Recruited Macrophages Control Dissemination of Group A <i>Streptococcus</i> from Infected Soft Tissues

Mishalian, Inbal; Ordan, Merav; Peled, Amnon; Maly, Alexander; Eichenbaum, Miriam B.; Ravins, Miriam; Aychek, Tegest; Jung, Steffen; Hanski, Emanuel

doi:10.4049/jimmunol.1101385

Cited by 51 publications

(67 citation statements)

References 48 publications

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“…1). Together, these results are in agreement with previous studies showing that subcutaneous injections of clodronate liposomes effectively deplete macrophages in mouse models of skin disorders (49,54,62).…”

Section: Resultssupporting

confidence: 83%

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Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

et al. 2015

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cOuter surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2r␥ null mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis. L yme disease, the most prevalent vector-borne illness in the United States (1), is a multisystem inflammatory disorder caused by infection with the spirochete Borrelia burgdorferi (2, 3). This spirochete is maintained in nature through a complex enzootic cycle involving Ixodes ticks and various small-mammal hosts. Humans, as accidental hosts, become infected after B. burgdorferiinfected ticks feed on them (4). Spirochetes replicate in the skin, spread locally, and induce an inflammatory response with a symptom known as erythema migrans, observed in most patients (2, 4). During disseminated infection, B. burgdorferi colonizes multiple tissues, leading to different clinical manifestations, including arthritis, myocarditis, and neurological and/or cutaneous abnormalities (2, 4). This acute, disseminated stage of human Lyme disease is largely recapitulated using inbred mouse strains which are susceptible to B. burgdorferi infection and develop carditis and subacute arthritis (5). Thus, the murine model provides a powerful tool to elucidate the role of spirochete virulence factors and host immunological responses during Lyme disease pathogenesis (4).The B. burgdorferi genome encodes a large number of surface lipoproteins, many of which are expressed during mammalian infection (4, 6, 7). One of these lipoproteins is the major outer surface protein C (OspC), whose production is induced within inf...

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Section: Resultssupporting

confidence: 83%

“…In order to reduce recruitment of monocytes to the skin, mice were i.p. injected with either clodronate or PBS liposomes 48 h and 96 h postchallenge (49).…”

Section: Methodsmentioning

confidence: 99%

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

et al. 2015

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“…A novel finding of this study is that neutrophils are required for the selection of CovRS mutations. Recruited macrophages play a role in clearance of GAS (43). However, macrophages appear not to play a critical role in the selection of covRS mutations in MGAS2221, since the decrease in the selection of SpeB AϪ variants of MGAS2221 in CXCR2 Ϫ/Ϫ mice is correlated with the impaired neutrophil recruitment but not with the increased levels of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Select Hypervirulent CovRS Mutants of M1T1 Group A Streptococcus during Subcutaneous Infection of Mice

Liu

Feng

et al. 2014

Infect Immun

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A؊ % among recovered GAS were reduced by 95% and 92%, respectively, in subcutaneous MGAS2221 infection of CXCR2 ؊/؊ mice compared with control mice. In air sac infection with MGAS2221, levels of neutrophils and macrophages in lavage fluid were reduced by 49% and increased by 287%, respectively, in CXCR2 ؊/؊ mice compared with control mice, implying that macrophages play an insignificant role in the reduction of selection for SpeB A؊ variants in CXCR2 ؊/؊ mice. One randomly chosen SpeB A؊ mutant outcompeted MGAS2221 in normal mice but was outcompeted by MGAS2221 in neutropenic mice and had enhancements in expression of virulence factors, innate immune evasion, skin invasion, and virulence. This and nine other SpeB A؊ variants from a mouse all had nonsynonymous covRS mutations that resulted in the SpeB A؊ phenotype and enhanced expression of the CovRS-controlled secreted streptococcal esterase (SsE). Our findings are consistent with a model that neutrophils select spontaneous covRS mutations that maximize the potential of GAS to evade neutrophil responses, resulting in variants with enhanced survival and virulence. To our knowledge, this is the first report of the critical contribution of neutrophils to the selection of pathogen variants.

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“…In this model, animals experience spreading necrosis, followed by bacteremia and mortality closely resembling severe necrotizing fasciitis in humans (21,22). We investigated TTP function in this infection model by using TTP ΔM mice, which lack TTP in neutrophils, monocytes, and macrophages (12), all of which are essential for defense against S. pyogenes infection (23)(24)(25)(26). Infection of Ttp fl/fl control animals (referred to herein as TTP fl/fl mice) led to 90% lethality (humane endpoint) 5 days post infection (p.i.…”

Section: Ttp Ablation In Myeloid Cells Protects the Host Against Invamentioning

confidence: 99%

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

Ebner

Sedlyarov

Tasciyan

et al. 2017

Journal of Clinical Investigation

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Recruited Macrophages Control Dissemination of Group A Streptococcus from Infected Soft Tissues

Cited by 51 publications

References 48 publications

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

Neutrophils Select Hypervirulent CovRS Mutants of M1T1 Group A Streptococcus during Subcutaneous Infection of Mice

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

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