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Atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides

Cifuentes Kottkamp, Angelica; De Jesus, Elfie; Grande, Rebecca; Brown, Julia A; Jacobs, Adam R; Lim, Jean K; Stapleford, Kenneth A
Arthropod-borne viruses represent a significant public health threat worldwide yet there are few antiviral therapies or prophylaxis targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy-acceptable antiviral compounds is to repurpose well-known and widely used FDA approved drugs. In this study, we addressed the antiviral role of atovaquone, a FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides indicating that atovaquone is functioning through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women and children.IMPORTANCE The ability to protect vulnerable populations such as pregnant women and children from Zika virus and other arbovirus infections is essential to preventing the devastating complications induced by these viruses. One class of antiviral therapies may lie in known pregnancy-acceptable drugs that have the potential to mitigate arbovirus infections and disease yet this has not been explored in detail. In this study, we show that the common antiparasitic drug, atovaquone, inhibits arbovirus replication through intracellular nucleotide depletion and can impair ZIKV infection in an ex vivo human placental explant model. Our study provides a novel function for atovaquone and highlights that the rediscovery of pregnancy-acceptable drugs with potential antiviral effects can be the key to better addressing the immediate need for treating viral infections and preventing potential birth complications and future disease.
PMID: 30894466
ISSN: 1098-5514
CID: 3735192

Post-chikungunya rheumatic disorders in travelers after return from the Caribbean

Zeana, Cosmina; Kelly, Paul; Heredia, Wilson; Cifuentes, Angelica; Franchin, Giovanni; Purswani, Murli; Tieng, Arlene; Hagmann, Stefan H F
BACKGROUND:Due to increasing concerns about post-chikungunya (pCHIK) rheumatic disorders in Latin America we aimed to evaluate its occurrence in travelers returning to NYC from the Caribbean. METHOD/METHODS:Patients diagnosed with chikungunya (CHIK) during 2014 at the Bronx-Lebanon Hospital Center (Bronx, NewYork) were identified by reviewing laboratory and electronic medical records. Patients and caregivers of pediatric patients were interviewed by phone ≥9 months after the CHIK diagnosis to survey for chronic symptomatology and current health care needs. Reported chronic musculoskeletal complaints were categorized according to validated criteria. RESULTS:A total of 28 patients (54% females, median age [range] of 51.5 [0, 88] years) diagnosed with CHIK at our center were identified. Most (82%) had returned from the Dominican Republic. Nineteen (68%) patients were successfully contacted at a median (range) of 13 (9, 16) months since the acute diagnosis. A third (37%) reported ongoing complaints related to CHIK including joint pain (32%), muscle pain (32%), and joint swelling (26%). A presumptive diagnosis of pCHIK chronic inflammatory arthritis (n = 4) and pCHIK musculoskeletal disorder (n = 3) was established. CONCLUSIONS:A third of travelers with CHIK acquired in the Caribbean may be at risk for developing persistent symptoms suggestive of pCHIK rheumatic disorder.
PMID: 26872414
ISSN: 1873-0442
CID: 3594182

Implementation of universal screening for strongyloidiasis among solid-organ and hematopoietic stem cell transplantation candidates in a non-endemic area [Meeting Abstract]

Kottkamp, A; Mehta, S
Background. Strongyloidiasis can lead to hyperinfection and dissemination afer transplantation with signifcant morbidity and mortality. Treatment for Strongyloidiasis prior to transplantation can reduce the risk of disseminated infection. Targeted screening based on travel history and country of origin incompletely identifes at-risk patients. Data on universal screening prior to solid-organ (SOT) or hematopoietic stem cell transplantation (HSCT) are limited. We implemented universal serology-based screening for strongyloides at our transplant center, located in a metropolitan non-ndemic area. Methods. We identifed patients screened with serum Strongyloides IgG by ELISA during pre-transplant evaluation for SOT or HSCT from August 1, 2017 to April 25, 2018. We reviewed adherence to the screening recommendation by program type and the medical record of seropositive patients for country of origin, history of eosinophilia (>500 cell/muL), Gram-negative bacteremia, ova and parasite (O&P) examination and treatment. Results. A total of 812 patients were evaluated for transplant during the study period: 484 for kidney, 152 for liver, 12 for liver/kidney transplant, 40 for heart, 24 for lung, and 100 for HSCT. 201 (24.7%) of the 812 patients were screened for Strongyloides; 107 (17%) evaluated for abdominal transplant, 32 (50%) for thoracic transplant, and 62 (60%) for HSCT. Seventeen (8.4%) of 201 patients screened tested positive: nine evaluated for kidney transplant, four for heart, one for liver, and three for HSCT. Nine of 17 patients (53%) were treated with Ivermectin or referred to Infectious Diseases clinic prior to our review. Ten (59%) seropositive patients were from the United States and 70% had no documented travel to endemic areas; six patients were from countries other than the United States; and one from Puerto Rico. Two patients with Strongyloidiasis had eosinophilia, one had history of Klebsiella pneumoniae bac-teremia and one had stool O&P examination. Screening was higher when using an electronic order set (57% vs. 17%). Conclusion. Universal screening for Strongyloidiasis identifed individuals with latent infection who did not have epidemiological or clinical fndings suggestive of Strongyloidiasis. Screening for Strongyloidiasis was higher in transplant programs that incorporated the recommendation into an electronic order set
ISSN: 2328-8957
CID: 4108762

A Rare Presentation of Cryptococcal Meningitis and Cerebellitis in an Asplenic Patient, Seronegative for Human Immunodeficiency Virus (HIV) [Case Report]

Abbas, Hafsa; CiFuentes Kottkamp, Angelica; Abbas, Naeem; Cindrich, Richard; Singh, Manisha
BACKGROUND Cryptococcal meningitis in patients who are seronegative for the human immunodeficiency virus (HIV) and in patients who are splenectomized is rare. This report is an unusual case of meningeal and cerebellar infection due to the encapsulated yeast, Cryptococcus neoformans, which has not previously been associated with asplenia. CASE REPORT A 65-year-old HIV-negative patient with a previous splenectomy, presented with a three-day history of fever, vomiting, and headache. His symptoms progressed to generalized body aches, persistent fever, and neck stiffness. A lumbar puncture was performed, and cerebrospinal fluid (CSF) culture grew Cryptococcus neoformans. Treatment commenced with intravenous amphotericin B and flucytosine. The patient required serial lumbar punctures due to persistent raised intracranial pressure (ICP). Magnetic resonance imaging (MRI) of the brain showed acute meningitis and cerebellitis. Antimicrobial therapy and CSF drainage resulted in clinical improvement.  CONCLUSIONS The occurrence of meningeal and cerebellar cryptococcosis in an asplenic patient is rare, and few cases have been previously reported. This case report highlights the possibility of invasive cryptococcal infection, or cryptococcosis, in asplenic individuals in the absence of HIV infection.
PMID: 29456239
ISSN: 1941-5923
CID: 3569812

The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides [PrePrint]

Kottkamp, Angelica Cifuentes; De Jesus, Elfie; Grande, Rebecca; Brown, Julia K; Jacobs, Adam R; Lim, Jean K; Stapleford, Kenneth
ISSN: 2692-8205
CID: 3575312

The anti-parasitic drug atovaquone inhibits arbovirus replication [Meeting Abstract]

Kottkamp, A; De, Jesus E; Stapleford, K
Background. Atovaquone, a hydroxynaphthoquinone, FDA Pregnancy category C, used for the treatment and prevention of pneumocysits jirovecii pneumonia (PCP), toxoplasmosis, babesiosis and malaria has in vitro activity against Zika virus (ZIKV). The mechanism of action against Plasmodium spp. and other parasites is based in the inhibition of mitochondrial cytochrome bc1 complex which further collapses parasite- mitochondrial membrane potential. But to date, antiviral activity of this drug has not been described. Methods. Vero cells (monkey kidney epithelial cells) were seeded. At 24 hours of incubation, the cells were pretreated with ribavirin and brequinar (known antiviral drugs) and atovaquone at different concentrations for 1 hour and then infected with ZIKV Brazilian strain and Ugandan strain, and subsequently treated with drugs again. After incubation for 72 hours virus antigen Env-protein production was quantified by immunodetection. The concentration of atovaquone that decreased the level of Env-protein production by 50% was calculated by non-linear regression analysis (CC50). Cell viability was measured using the CellTiter 96 aqueous one solution cell proliferation assay (Promega, Madison, WI), according to the manufacturers protocol. Viral infection was rescued adding uracil to Vero cells pre-treated with ribavirin, brequinar and atovaquone. Experiment was repeated with Chikungunya virus (CHIKV). Results. We found that atovaquone inhibits ZIKV infection in Vero cells at smaller concentration (CC50 = 0.52 muM) than those used for parasitic killing. The effect is more prominent in the Brazilian strain when compared with the Ugandan strain. No cytotoxic effect was found in Vero cells up to 15 muM; above this concentration atovaquone formed crystals. Uracil rescues ZIKV infection after treatment with atovaquone. Atovaquone also inhibited CHIKV infection in Vero cells. Conclusion. Atovaquone has antiviral activity against ZIKV likely via depletion of nucleotides blocking pyrimidine biosynthesis. Furthermore, the antiviral effect is applicable to other arboviruses which makes atovaquone a broad-spectrum antiviral drug and a potential attractive candidate for the treatment of ZIKV infection in vulnerable population such pregnant women and children. (Figure Presented)
ISSN: 2328-8957
CID: 4108752

Immunogenicity of a Two Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial

Rouphael, Nadine G; Branche, Angela R; Diemert, David J; Falsey, Ann R; Losada, Cecilia; Baden, Lindsey R; Frey, Sharon E; Whitaker, Jennifer A; Little, Susan J; Kamidani, Satoshi; Walter, Emmanuel B; Novak, Richard M; Rupp, Richard; Jackson, Lisa A; Babu, Tara M; Kottkamp, Angelica C; Luetkemeyer, Anne F; Immergluck, Lilly C; Presti, Rachel M; Bäcker, Martín; Winokur, Patricia L; Mahgoub, Siham M; Goepfert, Paul A; Fusco, Dahlene N; Atmar, Robert L; Posavad, Christine M; Netzl, Antonia; Smith, Derek J; Telu, Kalyani; Mu, Jinjian; McQuarrie, Lisa J; Makowski, Mat; Makhene, Mamodikoe K; Crandon, Sonja; Montefiori, David C; Roberts, Paul C; Beigel, John H
We compared the serologic responses of one versus two doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A two-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.
PMID: 37561027
ISSN: 1537-6613
CID: 5605532

Antibody Titers against Mpox Virus after Vaccination [Letter]

Kottkamp, Angelica C; Samanovic, Marie I; Duerr, Ralf; Oom, Aaron L; Belli, Hayley M; Zucker, Jane R; Rosen, Jennifer B; Mulligan, Mark J; ,
PMID: 38091537
ISSN: 1533-4406
CID: 5589312

Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

Branche, Angela R; Rouphael, Nadine G; Diemert, David J; Falsey, Ann R; Losada, Cecilia; Baden, Lindsey R; Frey, Sharon E; Whitaker, Jennifer A; Little, Susan J; Anderson, Evan J; Walter, Emmanuel B; Novak, Richard M; Rupp, Richard; Jackson, Lisa A; Babu, Tara M; Kottkamp, Angelica C; Luetkemeyer, Anne F; Immergluck, Lilly C; Presti, Rachel M; Bäcker, Martín; Winokur, Patricia L; Mahgoub, Siham M; Goepfert, Paul A; Fusco, Dahlene N; Malkin, Elissa; Bethony, Jeffrey M; Walsh, Edward E; Graciaa, Daniel S; Samaha, Hady; Sherman, Amy C; Walsh, Stephen R; Abate, Getahun; Oikonomopoulou, Zacharoula; El Sahly, Hana M; Martin, Thomas C S; Kamidani, Satoshi; Smith, Michael J; Ladner, Benjamin G; Porterfield, Laura; Dunstan, Maya; Wald, Anna; Davis, Tamia; Atmar, Robert L; Mulligan, Mark J; Lyke, Kirsten E; Posavad, Christine M; Meagher, Megan A; Stephens, David S; Neuzil, Kathleen M; Abebe, Kuleni; Hill, Heather; Albert, Jim; Telu, Kalyani; Mu, Jinjian; Lewis, Teri C; Giebeig, Lisa A; Eaton, Amanda; Netzl, Antonia; Wilks, Samuel H; Türeli, Sina; Makhene, Mamodikoe; Crandon, Sonja; Montefiori, David C; Makowski, Mat; Smith, Derek J; Nayak, Seema U; Roberts, Paul C; Beigel, John H; ,
Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. registration: NCT05289037 .
PMID: 37640860
ISSN: 1546-170x
CID: 5605562

Implementation and early outcomes of a telehealth visit model to deliver tecovirimat for mpox infection in New York City

Chan, Justin; DiTullio, David J; Pagan Pirallo, Patricia; Foote, Mary; Knutsen, Dorothy; Kottkamp, Angelica Cifuentes; McPherson, Tristan D; Mukherjee, Vikramjit; Pitts, Robert; Wallach, Andrew; Wong, Marcia; Mazo, Dana; Mgbako, Ofole
The 2022 mpox outbreak in New York City posed challenges to rapidly scaling up treatment capacity. We describe a telehealth treatment model launched during this outbreak that facilitated healthcare provider treatment capacity, and was able to adhere to a Centers for Disease Control and Prevention (CDC)-sponsored expanded access investigational new drug (EA-IND) protocol for tecovirimat. Sixty-nine patients were evaluated and prescribed tecovirimat for mpox through telehealth visits at NYC Health + Hospitals/Bellevue and NYU Langone Health from June to August 2022. Thirty-two (46.4%) were previously diagnosed with HIV. Forty-four (63.8%) reported full recovery, with the remainder lost to follow-up. Most patients (n = 60, 87.0%) attended at least one follow-up visit (either in person or through telehealth) after starting treatment. We observed favorable treatment outcomes, with no serious adverse events, hospitalizations, or deaths related to mpox. While equitable access to telehealth remains a limitation that needs to be addressed, this telehealth model enabled a rapid scale-up of tecovirimat prescription during the mpox outbreak, and should be considered as an important tool used to respond to future infectious disease outbreaks.
PMID: 37632124
ISSN: 1758-1109
CID: 5598892