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GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection
Benmerzoug, S Marinho, F.V Rose, S Mackowiak, C Gosset, D Sedda, D Poisson, E Uyttenhove, C Van Snick, J Jacobs, M
Benmerzoug, S
Marinho, F.V
Rose, S
Mackowiak, C
Gosset, D
Sedda, D
Poisson, E
Uyttenhove, C
Van Snick, J
Jacobs, M
Abstract
Host directed immunomodulation represents potential new adjuvant therapies in infectious diseases such as tuberculosis. Major cytokines like TNFα exert a multifold role in host control of mycobacterial infections. GM-CSF and its receptor are over-expressed during acute M. tuberculosis infection and we asked how GM-CSF neutralization might affect host response, both in immunocompetent and in immunocompromised TNFα-deficient mice. GM-CSF neutralizing antibodies, at a dose effectively preventing acute lung inflammation, did not affect M. tuberculosis bacterial burden, but increased the number of granuloma in wild-type mice. We next assessed whether GM-CSF neutralization might affect the control of M. tuberculosis by isoniazid/rifampicin chemotherapy.
GM-CSF neutralization compromised the bacterial control under sub-optimal isoniazid/rifampicin treatment in TNFα-deficient mice, leading to exacerbated lung inflammation with necrotic granulomatous structures and high numbers of intracellular M. tuberculosis bacilli. In vitro, GM-CSF neutralization promoted M2 anti-inflammatory phenotype in M. bovis BCG infected macrophages, with reduced mycobactericidal NO production and higher intracellular M. bovis BCG burden. Thus, GM-CSF pathway overexpression during acute M. tuberculosis infection contributes to an efficient M1 response, and interfering with GM-CSF pathway in the course of infection may impair the host inflammatory response against M. tuberculosis.
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Date
2018-06-05
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Springer Nature
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Keywords
Mycobacterium tuberculosis, Animals, Immunomodulation, Immunologic factors, SDG-03 Good health and well-being
Citation
Benmerzoug S, Marinho FV, Rose S, Mackowiak C, Gosset D, Sedda D, Poisson E, Uyttenhove C, Van Snick J, Jacobs M, Garcia I, Ryffel B, Quesniaux VFJ. GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection. Sci Rep. 2018 Jun 5;8(1):8652. doi: 10.1038/s41598-018-26984-3.
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Attribution 3.0 United States