The adaptor molecule CARD9 is essential for tuberculosis control

Area of Science:

• Immunology
• Infectious Diseases
• Molecular Biology

Background:

• Host-pathogen interactions are initiated by pattern recognition receptors (PRRs) triggering signaling cascades.
• Caspase recruitment domain family, member 9 (CARD9) is a cytosolic adaptor protein involved in innate immunity.
• Tuberculosis (TB) is a significant global health challenge requiring a deeper understanding of host defense mechanisms.

Purpose of the Study:

• To investigate the role of CARD9 in the innate immune response to Mycobacterium tuberculosis infection.
• To elucidate the mechanisms by which CARD9 influences host defense and disease progression in TB.

Main Methods:

• Utilized Card9 knockout (Card9(-/-)) mice for aerosol infection with Mycobacterium tuberculosis.
• Assessed mycobacterial burden, lung pathology, immune cell recruitment, and cytokine profiles.
• Investigated the impact of CARD9 deficiency on granulocyte function and T cell responses.
• Employed G-CSF neutralization and neutrophil depletion strategies.

Main Results:

• Card9(-/-) mice exhibited increased susceptibility to TB, characterized by higher bacterial load, pyogranulomatous pneumonia, and accelerated granulocyte recruitment.
• Lethality in Card9(-/-) mice was attributed to exacerbated systemic inflammation, evidenced by elevated pro-inflammatory cytokines and G-CSF.
• CARD9 deficiency impaired IL-10 production by granulocytes, suggesting a loss of anti-inflammatory feedback.
• T cell responses remained largely unaffected, while the hematopoietic compartment showed significant alterations.

Conclusions:

• CARD9 signaling is essential for mounting an effective innate immune response against tuberculosis.
• Dysregulated innate immunity, driven by CARD9 deficiency, leads to excessive lung inflammation and mortality.
• The absence of CARD9 disrupts the anti-inflammatory feedback loop, promoting granulocyte-dominated pathology and uncontrolled bacterial growth.