The role of reactive oxygen intermediates in the intracellular fate of Leptospira interrogans in the macrophages of different hosts

Li, Shijun; Li, Peili; Zhang, Lei; Hu, Weilin; Wang, Ming; Liu, Ying; Tang, Guangpeng; Wang, Dingming; Zhou, Biao; Yan, Jie

doi:10.1371/journal.pone.0178618

Cited by 11 publications

(15 citation statements)

References 40 publications

(70 reference statements)

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“…By opposition, in mice, leptospires do not trigger the recruitment of neutrophils in kidneys [25,15], although they recruit macrophages. Interestingly, a recent study showed that in murine macrophages, most of the killing of leptospires occurred through Reactive Oxygen Species (ROS), whereas L. interrogans barely stimulated ROS production in the THP-1 human macrophage cell line [26]. This is in line with a previous study from the same group showing cytosolic survival of leptospires in human macrophages, although murine macrophages would kill leptospires, present in vesicles [27].…”

Section: Complement/phagocytosis Escapesupporting

confidence: 84%

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

Vernel-Pauillac

Werts

2018

Microbes and Infection

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What are the new approaches and emerging ideas to prevent leptospirosis, a neglected bacterial re-emerging zoonotic disease? How do Leptospira interrogans escape the host defenses? We aim here to review and discuss the most recent literature that provides some answers to these questions, in particular data related to a better understanding of adaptive and innate immunity towards leptospires, and design of vaccines. This is an opinion paper, not a comprehensive review. We will try to highlight the new strategies and technologies boosting the search for drugs and vaccines. We will also address the bottlenecks and difficulties impairing the search for efficient vaccines and the many gaps in our knowledge of immunity against leptospirosis. Finally, we aim to delineate how Leptospira spp. escape the innate immune responses of Toll-Like receptors (TLR) and Nod-Like receptors (NLR). The rational use of TLR and NLR agonists as adjuvants could be key to design future vaccines against pathogenic leptospires.

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Section: Complement/phagocytosis Escapesupporting

confidence: 84%

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

Vernel-Pauillac

Werts

2018

Microbes and Infection

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“… 15 , 50 Our recent study also confirmed that L. interrogans in macrophages could be killed by high level of reactive oxygen species. 51 Rodent animals, the most important host of L. interrogans , have a critical role in transmission of leptospirosis by persistent discharge of leptospires in urine to contaminate environment. 9 , 11 Therefore, we focused on the roles of protein denaturation and denatured protein elimination in survival of L. interrogans in murine macrophages after phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: A leptospiral AAA+ chaperone–Ntn peptidase complex, HslUV, contributes to the intracellular survival of Leptospira interrogans in hosts and the transmission of leptospirosis

Dong

Ojcius

et al. 2017

Emerging Microbes & Infections

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Leptospirosis caused by Leptospira is a zoonotic disease of global importance but it is considered as an emerging or re-emerging infectious disease in many areas in the world. Until now, the mechanisms about pathogenesis and transmission of Leptospira remains poorly understood. As eukaryotic and prokaryotic proteins can be denatured in adverse environments and chaperone–protease/peptidase complexes degrade these harmful proteins, we speculate that infection may also cause leptospiral protein denaturation, and the HslU and HslV proteins of L. interrogans may compose a complex to degrade denatured proteins that enhances leptospiral survival in hosts. Here we show that leptospiral HslUV is an ATP-dependent chaperone–peptidase complex containing ATPase associated with various cellular activity (AAA+) and N-terminal nucleophile (Ntn) hydrolase superfamily domains, respectively, which hydrolyzed casein and chymotrypsin-like substrates, and this hydrolysis was blocked by threonine protease inhibitors. The infection of J774A.1 macrophages caused the increase of leptospiral denatured protein aggresomes, but more aggresomes accumulated in hslUV gene-deleted mutant. The abundant denatured leptospiral proteins are involved in ribosomal structure, flagellar assembly, two-component signaling systems and transmembrane transport. Compared to the wild-type strain, infection of cells in vitro with the mutant resulted in a higher number of dead leptospires, less leptospiral colony-forming units and lower growth ability, but also displayed a lower half lethal dose, attenuated histopathological injury and decreased leptospiral loading in lungs, liver, kidneys, peripheral blood and urine in hamsters. Therefore, our findings confirmed that HslUV AAA+ chaperone–Ntn peptidase complex of L. interrogans contributes to leptospiral survival in hosts and transmission of leptospirosis.

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“…The J774A.1 cell line was shown to produce NADPH oxidase and MPO during infections and on activation by drug treatment in vitro ( 55 , 65 ). Increased ROS levels significantly contributed to the antimicrobial activity and killing of intracellular pathogens by the J774A.1 macrophage cell line ( 54 ). Thus, MerA could be involved in the defense of S. aureus against ROS and HOCl also during macrophage infections.…”

Section: Discussionmentioning

confidence: 99%

Redox-Sensing Under Hypochlorite Stress and Infection Conditions by the Rrf2-Family Repressor HypR inStaphylococcus aureus

Busche

Tedin

et al. 2018

Antioxidants & Redox Signaling

153

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Aims: Staphylococcus aureus is a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections, which requires efficient protection mechanisms to avoid destruction. Here, we have investigated the changes in the RNA-seq transcriptome by the strong oxidant sodium hypochlorite (NaOCl) in S. aureus USA300 to identify novel redox-sensing mechanisms that provide protection under infection conditions.Results: NaOCl stress caused an oxidative stress response in S. aureus as indicated by the induction of the PerR, QsrR, HrcA, and SigmaB regulons in the RNA-seq transcriptome. The hypR-merA (USA300HOU_0588-87) operon was most strongly upregulated under NaOCl stress, which encodes for the Rrf2-family regulator HypR and the pyridine nucleotide disulfide reductase MerA. We have characterized HypR as a novel redox-sensitive repressor that controls MerA expression and directly senses and responds to NaOCl and diamide stress via a thiol-based mechanism in S. aureus. Mutational analysis identified Cys33 and the conserved Cys99 as essential for NaOCl sensing, while Cys99 is also important for repressor activity of HypR in vivo. The redox-sensing mechanism of HypR involves Cys33-Cys99 intersubunit disulfide formation by NaOCl stress both in vitro and in vivo. Moreover, the HypR-controlled flavin disulfide reductase MerA was shown to protect S. aureus against NaOCl stress and increased survival in J774A.1 macrophage infection assays.Conclusion and Innovation: Here, we identified a new member of the widespread Rrf2 family as redox sensor of NaOCl stress in S. aureus that uses a thiol/disulfide switch to regulate defense mechanisms against the oxidative burst under infections in S. aureus. Antioxid. Redox Signal. 29, 615–636.

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The role of reactive oxygen intermediates in the intracellular fate of Leptospira interrogans in the macrophages of different hosts

Abstract: Background

Cited by 11 publications

References 40 publications

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

RETRACTED ARTICLE: A leptospiral AAA+ chaperone–Ntn peptidase complex, HslUV, contributes to the intracellular survival of Leptospira interrogans in hosts and the transmission of leptospirosis

Redox-Sensing Under Hypochlorite Stress and Infection Conditions by the Rrf2-Family Repressor HypR inStaphylococcus aureus

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