Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone

Lawres, Lauren; Garg, Aayushi; Kumar, Vidya P.; Bruzual, Igor; Forquer, Isaac; Renard, Isaline; Virji, Azan Z.; Boulard, P; Rodriguez, Eduardo X.; Allen, Anita L.; Pou, Sovitj; Wegmann, Keith W.; Winter, R.; Nilsen, Aaron; Mao, Jialing; Preston, Douglas A.; Belperron, Alexia A.; Bockenstedt, Linda K.; Hinrichs, David J.; Riscoe, Michael K.; Doggett, J. Stone; Mamoun, Choukri Ben

doi:10.1084/jem.20151519

Cited by 81 publications

(115 citation statements)

References 49 publications

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“…with 10 6 B. microti-infected RBCs. As a control, another group of 5 BALB/c females were injected with B. microti-infected erythrocytes but also were subjected to combination therapy (atovaquone plus ELQ-334, 10 mg/kg each, daily for 7 days starting at day 4 postinfection), as described previously (20). Smears, serum samples, and plasma samples were collected prior to infection and every 4 days postinfection for 42 days.…”

Section: Methodsmentioning

confidence: 99%

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection

Mootien¹,

Lawres

Perrin

et al. 2018

J Clin Microbiol

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Human babesiosis is an emerging zoonotic infectious disease caused by intraerythrocytic protozoan parasites of the genus Most cases of human babesiosis are caused by and often manifest in individuals over the age of 50 years or in patients with a compromised immune system. Patients who develop symptomatic infections usually experience months of asymptomatic infection after the acute infection has resolved. About one-fifth of-infected adults never develop symptoms. These asymptomatically infected individuals sometimes donate blood and thus can transmit through blood transfusion. Current assays for detection of active infections can be used to screen donor blood prior to transfusion, but they rely primarily on microscopy or PCR methods, which have sensitivity and technical limitations. Here we report the development of an antigen capture enzyme-linked immunosorbent assay (BmGPAC) based on a major secreted immunodominant antigen of (BmGPI12/BmSA1), and we provide evidence that this assay is superior for detection of active infections, compared to available microscopy methods and serological assays. The assay has been evaluated using supernatants of -infected erythrocytes cultured, sera from -infected laboratory mice, and sera from wild mice and human patients. Our data suggest that the BmGPAC assay is a reliable assay for detection of active infections and is superior to real-time PCR and antibody assays for diagnosis of acute infections, screening of the blood supply, and epidemiological surveys of humans and animal reservoir hosts.

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Section: Methodsmentioning

confidence: 99%

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection

Mootien¹,

Lawres

Perrin

et al. 2018

J Clin Microbiol

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“…Furthermore, the mechanism by which these drugs exert their anti- Babesia activity has only recently begun to be elucidated. Recent studies using a short-term in vitro culture as well as immunocompromised mice have shown that, of the four drugs used for treatment of human babesiosis, only atovaquone shows efficacy against the parasite in mouse red blood cells both in vitro and in vivo 11. These results, along with the shortcomings of available diagnostic tools to distinguish between past and active infection to prevent transfusion-transmitted babesiosis, have stimulated efforts to improve therapies and diagnostics111213141516171819.…”

mentioning

confidence: 99%

Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions

Silva

Cornillot

McCracken

et al. 2016

Sci Rep

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Babesia microti, a tick-transmitted, intraerythrocytic protozoan parasite circulating mainly among small mammals, is the primary cause of human babesiosis. While most cases are transmitted by Ixodes ticks, the disease may also be transmitted through blood transfusion and perinatally. A comprehensive analysis of genome composition, genetic diversity, and gene expression profiling of seven B. microti isolates revealed that genetic variation in isolates from the Northeast United States is almost exclusively associated with genes encoding the surface proteome and secretome of the parasite. Furthermore, we found that polymorphism is restricted to a small number of genes, which are highly expressed during infection. In order to identify pathogen-encoded factors involved in host-parasite interactions, we screened a proteome array comprised of 174 B. microti proteins, including several predicted members of the parasite secretome. Using this immuno-proteomic approach we identified several novel antigens that trigger strong host immune responses during the onset of infection. The genomic and immunological data presented herein provide the first insights into the determinants of B. microti interaction with its mammalian hosts and their relevance for understanding the selective pressures acting on parasite evolution.

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“…The Lys228-Met substitution in S. cerevisiae, which is analogous to position 222 in the T. gondii cytochrome b, confers resistance to antimycin, and cocrystallization of antimycin with Bos taurus cytochrome b has shown that the analogous Lys227 forms a key bond with antimycin via a water molecule (16,19). In addition, a serine-to-tyrosine substitution at the same position in B. microti was associated with the development of ELQ-271 resistance in vivo (13). The degree of resistance associated with Thr222-Pro is consistent with Q i site inhibition being the primary mechanism of action of ELQ-316.…”

Section: Discussionmentioning

confidence: 99%

“…ELQs are efficacious against malaria, babesiosis, and acute and latent experimental toxoplasmosis (11)(12)(13). Among the large panel of ELQs that we have synthesized, ELQ-316 was found to have the greatest efficacy against T. gondii and did not inhibit human cytochrome bc 1 at concentrations up to 10 M. Previous genetic mutations in Saccharomyces cerevisiae and Plasmodium falciparum suggest that ELQ-271 and ELQ-300, respectively, inhibit the apicomplexan cytochrome bc 1 Q i site (10,12,14).…”

mentioning

confidence: 88%

Genetic Evidence for Cytochrome b Q _i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

Alday

Bruzual

Nilsen

et al. 2017

Antimicrob Agents Chemother

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Toxoplasma gondii is an apicomplexan parasite that causes fatal and debilitating brain and eye disease. Endochinlike quinolones (ELQs) are preclinical compounds that are efficacious against apicomplexan-caused diseases, including toxoplasmosis, malaria, and babesiosis. Of the ELQs, ELQ-316 has demonstrated the greatest efficacy against acute and chronic experimental toxoplasmosis. Although genetic analyses in other organisms have highlighted the importance of the cytochrome bc 1 complex Q i site for ELQ sensitivity, the mechanism of action of ELQs against T. gondii and the specific mechanism of ELQ-316 remain unknown. Here, we describe the selection and genetic characterization of T. gondii clones resistant to ELQ-316. A T. gondii strain selected under ELQ-316 drug pressure was found to possess a Thr222-Pro amino acid substitution that confers 49-fold resistance to ELQ-316 and 19-fold resistance to antimycin, a well-characterized Q i site inhibitor. These findings provide further evidence for ELQ Q i site inhibition in T. gondii and greater insight into the interactions of Q i site inhibitors with the apicomplexan cytochrome bc 1 complex.

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Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone

Abstract: Human babesiosis is a tick-borne multisystem disease, and current treatments have both adverse side effects and a significant rate of drug failure. Lawres et al. report that endochin-like quinolones, in combination with atovaquone, cure experimental babesiosis in immunodeficient mice.

Cited by 81 publications

References 49 publications

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection

Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions

Genetic Evidence for Cytochrome b Q _i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

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Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone

Abstract: Human babesiosis is a tick-borne multisystem disease, and current treatments have both adverse side effects and a significant rate of drug failure. Lawres et al. report that endochin-like quinolones, in combination with atovaquone, cure experimental babesiosis in immunodeficient mice.

Cited by 81 publications

References 49 publications

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection

BmGPAC, an Antigen Capture Assay for Detection of Active Babesia microti Infection

Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions

Genetic Evidence for Cytochrome b Q i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

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Genetic Evidence for Cytochrome b Q _i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii