GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection.

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.

• Authors: Sulayman Benmerzoug, Fabio Vitarelli Marinho, Stéphanie Rose, Claire Mackowiak, David Gosset, Delphine Sedda, Emeline Poisson, Catherine Uyttenhove, Jacques Van Snick, Muazzam Jacobs, Irene Garcia, Bernhard Ryffel, Valerie F J Quesniaux
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 8652 (06 05 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29872095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Antitubercular Agents
• Immunologic Factors
• Granulocyte-Macrophage Colony-Stimulating Factor
• Isoniazid
• Rifampin

Topics

• Animals
• Antibodies, Neutralizing (administration & dosage)
• Antitubercular Agents (administration & dosage)
• Cattle
• Disease Models, Animal
• Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors, metabolism)
• Immunologic Factors (antagonists & inhibitors, metabolism)
• Immunomodulation
• Isoniazid (administration & dosage)
• Macrophages (immunology)
• Mice
• Mycobacterium bovis (immunology)
• Mycobacterium tuberculosis (immunology)
• Rifampin (administration & dosage)
• Treatment Outcome
• Tuberculosis, Pulmonary (immunology, pathology)