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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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