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Listeria monocytogenes CadC Regulates Cadmium Efflux and Fine-tunes Lipoprotein Localization to Escape the Host
Rita Pombinho1,2,3, Ana Camejo1,2,3, Ana Vieira1,3
1Instituto de Investigação e Inovação em Saúde and.
Abstract:
Listeria monocytogenes is a major intracellular human foodborne bacterial pathogen. We previously revealed L. monocytogenes cadC as highly expressed during mouse infection. Here we show that L. monocytogenes CadC is a sequence-specific, DNA-binding and cadmium-dependent regulator of CadA, an efflux pump conferring cadmium resistance. CadC but not CadA is required for L. monocytogenes infection in vivo. Interestingly, CadC also directly represses lspB, a gene encoding a lipoprotein signal peptidase whose expression appears detrimental for infection. lspB overexpression promotes the release of the LpeA lipoprotein to the extracellular medium, inducing tumor necrosis factor α and interleukin 6 expression, thus impairing L. monocytogenes survival in macrophages. We propose that L. monocytogenes uses CadC to repress lspB expression during infection to avoid LpeA exposure to the host immune system, diminishing inflammatory cytokine expression and promoting intramacrophagic survival and virulence. CadC appears as the first metal efflux pump regulator repurposed during infection to fine-tune lipoprotein processing and host responses.
Insights
Listeria monocytogenes CadC regulates bacterial virulence by repressing lspB, a gene detrimental to infection. This mechanism helps the pathogen evade immune responses and survive within macrophages.
Area of Science:
- Microbiology
- Bacterial Pathogenesis
- Molecular Biology
Background:
- Listeria monocytogenes is a significant foodborne pathogen causing intracellular infections.
- The bacterial gene cadC was previously found to be highly expressed during mouse infection.
Purpose of the Study:
- To investigate the function of L. monocytogenes CadC during infection.
- To elucidate the regulatory role of CadC in bacterial virulence and host interaction.
Main Methods:
- DNA-binding assays to determine CadC's regulatory mechanism.
- In vivo infection models to assess the requirement of CadC and CadA.
- Gene expression analysis of lspB and related host immune responses.
Main Results:
- CadC is a sequence-specific, DNA-binding, cadmium-dependent regulator of the CadA efflux pump.
- CadC, but not CadA, is essential for L. monocytogenes infection in vivo.
- CadC represses lspB, encoding a lipoprotein signal peptidase, which is detrimental to infection when overexpressed.
- lspB overexpression leads to extracellular LpeA release, inducing inflammatory cytokines (TNF-α, IL-6) and impairing macrophage survival.
Conclusions:
- L. monocytogenes utilizes CadC to repress lspB during infection, preventing detrimental LpeA exposure and subsequent inflammatory responses.
- This repression by CadC promotes intramacrophagic survival and enhances bacterial virulence.
- CadC represents a novel example of a metal efflux pump regulator repurposed for controlling lipoprotein processing and host immune evasion during infection.