The L-lactate dehydrogenase LldD contributes to oxidative stress resistance, survival from neutrophils, and host colonization in Neisseria gonorrhoeae

TL;DR

The LldD enzyme helps Neisseria gonorrhoeae resist oxidative stress and survive in the host, contributing to its ability to cause infection.

Contribution

LldD is identified as a novel key factor for oxidative stress resistance and host colonization in Neisseria gonorrhoeae.

Findings

LldD enhances resistance to reactive oxygen species in Neisseria gonorrhoeae.

LldD is essential for host colonization in a murine model of gonorrhea.

LldD and LutACB have non-redundant roles in fitness during co-colonization with neutrophils.

Abstract

Metabolic adaptation to the host environment is a key determinant of bacterial pathogenesis, enabling both colonization and invasive disease. This is particularly true for Neisseria gonorrhoeae (Gc), the causative agent of gonorrhea, which lacks effector-injecting secretion systems or toxins. Gc infection triggers a rapid influx of neutrophils (polymorphonuclear cells [PMNs) that typically kill bacteria through multiple mechanisms, including a potent oxidative burst. Despite this, Gc exhibits remarkable resistance to reactive oxygen species and readily replicates in the presence of PMNs, which is in part due to the consumption of PMN-derived lactate. Previous studies demonstrated that the lactate permease, LctP, is required for oxidative stress resistance in Gc and host colonization in a murine model of gonorrhea, suggesting that lactate utilization contributes to virulence. Gc encodes four lactate dehydrogenases (LDHs) with distinct regulation and mechanisms, including two L-LDHs, LldD and LutACB. Although either enzyme alone supports L-lactate utilization, we found that both are required for full fitness during co-colonization with PMNs, indicating some non-redundant roles. Furthermore, LldD enhances oxidative stress resistance and is required for Gc colonization in a murine model of gonorrhea, whereas LutACB is dispensable. These findings identify LldD as a key factor promoting oxidative stress resistance, survival during PMN challenge, and host colonization.

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