Role of Macrophages in Host Resistance to Group A Streptococci

Abstract

Macrophages provide the first line of defense against invading pathogens. The aim of this study was to determine the role of macrophages during infection with group A streptococci (Streptococcus pyogenes) in mice. Here, we report that resident macrophages can efficiently take up and kill S. pyogenes during in vivo infection, as demonstrated by immunofluorescence and electron microscopy, as well as colony counts. To evaluate the contribution of macrophages to the resolution of experimental infection with S. pyogenes, we compared the susceptibility of BALB/c mice rendered macrophage deficient by treatment with carrageenan with that of intact mice. The results show that depletion of macrophages enhanced the susceptibility of BALB/c mice to S. pyogenes infection, as evidenced by 100% mortality of macrophage-depleted mice compared to 90% survival of nondepleted control animals. The in vivo depletion of macrophages strongly enhanced bacterial loads in the blood and systemic organs. Resistance to S. pyogenes can be restored in macrophage-depleted mice by adoptive transfer of purified macrophages. The in vivo blocking of the macrophage phagocytic function by treatment with gadolinium III chloride also resulted in enhanced susceptibility to S. pyogenes. Interestingly, depletion of macrophages prior to or during the first 24 h of infection decreased survival dramatically; in contrast, no mortality was observed in infected nondepleted animals or mice depleted after 48 h of infection. These results emphasize the important contribution of macrophages to the early control of S. pyogenes infection.

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

“…Remarkably little information is available also about the signaling pathways triggered by GAS in infected innate immune cells that are known to be required for defense against GAS (22). Here we show that GAS activates p38 MAPK, NF-B, TNF␣, and IL-6 production in infected bone marrow-derived mouse macrophages (BMDMs).…”

“…Activation of both NF-B and p38 MAPK was shown in numerous studies to be essential for production of proinflammatory cytokines (38 -42). Furthermore, macrophages express all components of the TLR signaling cascade and are known to be required for defenses against GAS infection (22). We first compared the activation of p38 MAPK and NF-B in WT and TLR2 Ϫ/Ϫ BMDMs, since many Gram-positive pathogens are recognized by this receptor.…”

Bacterial Superantigens Enhance the In Vitro Proinflammatory Response and In Vivo Lethality of the TLR2 Agonist Bacterial Lipoprotein

“…Depletion of the monocyte/macrophage subpopulation was achieved by using carrageenan as described previously (16,17). Briefly, mice were injected i.p.…”

Systems Biology Approach to Identifying Host Interactive Pathways Modulating the Severity of Streptococcal Sepsis

“…Specifically, we wanted to test the hypothesis that effective innate responses in the early stages of infection is directly associated with resolution of GAS infection, and better outcome of GAS sepsis. We based our hypothesis on studies from our group and other groups that showed that neutrophils (Voyich et al, 2004;Buchanan et al, 2006;Nilsson et al, 2006;Soehnlein et al, 2008a;Navarini et al, 2009), macrophages (Goldmann et al, 2004a;Thulin et al, 2006;Goldmann et al, 2009), NK cells (Goldmann et al, 2005b;Takahashi et al, 2007) and dendritic cells (Loof et al, 2008;Cortes and Wessels, 2009;Yong et al, 2009), each play an important role in streptococcal infections according to the site and the stage of infection. We started our cellular dissection by examining the role of neutrophils in differential susceptibility to GAS sepsis.…”

“…Neutrophils and macrophages play an important role in modulating host responses to GAS sepsis (Goldmann et al, 2004a;Voyich et al, 2004;Medina and Lengeling, 2005). To dissect the role of these cells, we examined the effect of depleting them in vivo on differential mice susceptibility to severe GAS sepsis.…”