THP-1 Monocytes Up-Regulate Intercellular Adhesion Molecule 1 in Response to Pneumolysin fromStreptococcus pneumoniae

Abstract

Pneumolysin (PLY) is a major virulence factor of Streptococcus pneumoniae that elicits a variety of proinflammatory responses from cells of the host immune system. Intercellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule involved in leukocyte trafficking toward inflammatory stimuli in extravascular sites. In this study, we evaluated the effect of PLY on expression of ICAM-1 in THP-1 monocytic cells exposed to S. pneumoniae. Exposure of cells to PLY-expressing S. pneumoniae strain WU2 for 6 h led to significantly higher levels of ICAM-1 message than those in cells exposed to either medium alone or ⌬PLY1, a PLY-negative isogenic mutant of WU2. Cells exposed to purified recombinant PLY also showed a dose-dependent increase in ICAM-1 mRNA compared to cells exposed to medium alone. Exposure to recombinant PLY containing a single amino acid substitution (Trp4333Phe) that decreases cytolytic activity did not increase ICAM-1 mRNA to levels seen with wild-type PLY. In addition, THP-1 cells exposed to wild-type strain WU2 or D39 had increased ICAM-1 on their surface compared to cells exposed to medium alone or their PLY-negative isogenic mutants ⌬PLY1 and ⌬PLY2, respectively. These data indicate that PLY induces transcription and production of a cell adhesion molecule involved in the inflammatory response that may play a role in pneumococcal infection.

Pneumococcal Virulence Gene Expression and Host Cytokine Profiles during Pathogenesis of Invasive Disease

“…With regard to the host innate immune response, all the tested host molecules were significantly upregulated, especially in the lungs, blood, and brain tissues of mice infected by the three strains. The response most likely corresponds to the intense inflammation usually observed during severe pneumococcal pneumonia in humans, which often leads to tissue injury, shock, and death (4,15,16,26,71,73). The expression of TNF-␣ is important for surviving pneumococcal infection but may also cause inflammatory host injury under certain conditions (61).…”

“…Indeed, Ply has been shown to activate murine macrophages (27), resulting in the secretion of TNF-␣ and IL-6, proposed to occur through Toll-like receptor 4 signaling (36). Ply also stimulates expression of TNF-␣ and IL-1 from monocytes (25), as well as that of CD54, an important component of the leukocyte-trafficking system (71). Surprisingly, CD54 expression was significantly downregulated in the lungs of WCH16-infected mice and was not significantly upregulated in the blood.…”

Pneumolysin, PspA, and PspC Contribute to Pneumococcal Evasion of Early Innate Immune Responses during Bacteremia in Mice

“…Also, Ply, PspA, and PspC expression resulted in C3 degradation in vitro and in vivo. Finally, blood clearance assays demonstrated that there was enhanced clearance of ⌬ply PspA ؊ PspC ؊ pneumococci compared to the clearance of nonencapsulated pneumococci.Streptococcus pneumoniae possesses virulence factors that function in evasion of complement (3,(27)(28)(29). The capsular polysaccharide (CPS) is considered a key factor in complement resistance (13,21), and the interaction of pneumococci with complement varies according to the CPS type (1,15,19).…”

“…The capsular polysaccharide (CPS) is considered a key factor in complement resistance (13,21), and the interaction of pneumococci with complement varies according to the CPS type (1,15,19). Ply can activate the classical pathway, diverting complement activation (26,29). Pneumococcal surface protein A (PspA) can also interfere with complement deposition, blocking recruitment of alternative pathway (AP) proteins (4, 24).…”

“…The pneumococci used are listed in Table 1 and include R36A, D39, and isogenic mutants of D39. LM91, TRE108, and TRE121 are insertion-duplication mutants, and ⌬PLY2 and ⌬PAC (generated for this study by deleting ply of TRE121) were generated by allelic replacement (29). Bacteria were grown to mid-log phase as described previously (22).…”