Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens

Cockburn, Chelsea L.; Green, Ryan S.; Damle, Sheela R.; Martin, Rebecca; Ghahrai, Naomi N.; Colonne, Punsiri M.; Fullerton, Marissa S.; Conrad, Daniel H.; Chalfant, Charles E.; Voth, Daniel E.; Rucks, Elizabeth A.; Gilk, Stacey D.; Carlyon, Jason A.

doi:10.26508/lsa.201800292

Cited by 21 publications

(23 citation statements)

References 84 publications

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“…For example, A. phagocytophilum targets flotillins and Neimann-Pick type C1 (NPC1)-bearing vesicles to redirect cholesterol to bacterial inclusions ( Xiong and Rikihisa, 2012 ; Xiong et al, 2019 ). It was also shown that inhibiting cholesterol efflux from lysosomes halts A. phagocytophilum infection, further demonstrating their dependence on host cholesterol ( Cockburn et al, 2019 ).…”

Section: Intracellular Growthmentioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

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Vector-borne illnesses comprise a significant portion of human maladies, representing 17% of global infections. Transmission of vector-borne pathogens to mammals primarily occurs by hematophagous arthropods. It is speculated that blood may provide a unique environment that aids in the replication and pathogenesis of these microbes. Lipids and their derivatives are one component enriched in blood and are essential for microbial survival. For instance, the malarial parasite Plasmodium falciparum and the Lyme disease spirochete Borrelia burgdorferi, among others, have been shown to scavenge and manipulate host lipids for structural support, metabolism, replication, immune evasion, and disease severity. In this Review, we will explore the importance of lipid hijacking for the growth and persistence of these microbes in both mammalian hosts and arthropod vectors.

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Section: Intracellular Growthmentioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

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“…Endogenous cationic sphingoid bases such as sphingosine and sphinganine inhibit the catabolism of ganglioside GM2 [46], of glucosylceramide [43] at a posttranslational level and presumably also that of SM in ASMD. Many antidepressant drugs such as desipramine and other CADs or synthetic cationic lipids can act as so called "functional inhibitors of ASM" (FIASMAs) [109] (Figure 3A) which is little misleading because it incorrectly implies an ASM specific effect. Due to their physicochemical properties, CADs can easily reach and enter the acidic compartments and accumulate there up to rather high concentrations, thereby significantly increasing the luminal pH value.…”

Section: Activation and Inhibition Of Asmmentioning

confidence: 99%

“…On the other hand, the functional inhibition of ASM activity stops infection cycles of vacuole adapted bacteria such as Anaplasma-phagocytophilum, Chlamydia trachomatis, and Chlamydia pneumoniae or even kills Coxiella burnettii [109,178]. ASM is also an essential regulator of mucosal immunity to enteric pathogens.…”

Section: The Role Of Asm In Bacterial Mycobacterial Fungal and Viral Infectionsmentioning

confidence: 99%

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden¹,

Sandhoff

2021

IJMS

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Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.

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“…Activation of surface receptor (CD95) leads to the translocation of these enzymes from its intracellular location to the sphingomyelin lipid-rich plasma membrane during apoptosis [46,47]. A study by Cockburn et al [48] revealed that mutations in the asmase gene affect the enzyme function, which depletes the efflux of low-density lipoprotein-cholesterol required by vacuole-adapted intracellular pathogens.…”

Section: Role Of Smases In Metabolic Pathwaysmentioning

confidence: 99%

Sphingomyelinases in a journey to combat arthropod‐borne pathogen transmission

2021

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Ixodes scapularis ticks feed on humans and other vertebrate hosts and transmit several pathogens of public health concern. Tick saliva is a complex mixture of bioactive proteins, lipids and immunomodulators, such as I. scapularis sphingomyelinase (IsSMase)-like protein, an ortholog of dermonecrotoxin SMase D found in the venom of Loxosceles spp. of spiders. IsSMase modulates the host immune response towards Th2, which suppresses Th1-mediated cytokines to facilitate pathogen transmission. Arboviruses utilize exosomes for their transmission from tick to the vertebrate host, and exosomes derived from tick saliva/salivary glands suppress C-X-C motif chemokine ligand 12 and interleukin-8 immune response(s) in human skin to delay wound healing and repair processes. IsSMase affects also viral replication and exosome biogenesis, thereby inhibiting tick-to-vertebrate host transmission of pathogenic exosomes. In this review, we elaborate on exosomes and their biogenesis as potential candidates for developing novel control measure(s) to combat tickborne diseases. Such targets could help with the development of an efficient anti-tick vaccine for preventing the transmission of tick-borne pathogens.

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Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens

Abstract: Many intracellular pathogens hijack cholesterol. Inhibiting acid sphingomyelinase alters cholesterol traffic to target different intracellular bacteria, signifying a host-directed approach for treating infectious disease.

Cited by 21 publications

References 84 publications

Lipid hijacking: A unifying theme in vector-borne diseases

Lipid hijacking: A unifying theme in vector-borne diseases

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Sphingomyelinases in a journey to combat arthropod‐borne pathogen transmission

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