A Role for Complement C5 in Organism Containment and Granulomatous Response during Murine Tuberculosis

Abstract

The molecular mechanisms underlying protective granuloma formation and control of bacterial growth during infection with Mycobacterium tuberculosis (MTB) are not yet completely understood. MTB-infected mice with natural deficiency in complement component C5 are unable to develop productive granulomatous responses, and are impaired in limiting organism growth within the lung. To address the molecular basis for this histologic dysfunction, congenic complement C5-sufficient (B10.D2-H2d H2-T18c Hcl/nSnJ) and complement C5-deficient 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 messages for multiple inflammatory cytokines in both congenic strains. Interleukin (IL)-12(p40) mRNA was also induced during infection in C5-deficient mice, although levels were significantly decreased compared to C5-sufficient congenics. C5-deficient mice also demonstrated reduced KC, MIP-2, IP-10, and MCP-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-1a and MIP-2 compared to C5-sufficient macrophages following in vitro infection. These findings indicate a role for C5 in mediation of chemotactic and activation events that are the basis for granulomatous responses during murine tuberculosis.

Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines

“…Granulomas are considered critical for containment of M. tuberculosis; in numerous experimental models, control of M. tuberculosis infection depended on granuloma formation [44,[51][52][53][54][55]. Our results argue against a strict correlation between control of M. tuberculosis and granulomatous pulmonary tissue reaction at early time points after infection.…”

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

“…Although tissue specific CFU reduction is a good indicator, the correlation with disease should also be evaluated by histopathology, as controlling pathological damage is key to surviving tuberculosis. Indeed, animals are able to survive with markedly elevated organism loads, provided that protective granulomatous responses occur, allowing sequestration of organisms and localization of inflammatory response [36,59,67]. In these experiments, control of MTB proliferation in the lungs correlated well with formulation of granulomas, with limited presence of complex and activated cellular clusters of macrophages and lymphocytes in the lactoferrin adjuvant groups.…”

“…Bacteria were taken during log phase growth, resuspended in 1x PBS, sonicated for 10 seconds to dislodge any clumping that might have occurred. Organisms were diluted in 1x PBS and aerosolized using an inhalation exposure system (IES) (GLAS-COL Model #A4212 099c Serial #377782) [36].…”

The Reduced Bactericidal Function of Complement C5-Deficient Murine Macrophages Is Associated with Defects in the Synthesis and Delivery of Reactive Oxygen Radicals to Mycobacterial Phagosomes

“…C5a is a known chemoattractant for monocytes, dendritic cells, and T cells, and has been found to induce maturation of DCs (24,61,62). We demonstrated earlier that C5-deficient mice had defective formation of lung granulomas during tuberculosis (9). C5-deficient SWR mice have also been found to have a defective influx of T cells into the lungs after MTB infection (11).…”

“…Ϫ/Ϫ mice were more susceptible to tuberculosis (9). C5-deficient DBA/2 and SWR strains were subsequently found to be hyper susceptible to tuberculosis (10,11).…”