The Sialomucin CD43 Drives Tuberculosis Immunopathology Across Different Host Genetic Backgrounds

Tuberculosis (TB) remains a major global health challenge, with 10 million cases and 1.5 million deaths annually. Understanding the interplay between Mycobacterium tuberculosis (Mtb) and the host immune response is essential to better understand TB pathogenesis and develop new therapeutic strategies. Although the host immune bias strongly influences this interaction and shapes the ensuing response, the roles of specific immune receptors remain incompletely understood. Here, we investigated the role of CD43 in shaping the immune microenvironment during Mtb infection using Th2-biased BALB/c and Th1-biased C57BL/6 mice. CD43 deficiency consistently reduced pulmonary inflammation and improved survival in both strains, but through distinct mechanisms. In BALB/c mice, it enhanced early pulmonary cytokine production and promoted a more anti-inflammatory environment during late TB, leading to better control of bacterial growth and limiting the development of pneumonia. In contrast, in C57BL/6 mice, CD43 deficiency delayed pro-inflammatory cytokine responses and reduced the accumulation of inflammatory cells in the lungs, but it did not improve bacterial clearance. Together, these findings indicate that CD43 drives detrimental inflammation in TB through mechanisms that depend on the host immune bias, and highlight the complex and nuanced role of CD43 in regulating immune cell dynamics during TB progression, underscoring the need for tailored therapeutic approaches considering the context-dependent contributions of specific molecules such as CD43.