<i>Galleria mellonella</i> as an Insect Model for <i>P. destructans</i>, the Cause of White-Nose Syndrome in Bats

Beekman, Chapman; Meckler, Lauren; Kim, Eleanor

doi:10.1101/244921

Cited by 5 publications

(2 citation statements)

References 46 publications

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“…2 At the same time, significant advances in host−pathogen biology and immunology have refined our appreciation of the limitations of laboratory media with regard to modeling the microenvironment experienced by microbes during infection. 3,4 As the fields of host−pathogen biology and antibiotic discovery converge, investigators have been developing screening platforms that rely upon cell 5−8 or whole-animal infection 9,10 to identify new compounds that disrupt the host−pathogen relationship. 11 Among microbial pathogens, Gram-negative bacteria are particularly difficult to treat because of their distinctive physiology.…”

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confidence: 99%

Clofazimine Reduces the Survival of Salmonella enterica in Macrophages and Mice

et al. 2020

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Drug resistant pathogens are on the rise, and new treatments are needed for bacterial infections. Efforts toward antimicrobial discovery typically identify compounds that prevent bacterial growth in microbiological media. However, the microenvironments to which pathogens are exposed during infection differ from rich media and alter the biology of the pathogen. We and others have therefore developed screening platforms that identify compounds that disrupt pathogen growth within cultured mammalian cells. Our platform focuses on Gram-negative bacterial pathogens, which are of particular clinical concern. We screened a panel of 707 drugs to identify those with efficacy against Salmonella enterica Typhimurium growth within macrophages. One of the drugs identified, clofazimine (CFZ), is an antibiotic used to treat mycobacterial infections that is not recognized for potency against Gram-negative bacteria. We demonstrated that in macrophages CFZ enabled the killing of S. Typhimurium at single digit micromolar concentrations, and in mice, CFZ reduced tissue colonization. We confirmed that CFZ does not inhibit the growth of S. Typhimurium and E. coli in standard microbiological media. However, CFZ prevents bacterial replication under conditions consistent with the microenvironment of macrophage phagosomes, in which S. Typhimurium resides during infection: low pH, low magnesium and phosphate, and the presence of certain cationic antimicrobial peptides. These observations suggest that in macrophages and mice the efficacy of CFZ against S. Typhimurium is facilitated by multiple aspects of soluble innate immunity. Thus, systematic screens of existing drugs for infection-based potency are likely to identify unexpected opportunities for repurposing drugs to treat difficult pathogens.

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confidence: 99%

Clofazimine Reduces the Survival of Salmonella enterica in Macrophages and Mice

et al. 2020

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“…More in-depth experiments will be needed to discern the outcome of PdPV-1 infection on P. destructans phenotype and virulence. These investigations will be facilitated by the recent availability of a molecular tool kit and experimental infection model of P. destructans [46][47][48][49][50][51] .…”

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confidence: 99%

A common partitivirus infection in United States and Czech Republic isolates of bat white-nose syndrome fungal pathogen Pseudogymnoascus destructans

Ren

Rajkumar

Zhang

et al. 2020

Sci Rep

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the psychrophilic (cold-loving) fungus Pseudogymnoascus destructans was discovered more than a decade ago to be the pathogen responsible for white-nose syndrome, an emerging disease of North American bats causing unprecedented population declines. The same species of fungus is found in Europe but without associated mortality in bats. We found P. destructans was infected with a mycovirus [named Pseudogymnoascus destructans partitivirus 1 (PdPV-1)]. The virus is bipartite, containing two double-stranded RNA (dsRNA) segments designated as dsRNA1 and dsRNA2. The cDNA sequences revealed that dsRNA1 dsRNA is 1,683 bp in length with an open reading frame (ORF) that encodes 539 amino acids (molecular mass of 62.7 kDa); dsRNA2 dsRNA is 1,524 bp in length with an ORF that encodes 434 amino acids (molecular mass of 46.9 kDa). The dsRNA1 ORF contains motifs representative of RNA-dependent RNA polymerase (RdRp), whereas the dsRNA2 ORF sequence showed homology with the putative capsid proteins (CPs) of mycoviruses. Phylogenetic analyses with PdPV-1 RdRp and CP sequences indicated that both segments constitute the genome of a novel virus in the family Partitiviridae. The purified virions were isometric with an estimated diameter of 33 nm. Reverse transcription pcR (Rt-pcR) and sequencing revealed that all US isolates and a subset of czech Republic isolates of P. destructans were infected with PdPV-1. However, PdPV-1 appears to be not widely dispersed in the fungal genus Pseudogymnoascus, as non-pathogenic fungi P. appendiculatus (1 isolate) and P. roseus (6 isolates) tested negative. P. destructans PdPV-1 could be a valuable tool to investigate fungal biogeography and the host-pathogen interactions in bat WNS. The fungus Pseudogymnoascus destructans (previously named as Geomyces destructans) is a psychrophilic (cold-loving) fungus responsible for the white-nose syndrome (WNS) in bat populations in North America 1-3. This newly discovered pathogen has directly or indirectly caused the death of more than 5.7 million bats since 2006 4,5. P. destructans was found to infect at least eleven species of bats, of which seven species exhibited disease

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The Use of Galleria mellonella Larvae to Identify Novel Antimicrobial Agents against Fungal Species of Medical Interest

Kavanagh

Sheehan

2018

JoF

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The immune system of insects and the innate immune response of mammals share many similarities and, as a result, insects may be used to assess the virulence of fungal pathogens and give results similar to those from mammals. Larvae of the greater wax moth Galleria mellonella are widely used in this capacity and also for assessing the toxicity and in vivo efficacy of antifungal drugs. G. mellonella larvae are easy to use, inexpensive to purchase and house, and have none of the legal/ethical restrictions that are associated with use of mammals. Larvae may be inoculated by intra-hemocoel injection or by force-feeding. Larvae can be used to assess the in vivo toxicity of antifungal drugs using a variety of cellular, proteomic, and molecular techniques. Larvae have also been used to identify the optimum combinations of antifungal drugs for use in the treatment of recalcitrant fungal infections in mammals. The introduction of foreign material into the hemocoel of larvae can induce an immune priming effect which may operate independently with the activity of the antifungal drug. Procedures to identify this effect and limit its action are required.

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Galleria mellonella as an Insect Model for P. destructans, the Cause of White-Nose Syndrome in Bats

Cited by 5 publications

References 46 publications

Clofazimine Reduces the Survival of Salmonella enterica in Macrophages and Mice

Clofazimine Reduces the Survival of Salmonella enterica in Macrophages and Mice

A common partitivirus infection in United States and Czech Republic isolates of bat white-nose syndrome fungal pathogen Pseudogymnoascus destructans

The Use of Galleria mellonella Larvae to Identify Novel Antimicrobial Agents against Fungal Species of Medical Interest

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