Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular

By Jason H. Melehani, David B. A. James, Ashley L. DuMont, Victor J. Torres, J. Duncan. 2015

131 citations recorded by the source corpus.

Staphylococcus aureus infections are a growing health burden worldwide, and paramount to this bacterium’s pathogenesis is the production of virulence factors, including pore-forming leukotoxins. Leukocidin A/B (LukAB) is a recently discovered toxin that kills primary human phagocytes, though the underlying mechanism of cell death is not understood. We demonstrate here that LukAB is a major contributor to the death of human monocytes. Using a variety of in vitro and ex vivo intoxication and infection models, we found that LukAB activates Caspase 1, promotes IL-1β secretion and induces necrosis in human monocytes. Using THP1 cells as a model for human monocytes, we found that the inflammasome components NLRP3 and ASC are required for LukAB-mediated IL-1β secretion and necrotic cell death. S. aureus was shown to kill human monocytes in a LukAB dependent manner under both extracellular and intracellular ex vivo infection models. Although LukAB-mediated killing of THP1 monocytes from extracellular S. aureus requires ASC, NLRP3 and the LukAB-receptor CD11b, LukAB-mediated killing from phagocytosed S. aureus is independent of ASC or NLRP3, but dependent on CD11b. Altogether, this study provides insight into the nature of LukAB-mediated killing of human monocytes. The discovery that S. aureus LukAB provokes differential host responses in a manner dependent on the cellular contact site is critical for the development of anti-infective/anti-inflammatory therapies that target the NLRP3 inflammasome.

Subfields: Immunology, Infectious Diseases, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Victor J. Torres
2. Francis Alonzo
3. Tamara Reyes-Robles

In Infectious Diseases

1. Victor J. Torres
2. Francis Alonzo
3. Tamara Reyes-Robles
4. Ashira Lubkin
5. Bo Shopsin
6. Xuhui Zheng

In Molecular Biology

1. Victor J. Torres
2. Francis Alonzo
3. Tamara Reyes-Robles
4. Bo Shopsin
5. Sergei B Koralov

Citations in the corpus

• Identification of biologic agents to neutralize the bicomponent leukocidins of Staphylococcus aureus (2019, background): “aureus to kill phagocytes following phagocytosis, a process mediated by targeting of CD11b in the phagosome (16, 25, 26).”
• Staphylococcus aureus Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin (2019, background): “LukAB targets CD11b for lysis of human PMNs and monocytes (24, 25).”
• Staphylococcus aureus leukocidins target endothelial DARC to cause lethality in mice (2019, background): “As the leukocidins activate the NLRP3 inflammasome (Holzinger et al., 2012; Mariathasan et al., 2006; Melehani et al., 2015), and systemic inflammasome activation can lead to a similar rapid lethality phenotype (von Moltke et al.”