The Role of Macrophages in Staphylococcus aureus Infection

Pidwill, Grace R.; Gibson, Josie; Cole, Joby; Renshaw, Stephen A.; Foster, Simon J.

doi:10.3389/fimmu.2020.620339

Cited by 153 publications

(187 citation statements)

References 444 publications

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“…Furthermore, only few S. aureus strains were investigated in a single strain of mice (C57BL/6J), which does not allow for generalizations. However, this study is consistent with and extends previous excellent reports from many other laboratories, who analyzed the interaction of macrophages and S. aureus in great detail (36,37), for review (6,53). In this study, we recapitulated these observations with BMDMs of different genotypes and found no reason to believe that BMDM were fundamentally different to in vivo differentiated macrophages in this context.…”

Section: Discussionsupporting

confidence: 92%

“…Professional phagocytes, especially neutrophils, are crucial for the clearance of the bacteria, as several naturally occurring genetic disorders impairing neutrophil function are associated with an increased incidence and severity of S. aureus infections (4). Similarly, macrophages play a crucial role in the control of S. aureus infection (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…The interaction of S. aureus with macrophages is multifaceted (6, 36, 37). On the one hand, macrophages use a wide array of antimicrobial mechanisms to kill S. aureus (6) and, in the absence of macrophages, bacterial burden and mortality following S. aureus infection are markedly increased (5,(38)(39)(40). On the other hand, S. aureus has evolved multiple strategies to survive within, manipulate and escape from macrophages (6).…”

Section: Introductionmentioning

confidence: 99%

“…On the one hand, macrophages use a wide array of antimicrobial mechanisms to kill S. aureus (6) and, in the absence of macrophages, bacterial burden and mortality following S. aureus infection are markedly increased (5,(38)(39)(40). On the other hand, S. aureus has evolved multiple strategies to survive within, manipulate and escape from macrophages (6). While the majority of phagocytosed S. aureus are killed by macrophages such as Kupffer cells that filter the bloodstream, a small proportion of bacteria survives (12,41).…”

Section: Introductionmentioning

confidence: 99%

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NOX2 Deficiency Permits Sustained Survival of S. aureus in Macrophages and Contributes to Severity of Infection

et al. 2021

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Although the crucial role of professional phagocytes for the clearance of S. aureus infections is well-established, several studies indicate an adverse role of leukocytes in the dissemination of S. aureus during infection. Since only little is known about macrophages in this context, we analyzed the role of macrophages, and in particular reactive oxygen species deficiency, for the seeding of S. aureus metastases. Infection of bone marrow-derived macrophages (BMDM) with S. aureus revealed that NADPH oxidase 2 (NOX2-) deficient, but not NOX1- or NOX4-deficient, BMDM failed to clear intracellular S. aureus. Despite of larger intracellular bacterial burden, NOX2-deficient BMDM showed significantly improved survival. Intravenous injection of mice with in vitro-infected BMDMs carrying intracellular viable S. aureus led to higher bacterial loads in kidney and liver of mice compared to injection with plain S. aureus. An even higher frequency of liver abscesses was observed in mice infected with S. aureus-loaded nox2−/− BMDM. Thus, the improved intracellular survival of S. aureus and improved viability of NOX2-deficient BMDM is associated with an aggravated metastatic dissemination of S. aureus infection. A combination of vancomycin and the intracellularly active antibiotic rifampicin led to complete elimination of S. aureus from liver within 48 h, which was not achieved with vancomycin treatment alone, underscoring the impact of intracellular S. aureus on the course of disease. The results of our study indicate that intracellular S. aureus carried by macrophages are sufficient to establish a systemic infection. This suggests the inclusion of intracellularly active antibiotics in the therapeutic regimen of invasive S. aureus infections, especially in patients with NADPH oxidase deficiencies such as chronic granulomatous disease.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NOX2 Deficiency Permits Sustained Survival of S. aureus in Macrophages and Contributes to Severity of Infection

et al. 2021

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“…Livestock-associated methicillin-resistant S. aureus is a serious problem worldwide. Some S. aureus strains have even developed resistance to the last-resort antibiotic vancomycin, and vaccine candidates have thus far been unsuccessful [ 3 ]. Further elucidation of the immune mechanisms of host resistance to S. aureus skin infection is needed to guide future host-directed therapies.…”

Section: Introductionmentioning

confidence: 99%

GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis

Liu

Yang

Zhou

et al. 2021

Vet Res

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Gasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1β secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1–Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1β production, the critical role of IL-1β was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1β production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus. Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1–Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1–Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.

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Characterization of genetic humanized mice with transgenic HLA DP401 or DRA but deficient in endogenous murine MHC class II genes upon Staphylococcus aureus pneumonia

Niu

Liu

et al. 2023

Anim Models and Exp Med

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BackgroundStaphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in “carrier” or “pathogenic” states. HLADQ and HLADR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLADP to S. aureus infection is unknown yet.MethodsIn this study, we have produced HLADP401 and HLADRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo‐floxed IAβ+/− mice were crossbred with Ella‐Cre and further crossbred with HLADP401 or HLA‐DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ−/− mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108 CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice.ResultsWe evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN‐γ and IL‐6 protein was observed in HLADRA‐IAβ−/− mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLADP401‐IAβ−/− mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ−/− mice and HLA DP401‐IAβ−/− mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ−/− mice and HLA DP401‐IAβ−/− mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ−/− genetic background mice.ConclusionThese humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection.

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The Role of Macrophages in Staphylococcus aureus Infection

Cited by 153 publications

References 444 publications

NOX2 Deficiency Permits Sustained Survival of S. aureus in Macrophages and Contributes to Severity of Infection

NOX2 Deficiency Permits Sustained Survival of S. aureus in Macrophages and Contributes to Severity of Infection

GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis

Characterization of genetic humanized mice with transgenic HLA DP401 or DRA but deficient in endogenous murine MHC class II genes upon Staphylococcus aureus pneumonia

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