The Differential Roles of LFA-1 and Mac-1 in Host Defense Against Systemic Infection with Streptococcus pneumoniae

Abstract

Mice deficient in CD18, which lack all four CD11 integrins, have leukocytosis and increased susceptibility to bacterial infection. To determine the effect of deficiencies in LFA-1 (CD11a/CD18) or Mac-1 (CD11b/CD18) on host defense against systemic bacterial infection, knockout mice were inoculated i.p. with Streptococcus pneumoniae. Increased mortality occurred in both LFA-1−/− (15 of 17 vs 13 of 35 in wild type (WT), p < 0.01) and Mac-1−/− (17 of 34 vs 6 of 25, p < 0.01) mice. All deaths in LFA-1−/− mice occurred after 72 h, whereas most deaths in Mac-1−/− mice occurred within 24–48 h. At 24 h, 21 of 27 Mac-1−/− mice were bacteremic, vs 15 of 25 WT (p = 0.05); no difference was observed between LFA-1−/− and WT. Increased bacteria were recovered from Mac-1−/− spleens at 2 h (p = 0.03) and 6 h (p = 0.002) and from livers (p = 0.001) by 6 h. No difference was observed at 2 h in LFA-1−/− mice, but by 6 h increased bacteria were recovered from spleens (p = 0.008) and livers (p = 0.04). Baseline and peak leukocyte counts were similar between Mac-1−/− and WT, but elevated in LFA-1−/−. At 8 h, peritoneal neutrophils were increased in Mac-1−/−, but not significantly different in LFA-1−/−. Histopathologically, at 24 h Mac-1−/− animals had bacteremia and lymphoid depletion, consistent with sepsis. LFA-1−/− mice had increased incidence of otitis media and meningitis/encephalitis vs WT at 72 and 96 h. Both Mac-1 and LFA-1 play important but distinct roles in host defense to S. pneumoniae.

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

“…CD18 Ϫ/Ϫ mice lack CR3 and CR4 and have lower expression of CR1/2, which tends to make them more susceptible. In contrast, these mice are predicted to have neutrophilia associated with their lack of LFA-1 (33,34), and we showed that they express elevated levels of anti-pneumococcal Abs. We propose that in CD18 Ϫ/Ϫ mice, the combined benefits of neutrophilia and high protective Ab titers overcomes the detrimental effects of low CR1/2 expression and the absence of CR3 and CR4.…”

“…experiment a serotype 6 pneumococcal strain was used (34), whereas we used a serotype 3 strain. Notably, LFA-1 Ϫ/Ϫ animals reportedly have a higher number of neutrophils in the peripheral blood than WT (33,34), which could also account for their improved resistance to i.v. infection.…”

“…As in this study, others have infected mutant mice with S. pneumoniae to study the contributions to protection made by CR1/2, CR3, CD18, and LFA-1 (19,33,34). These earlier studies focused on the impact of CR1/2 deficiency on the development of protective adaptive immunity or on the effects of CD18, LFA-1, and CR3 on long term survival after i.p.…”

Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1

“…Although LFA-1-deficient mice have deficits in experimental tumor models and increased mortality to gram (ϩ) sepsis with Streptococcus pneumoniae, they exist without apparent spontaneous illness in conventional mouse housing facilities (45,46). Our findings portend several therapeutic implications.…”

Regulation of dextran sodium sulfate induced colitis by leukocyte beta 2 integrins

“…CD11b is also important for innate immune/host defense responses in that loss of CD11b significantly impairs resistance against bacterial challenge. 54,55 Moreover, it has been reported that the severity of DSS colitis is influenced by enteric bacterial; therefore, it could be that genetic loss of CD11b is permissive for bacterial translocation from the colon thereby enhancing disease. 56,57 Blood and mesenteric lymph node cultures from all of the genetic variants in this study were not different from one another, suggesting that bacterial burden is not a mitigating factor for enhanced disease activity in CD11b null mice.…”