Parabens as an Avenue for Prophylaxis of Thrombosis in Lemierre’s Syndrome
Introduction & Hypothesis: Fusobacterium species, especially F. necrophorum, are the causative pathogens of Lemierre’s Syndrome (LS), which is characterized by disseminated intravascular coagulation and septic emboli.1,2 First-line treatment consists of aggressive antibiotic cocktails; the use of anticoagulants remains controversial, and might increase mortality by creating surgical complications.1,2 How Fusobacterium causes thrombosis remains unclear;1 a better understanding of this mechanism could lead to novel treatments. I propose inflammasome dysregulation as a mechanism for coagulation, and an inhibitor of this mechanism (parabens) as an avenue towards a treatment. Methods: Transcription levels of NLRP3 and AIM2 inflammasomes in human cells were measured after exposure to F. nucleatum using RT-PCR, and expression of interleukin-1-β (IL-1β) was quantified via ELISA.3,4 Independently, the effects of Fusobacterium infection on both canonical and noncanonical inflammasome pathways were examined by infection of wild-type and caspase-11 knockout cells (murine bone-marrow derived macrophages) with F. nucleatum in the presence and absence of ATP, again measuring IL-1β with ELISA.5 In an unrelated experiment, researchers exposed wild-type and knockout mice and murine cells (without caspase-1, caspase-11, or gasdermin-D) to type III secretion system (T3SS) rod proteins and LPS as inflammasome triggers, measuring a series of coagulation markers too numerous to list here.6 Additionally, they measured the effects of T3SS and LPS challenge on mice with depleted tissue factor (TF) in microvesicles using an anti-TF antibody.6 In the final experiment of note, IL-1β levels were measured after exposure to inflammasome triggers in mice (in vivo) and murine cells (in vitro), and the effects of pre-treatment with ethylparaben and methylparaben on IL-1β levels quantified.7 Results: Fusobacterium infection activated inflammasome pathways, increasing IL-1β levels.3,4 Caspase-11 knockout cells showed significantly attenuated IL-1β levels after exposure to F. nucleatum, demonstrating activation of the non-canonical pathway.5 Activation of inflammasome pathways increased all markers of coagulation in mice, and this was dependent on gasdermin-D and pyroptosis.6 Parabens inhibited the non-canonical inflammasome pathway in a dose-dependent manner, acting on caspase-11 to prevent cleavage of gasdermin-D.7 Discussion: Non-canonical inflammasome activation may drive disseminated intravascular coagulation in LS, and parabens could represent an avenue for treatment of thrombosis by inhibiting this pathway. Several questions remain unanswered: Is the mechanism causing coagulation the same in F. necrophorum and F. nucleatum? Are parabens similarly effective on human orthologs of caspase-11 (caspases 4 and 5)? What are the side effects of paraben administration, and do they outweigh the benefits (if any) in treatment of LS?
- Gore MR. Lemierre Syndrome: A Meta-analysis. Int Arch Otorhinolaryngol. 2020;24(3):e379-e385. doi:10.1055/s-0039-3402433
- Mesrar H, Mesrar J, Maillier B, Kraoua S, Chapoutot L, Delclaux B. Syndrome de Lemierre: diagnostic, exploration, traitement [Lemierre’s syndrome: Diagnosis, exploration, treatment]. Rev Med Interne. 2018 May;39(5):339-345. French. doi: 10.1016/j.revmed.2017.11.005
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- De Andrade KQ, Almeida-da-Silva CLC, Ojcius DM, Coutinho-Silva R. Differential involvement of the canonical and noncanonical inflammasomes in the immune response against infection by the periodontal bacteria Porphyromonas gingivalis and Fusobacterium nucleatum. Curr Res Microb Sci. 2021;2:100023. Published 2021 Feb 23. doi:10.1016/j.crmicr.2021.100023
- Wu C, Lu W, Zhang Y, Zhang G, Shi X, Hisada Y, Grover SP, Zhang X, Li L, Xiang B, Shi J, Li XA, Daugherty A, Smyth SS, Kirchhofer D, Shiroishi T, Shao F, Mackman N, Wei Y, Li Z. Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis. Immunity. 2019 Jun 18;50(6):1401-1411.e4. doi: 10.1016/j.immuni.2019.04.003.
- Ahn H, Lee H, Lee G, Park J, Sung HW, Lee E, Lee GS. Parabens disrupt non-canonical inflammasome activation. Int Immunopharmacol. 2021 Dec;101(Pt A):108196. doi: 10.1016/j.intimp.2021.108196.