A role for complement C5 in organism containment and granulomatous response during murine tuberculosis

The molecular mechanisms underlying protective granuloma formation and cont rol of bacterial growth during infection with Mycobacterium tuberculosis (M TB) are not yet completely understood, MTB-infected mice with natural defic iency in complement component C5 are unable to develop productive granuloma tous responses. and are impaired in limiting organism growth within the lun g. To address the molecular basis for this histologic dysfunction, congenic complement C5-sufficient (B10.D2-H2d H2-T18c Hcl/nSnJ) and complement CS-d eficient strains (B10.D2-H2d H2-T18c Hco/oSnJ) congenic mice were infected with Mycobacterium tuberculosis, and cytokine and chemokine responses were examined. Twelve and 28 days after infection, lungs showed elevated message s for multiple inflammatory cytokines in both congenic strains. Interleukin (IL)-12(p40) mRNA was also induced during infection in CS-deficient mice, although levels were significantly decreased compared to C5-sufficient cong enics. C5-deficient mice also demonstrated reduced KC, MIP-2, IP-10, and MC P-1 mRNA, The defect may directly involve C5-mediated effects on macrophage responses; C5-deficient bone marrow derived macrophages had significantly reduced secretion of KC, MIP-1 alpha and MIP-2 compared to C5-sufficient ma crophages following in vivo infection. These findings indicate a role for C 5 in mediation of chemotactic and activation events that are the basis for granulomatous responses during murine tuberculosis.