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

Area of Science:

• Immunology
• Infectious Diseases
• Microbiology

Background:

• Host-directed immunomodulation offers potential adjuvant therapies for tuberculosis.
• Tumor necrosis factor-alpha (TNFα) plays a critical role in controlling mycobacterial infections.
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) is overexpressed during acute Mycobacterium tuberculosis infection.

Purpose of the Study:

• To investigate the effects of GM-CSF neutralization on host response during M. tuberculosis infection.
• To assess the impact of GM-CSF neutralization in both immunocompetent and TNFα-deficient mice.
• To determine if GM-CSF neutralization affects tuberculosis control during chemotherapy.

Main Methods:

• Administration of GM-CSF neutralizing antibodies in wild-type and TNFα-deficient mice.
• Assessment of M. tuberculosis bacterial burden and granuloma formation.
• In vitro studies using M. bovis BCG infected macrophages to evaluate inflammatory phenotype and mycobactericidal activity.

Main Results:

• GM-CSF neutralization did not affect M. tuberculosis bacterial burden but increased granuloma numbers in wild-type mice.
• In TNFα-deficient mice, GM-CSF neutralization compromised bacterial control during sub-optimal isoniazid/rifampicin treatment, leading to exacerbated lung inflammation.
• In vitro, GM-CSF neutralization promoted an M2 anti-inflammatory macrophage phenotype, reducing nitric oxide (NO) production and increasing intracellular M. bovis BCG burden.

Conclusions:

• GM-CSF pathway overexpression during acute M. tuberculosis infection supports an effective M1 inflammatory response.
• Interfering with the GM-CSF pathway during infection may impair the host's inflammatory response against M. tuberculosis.
• GM-CSF neutralization's impact varies depending on host immune status and treatment context.