vaccine is urgently needed to boost the level of protection afforded by BCG. Herein, we describe a safe potent live vaccine that utilizes as a vector an attenuated strain of Listeria monocytogenes, a bacterium that mimics the intracellular lifestyle of Mycobacterium tuberculosis, the causative agent of TB. The vaccine produces multiple immunologically protective proteins of M. tuberculosis. In two mouse models of pulmonary TB, the vaccine boosts the level of protection afforded by BCG. Thus, this vaccine holds considerable promise as a new vaccine to combat the TB pandemic, especially for the majority of the world's population immunized with BCG.

Dataset Information

Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosol-challenged mice.

Publications

Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate <i>Mycobacterium tuberculosis</i> infection in aerosol-challenged mice.

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