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Reverse Genetics System for Crimean-Congo Hemorrhagic Fever Virus
Scholte F , Karaaslan E , Bergeron É . Methods Mol Biol 2025 2893 247-256 Reverse genetic systems are powerful tools in molecular virology that allow the generation of infectious recombinant virus and the manipulation of viral genomes. Reverse genetic systems enable the incorporation of reporter genes, facilitating many virological assays, including high-throughput screening. Additionally, reverse genetic systems can be used to introduce targeted mutations into the viral genome, allowing investigations of viral genetic elements and protein functions in virus pathogenesis and biology. Here we describe in detail the materials and methods required for the Crimean-Congo hemorrhagic fever virus (CCHFV) reverse genetic system. This system can be used to generate complete infectious recombinant virus, and virus-like replicon particles (VRPs) lacking the M segment but complemented with an exogenous source of glycoprotein precursor (GPC); resulting in single-round replicon particles that can be used to study components of the viral replicative cycle at a lower biosafety level. |
Crimean-Congo hemorrhagic fever virus replicon particle vaccine is safe and elicits functional, non-neutralizing anti-nucleoprotein antibodies and T cell activation in rhesus macaques
Kleymann A , Karaaslan E , Scholte FEM , Sorvillo TE , Welch SR , Bergeron É , Elser S , Almanzar-Jordan MR , Velazquez E , Genzer SC , Jean SM , Spiropoulou CF , Spengler JR . Antiviral Res 2024 106045 Advancement of vaccine candidates that demonstrate protective efficacy in screening studies necessitates detailed safety and immunogenicity investigations in pre-clinical models. A non-spreading Crimean-Congo hemorrhagic fever virus (CCHFV) viral replicon particle (VRP) vaccine was developed for single-dose administration to protect against disease. To date, several studies have supported safety, immunogenicity, and efficacy of the CCHF VRP in multiple highly sensitive murine models of lethal disease, but the VRP had yet to be evaluated in large animals. Here, we performed studies in non-human primates to further evaluate clinical utility of the VRP vaccine. Twelve adult male and female rhesus macaques were vaccinated intramuscularly and followed daily for clinical monitoring. At 3, 7, 14, 21, and 28 days post vaccination, animals were sedated for more detailed clinical assessment; for quantification of vaccine presence in blood and mucosal samples; and for evaluation of hematology, plasma inflammatory markers, and immunity. Consistent with findings in mice, vaccination was well tolerated, with no clinical alterations nor indication of vaccine spread or shedding. In addition, vaccination induced both humoral and cell-mediated responses, with immune profile and kinetics also corroborating data from small animal models. These studies provide key data in non-human primates further supporting development of the VRP for human clinical use. |
Delayed low-dose oral administration of 4'-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease
Welch SR , Spengler JR , Westover JB , Bailey KW , Davies KA , Aida-Ficken V , Bluemling GR , Boardman KM , Wasson SR , Mao S , Kuiper DL , Hager MW , Saindane MT , Andrews MK , Krueger RE , Sticher ZM , Jung KH , Chatterjee P , Shrivastava-Ranjan P , Lo MK , Coleman-McCray JD , Sorvillo TE , Genzer SC , Scholte FEM , Kelly JA , Jenks MH , McMullan LK , Albariño CG , Montgomery JM , Painter GR , Natchus MG , Kolykhalov AA , Gowen BB , Spiropoulou CF , Flint M . Sci Transl Med 2024 16 (774) eado7034 Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4'-fluorouridine (4'-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4'-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4'-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4'-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4'-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4'-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens. |
Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 subunit vaccine combination prevents morbidity in mice
Karaaslan E , Sorvillo TE , Scholte FEM , O'Neal TJ , Welch SR , Davies KA , Coleman-McCray JD , Harmon JR , Ritter JM , Pegan SD , Montgomery JM , Spengler JR , Spiropoulou CF , Bergeron É . NPJ Vaccines 2024 9 (1) 148 Immunizing mice with Crimean-Congo hemorrhagic fever virus (CCHFV) nucleoprotein (NP), glycoprotein precursor (GPC), or with the GP38 domain of GPC, can be protective when the proteins are delivered with viral vectors or as a DNA or RNA vaccine. Subunit vaccines are a safe and cost-effective alternative to some vaccine platforms, but Gc and Gn glycoprotein subunit vaccines for CCHFV fail to protect despite eliciting high levels of neutralizing antibodies. Here, we investigated humoral and cellular immune responses and the protective efficacy of recombinant NP, GP38, and GP38 forms (GP85 and GP160) associated with the highly glycosylated mucin-like (MLD) domain, as well as the NP + GP38 combination. Vaccination with GP160, GP85, or GP38 did not confer protection, and vaccination with the MLD-associated GP38 forms blunted the humoral immune responses to GP38, worsened clinical chemistry, and increased viral RNA in the blood compared to the GP38 vaccination. In contrast, NP vaccination conferred 100% protection from lethal outcome and was associated with mild clinical disease, while the NP + GP38 combination conferred even more robust protection by reducing morbidity compared to mice receiving NP alone. Thus, recombinant CCHFV NP alone is a promising vaccine candidate conferring 100% survival against heterologous challenge. Moreover, incorporation of GP38 should be considered as it further enhances subunit vaccine efficacy by reducing morbidity in surviving animals. |
Case series of patients with Marburg Virus Disease, Equatorial Guinea, 2023
Fontana L , Ondo Avomo CO , Ngomo Mikue LE , Fuga Eyemam DÑ , Nguere MA , Mometolo IE , Bibang Nzang RN , Nguema Maye DM , Giuliani R , Jacquerioz F , Lang HJ , Kojan R , Chaillon A , Ngai S , le Polain de Waroux O , Silenzi A , Di Marco M , Negrón ME , Klena JD , Choi MJ , Mayer O , Scholte FEM , Welch SR , Zielinski-Gutierrez E , Diaz J . N Engl J Med 2024 391 (3) 283-285 |
Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus
Sorvillo TE , Karaaslan E , Scholte FEM , Welch SR , Coleman-McCray JD , Genzer SC , Ritter JM , Hayes HM , Jain S , Pegan SD , Bergeron É , Montgomery JM , Spiropoulou CF , Spengler JR . NPJ Vaccines 2024 9 (1) 88 Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe human disease and is considered a WHO priority pathogen due to the lack of efficacious vaccines and antivirals. A CCHF virus replicon particle (VRP) has previously shown protective efficacy in a lethal Ifnar(-/-) mouse model when administered as a single dose at least 3 days prior to challenge. Here, we determine that non-specific immune responses are not sufficient to confer short-term protection, since Lassa virus VRP vaccination 3 days prior to CCHFV challenge was not protective. We also investigate how CCHF VRP vaccination confers protective efficacy by examining viral kinetics, histopathology, clinical analytes and immunity early after challenge (3 and 6 days post infection) and compare to unvaccinated controls. We characterize how these effects differ based on vaccination period and correspond to previously reported CCHF VRP-mediated protection. Vaccinating Ifnar(-/-) mice with CCHF VRP 28, 14, 7, or 3 days prior to challenge, all known to confer complete protection, significantly reduced CCHFV viral load, mucosal shedding, and markers of clinical disease, with greater reductions associated with longer vaccination periods. Interestingly, there were no significant differences in innate immune responses, T cell activation, or antibody titers after challenge between groups of mice vaccinated a week or more before challenge, but higher anti-NP antibody avidity and effector function (ADCD) were positively associated with longer vaccination periods. These findings support the importance of antibody-mediated responses in VRP vaccine-mediated protection against CCHFV infection. |
Evaluation of two inoculation routes of an adenovirus-mediated viral protein inhibitor in a Crimean-Congo hemorrhagic fever mouse model
Scholte FEM , Spengler JR , Welch SR , Harmon JR , Coleman-McCray JD , Davies KA , Pegan SD , Montgomery JM , Spiropoulou CF , Bergeron É . Virus Res 2024 345 199398 Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne nairovirus with a wide geographic spread that can cause severe and lethal disease. No specific medical countermeasures are approved to combat this illness. The CCHFV L protein contains an ovarian tumor (OTU) domain with a cysteine protease thought to modulate cellular immune responses by removing ubiquitin and ISG15 post-translational modifications from host and viral proteins. Viral deubiquitinases like CCHFV OTU are attractive drug targets, as blocking their activity may enhance cellular immune responses to infection, and potentially inhibit viral replication itself. We previously demonstrated that the engineered ubiquitin variant CC4 is a potent inhibitor of CCHFV replication in vitro. A major challenge of the therapeutic use of small protein inhibitors such as CC4 is their requirement for intracellular delivery, e.g., by viral vectors. In this study, we examined the feasibility of in vivo CC4 delivery by a replication-deficient recombinant adenovirus (Ad-CC4) in a lethal CCHFV mouse model. Since the liver is a primary target of CCHFV infection, we aimed to optimize delivery to this organ by comparing intravenous (tail vein) and intraperitoneal injection of Ad-CC4. While tail vein injection is a traditional route for adenovirus delivery, in our hands intraperitoneal injection resulted in higher and more widespread levels of adenovirus genome in tissues, including, as intended, the liver. However, despite promising in vitro results, neither route of in vivo CC4 treatment resulted in protection from a lethal CCHFV infection. |
Characterization of humoral responses to Nipah virus infection in the Syrian Hamster model of disease
Scholte FEM , Rodriguez SE , Welch SR , Davies KA , Genzer SC , Coleman-McCray JD , Harmon JR , Sorvillo TE , Lo MK , Karaaslan E , Bergeron E , Montgomery JM , Spengler JR , Spiropoulou CF . J Infect Dis 2023 Nipah virus (NiV) is a highly pathogenic paramyxovirus. The Syrian hamster model recapitulates key features of human NiV disease and is a critical tool for evaluating antivirals and vaccines. Here we describe longitudinal humoral immune responses in NiV-infected Syrian hamsters. Samples were obtained 1-28 days after infection and analyzed by ELISA, neutralization, and Fc-mediated effector function assays. NiV infection elicited robust antibody responses against the nucleoprotein and attachment glycoprotein. Levels of neutralizing antibodies were modest and only detectable in surviving animals. Fc-mediated effector functions were mostly observed in nucleoprotein-targeting antibodies. Antibody levels and activities positively correlated with challenge dose. |
Molecular characterization of the 2022 Sudan virus disease outbreak in Uganda
Balinandi S , Whitmer S , Mulei S , Nassuna C , Pimundu G , Muyigi T , Kainulainen M , Shedroff E , Krapiunaya I , Scholte F , Nyakarahuka L , Tumusiime A , Kyondo J , Baluku J , Kiconco J , Harris JR , Ario AR , Kagirita A , Bosa HK , Ssewanyana I , Nabadda S , Mwebesa HG , Aceng JR , Atwine D , Lutwama JJ , Shoemaker TR , Montgomery JM , Kaleebu P , Klena JD . J Virol 2023 97 (10) e0059023 Uganda experienced five Ebola disease outbreaks caused by Bundibugyo virus (n = 1) and Sudan virus (SUDV) (n = 4) from 2000 to 2021. On 20 September 2022, Uganda declared a fifth Sudan virus disease outbreak in the Mubende district, resulting in 142 confirmed and 22 probable cases by the end of the outbreak declaration on 11 January 2023. The earliest identified cases, through retrospective case investigations, had onset in early August 2022. From the 142 confirmed cases, we performed unbiased (Illumina) and SUDV-amplicon-specific (Minion) high-throughput sequencing to obtain 120 SUDV genome-and coding-complete sequences, representing 95.4% (104/109) of SVD-confirmed individuals within a sequence-able range (Ct ≤30) and 10 genome sequences outside of this range and 6 duplicate genome sequences. A comparison of the nucleotide genetic relatedness for the newly emerged Mubende variant indicated that it was most closely related to the Nakisamata SUDV sequence from 2011, represented a likely new zoonotic spillover event, and exhibited an inter- and intra-outbreak substitution rate consistent with previous outbreaks. The most recent common ancestor for the Mubende variant was estimated to have occurred in October and November 2021. The Mubende variant glycoprotein amino acid sequences exhibited 99.7% similarity altogether and a maximum of 96.1% glycoprotein similarity compared to historical SUDV strains from 1976. Integrating the genetic sequence and epidemiological data into the response activities generated a broad overview of the outbreak, allowing for quick fact-checking of epidemiological connections between the identified patients. IMPORTANCE Ebola disease (EBOD) is a public health threat with a high case fatality rate. Most EBOD outbreaks have occurred in remote locations, but the 2013-2016 Western Africa outbreak demonstrated how devastating EBOD can be when it reaches an urban population. Here, the 2022 Sudan virus disease (SVD) outbreak in Mubende District, Uganda, is summarized, and the genetic relatedness of the new variant is evaluated. The Mubende variant exhibited 96% amino acid similarity with historic SUDV sequences from the 1970s and a high degree of conservation throughout the outbreak, which was important for ongoing diagnostics and highly promising for future therapy development. Genetic differences between viruses identified during the Mubende SVD outbreak were linked with epidemiological data to better interpret viral spread and contact tracing chains. This methodology should be used to better integrate discrete epidemiological and sequence data for future viral outbreaks. |
Vaccination with the Crimean-Congo hemorrhagic fever virus viral replicon vaccine induces NP-based T-cell activation and antibodies possessing Fc-mediated effector functions
Scholte FEM , Karaaslan E , O'Neal TJ , Sorvillo TE , Genzer SC , Welch SR , Coleman-McCray JD , Spengler JR , Kainulainen MH , Montgomery JM , Pegan SD , Bergeron E , Spiropoulou CF . Front Cell Infect Microbiol 2023 13 1233148 Crimean-Congo hemorrhagic fever virus (CCHFV; family Nairoviridae) is a tick-borne pathogen that frequently causes lethal disease in humans. CCHFV has a wide geographic distribution, and cases have been reported in Africa, Asia, the Middle East, and Europe. Availability of a safe and efficacious vaccine is critical for restricting outbreaks and preventing disease in endemic countries. We previously developed a virus-like replicon particle (VRP) vaccine that provides complete protection against homologous and heterologous lethal CCHFV challenge in mice after a single dose. However, the immune responses induced by this vaccine are not well characterized, and correlates of protection remain unknown. Here we comprehensively characterized the kinetics of cell-mediated and humoral immune responses in VRP-vaccinated mice, and demonstrate that they predominantly target the nucleoprotein (NP). NP antibodies are not associated with protection through neutralizing activity, but VRP vaccination results in NP antibodies possessing Fc-mediated antibody effector functions, such as complement activation (ADCD) and antibody-mediated cellular phagocytosis (ADCP). This suggests that Fc-mediated effector functions may contribute to this vaccine's efficacy. |
Rhesus macaques show increased resistance to repeated SHIV intrarectal exposure following a heterologous regimen of rVSV vector vaccine expressing HIV antigen
Jelinski J , Kowatsch MM , Lafrance MA , Berger A , Pedersen J , Azizi H , Li Y , Scholte F , Gomez A , Hollett N , Le T , Wade M , Fausther-Bovendo H , de La Vega MA , Babuadze G , X A 3rd , Lamarre C , Racine T , Kang CY , Yao XJ , Alter G , Arts E , Fowke KR , Kobinger GP . Emerg Microbes Infect 2023 12 (2) 2251595 ABSTRACTDespite the human immunodeficiency virus (HIV) pandemic continuing worldwide for 40 years, no vaccine to combat the disease has been licensed for use in at risk populations. Here, we describe a novel recombinant vesicular stomatitis virus (rVSV) vector vaccine expressing modified HIV envelope glycoproteins and Ebola virus glycoprotein. Three heterologous immunizations successfully prevented infection by a different clade SHIV in 60% of nonhuman primates (NHPs). No trend was observed between resistance and antibody interactions. Resistance to infection was associated with high proportions of central memory T cell CD69 and CD154 marker upregulation, increased IL-2 production, and a reduced IFN-γ response, offering insight into correlates of protection. |
Single-dose mucosal replicon-particle vaccine protects against lethal Nipah virus infection up to 3 days after vaccination
Welch SR , Spengler JR , Genzer SC , Coleman-McCray JD , Harmon JR , Sorvillo TE , Scholte FEM , Rodriguez SE , O'Neal TJ , Ritter JM , Ficarra G , Davies KA , Kainulainen MH , Karaaslan E , Bergeron É , Goldsmith CS , Lo MK , Nichol ST , Montgomery JM , Spiropoulou CF . Sci Adv 2023 9 (31) eadh4057 Nipah virus (NiV) causes a highly lethal disease in humans who present with acute respiratory or neurological signs. No vaccines against NiV have been approved to date. Here, we report on the clinical impact of a novel NiV-derived nonspreading replicon particle lacking the fusion (F) protein gene (NiVΔF) as a vaccine in three small animal models of disease. A broad antibody response was detected that included immunoglobulin G (IgG) and IgA subtypes with demonstrable Fc-mediated effector function targeting multiple viral antigens. Single-dose intranasal vaccination up to 3 days before challenge prevented clinical signs and reduced virus levels in hamsters and immunocompromised mice; decreases were seen in tissues and mucosal secretions, critically decreasing potential for virus transmission. This virus replicon particle system provides a vital tool to the field and demonstrates utility as a highly efficacious and safe vaccine candidate that can be administered parenterally or mucosally to protect against lethal Nipah disease. |
Addressing Personal Protective Equipment (PPE) Decontamination: Methylene Blue and Light Inactivates SARS-CoV-2 on N95 Respirators and Masks with Maintenance of Integrity and Fit (preprint)
Lendvay TS , Chen J , Harcourt BH , Scholte FE , Lin YL , Kilinc-Balci FS , Lamb MM , Homdayjanakul K , Cui Y , Price A , Heyne B , Sahni J , Kabra KB , Lin YC , Evans D , Mores CN , Page K , Chu LF , Haubruge E , Thiry E , Ludwig-Begall LF , Wielick C , Clark T , Wagner T , Timm E , Gallagher T , Faris P , Macia N , Mackie CJ , Simmons SM , Reader S , Malott R , Hope K , Davies JM , Tritsch SR , Dams L , Nauwynck H , Willaert JF , De Jaeger S , Liao L , Zhao M , Laperre J , Jolois O , Smit SJ , Patel AN , Mayo M , Parker R , Molloy-Simard V , Lemyre JL , Chu S , Conly JM , Chu MC . medRxiv 2020 2020.12.11.20236919 Background The coronavirus disease 2019 (COVID-19) pandemic has resulted in severe shortages of personal protective equipment (PPE) necessary to protect front-line healthcare personnel. These shortages underscore the urgent need for simple, efficient, and inexpensive methods to decontaminate SARS-CoV-2-exposed PPE enabling safe reuse of masks and respirators. Efficient decontamination must be available not only in low-resourced settings, but also in well-resourced settings affected by PPE shortages. Methylene blue (MB) photochemical treatment, hitherto with many clinical applications including those used to inactivate virus in plasma, presents a novel approach for widely applicable PPE decontamination. Dry heat (DH) treatment is another potential low-cost decontamination method.Methods MB and light (MBL) and DH treatments were used to inactivate coronavirus on respirator and mask material. We tested three N95 filtering facepiece respirators (FFRs), two medical masks (MMs), and one cloth community mask (CM). FFR/MM/CM materials were inoculated with SARS-CoV-2 (a Betacoronavirus), murine hepatitis virus (MHV) (a Betacoronavirus), or porcine respiratory coronavirus (PRCV) (an Alphacoronavirus), and treated with 10 µM MB followed by 50,000 lux of broad-spectrum light or 12,500 lux of red light for 30 minutes, or with 75°C DH for 60 minutes. In parallel, we tested respirator and mask integrity using several standard methods and compared to the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method. Intact FFRs/MMs/CM were subjected to five cycles of decontamination (5CD) to assess integrity using International Standardization Organization (ISO), American Society for Testing and Materials (ASTM) International, National Institute for Occupational Safety and Health (NIOSH), and Occupational Safety and Health Administration (OSHA) test methods.Findings Overall, MBL robustly and consistently inactivated all three coronaviruses with at least a 4-log reduction. DH yielded similar results, with the exception of MHV, which was only reduced by 2-log after treatment. FFR/MM integrity was maintained for 5 cycles of MBL or DH treatment, whereas one FFR failed after 5 cycles of VHP+O3. Baseline performance for the CM was variable, but reduction of integrity was minimal.Interpretation Methylene blue with light and DH treatment decontaminated masks and respirators by inactivating three tested coronaviruses without compromising integrity through 5CD. MBL decontamination of masks is effective, low-cost and does not require specialized equipment, making it applicable in all-resource settings. These attractive features support the utilization and continued development of this novel PPE decontamination method.Competing Interest StatementAuthors Thomas S. Lendvay, James Chen are Co-Founders and equity owners of Singletto, Inc. (Seattle, WA, USA) Authors Yi Cui and Steven Chu are Co-Founders and equity owners of 4C Air, Inc. (Sunnyvale, CA)Funding StatementThis study was funded by Open Philanthropy; Amazon Inc./University of Washington Catalyst Award; University of Liege (Belgium) and the Walloon Region, Belgium; Li Ka Shing Institute; Alberta Health Services; and an Anonymous donor to the University of Washington, Department of Urology.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Stanford University and Alberta Health Services/University of Calgary were exempt from IRB as the human fit testing was considered Quality Improvement. ERB for clinical specimen use: A clinical saliva specimen with a SARS-CoV-2 was provided by Dr. John Conly from Calgary, Alberta with Calgary ERB approval (ID# Pro00099761).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective inte ventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will be freely shared post publication on reasonable request by contacting the corresponding author of the study. |
Mouse models of Ebola virus tolerance and lethality: Characterization of CD-1 mice infected with wild-type, guinea pig-adapted, or mouse-adapted variants
Spengler JR , Welch SR , Ritter JM , Harmon JR , Coleman-McCray JD , Genzer SC , Nascimento Seixas J , Scholte FEM , Davies KA , Bradfute SB , Montgomery JM , Spiropoulou CF . Antiviral Res 2022 210 105496 Development of lethal models of Ebola virus disease has been achieved by the serial passage of virus isolates from human cases in mice and guinea pigs. Use of mice infected with non-adapted virus has been limited due to the absence of overt clinical disease. In recent years, newly recognized sequelae identified in human cases has highlighted the importance of continued investigations of non-lethal infection both in humans and animal models. Here, we revisit the use of rodent-adapted and non-adapted Ebola virus (EBOV) variants in mice to investigate infection tolerance and future utility of these models in pathogenesis and therapeutic intervention studies. We found that like non-adapted wild-type EBOV, guinea pig-adapted EBOV results in widespread tissue infection, variably associated with tissue pathology, and alterations in clinical and immunological analytes in the absence of overt disease. Notably, infection with either non-lethal variant does not greatly differ from lethal mouse-adapted EBOV until near the time end-point criteria are reached in these mice, supporting use of these models of virus tolerance for continued investigations of non-lethal infection and sequelae. |
Exploring inactivation of SARS-CoV-2, MERS-CoV, Ebola, Lassa, and Nipah viruses on N95 and KN95 respirator material using photoactivated methylene blue to enable reuse.
Scholte Florine EM , Kabra Kareem B , Tritsch Sarah R , Montgomery Joel M , Spiropoulou Christina F , Mores Christopher N , Harcourt Brian H . Am J Infect Control 2022 50 (8) 863-870 The photoactivated dye methylene blue inactivates many human pathogens. The technique inactivates SARS-CoV-2, Ebola, Lassa and Nipah viruses on respirators. Decontamination of N95 and KN95 respirators allows safe limited reuse. Methylene blue can be used for pretreatment and decontamination of respirators. Pretreatment of PPE could allow for real-time virus inactivation. The COVID-19 pandemic resulted in a worldwide shortage of N95 respirators, prompting the development of decontamination methods to enable limited reuse. Countries lacking reliable supply chains would also benefit from the ability to safely reuse PPE. Methylene blue (MB) is a light-activated dye with demonstrated antimicrobial activity used to sterilize blood plasma. Decontamination of respirators using photoactivated MB requires no specialized equipment, making it attractive for use in the field during outbreaks. We examined decontamination of N95 and KN95 respirators using photoactivated MB and 3 variants of SARS-CoV-2, the virus that causes COVID-19; and 4 World Health Organization priority pathogens: Ebola virus, Middle East respiratory syndrome coronavirus, Nipah virus, and Lassa virus. Virus inactivation by pretreating respirator material was also tested. Photoactivated MB inactivated all tested viruses on respirator material, albeit with varying efficiency. Virus applied to respirator material pre-treated with MB was also inactivated, thus MB pretreatment may potentially protect respirator wearers from virus exposure in real-time. These results demonstrate that photoactivated MB represents a cost-effective, rapid, and widely deployable method to decontaminate N95 respirators for reuse during supply shortages. |
Viral RNA and infectious virus in mucosal specimens from guinea pigs modeling early phases of lethal and non-lethal Lassa fever
Welch SR , Genzer SC , Coleman-McCray JD , Harmon JR , Scholte FEM , Montgomery JM , Spiropoulou CF , Spengler JR . Emerg Microbes Infect 2022 11 (1) 1-17 ABSTRACTLassa fever (LF) is endemic to broad regions of West Africa. Infection with Lassa virus (LASV), the etiologic agent of LF, results in a spectrum of clinical signs in humans, including severe and lethal hemorrhagic disease. Person-to-person transmission occurs through direct contact with body fluids or contaminated bedding and clothing. To investigate transmission risk in acute LASV infection, we evaluated viral RNA and infectious virus obtained from conjunctival, nasal, oral, genital, and rectal swab specimens from guinea pigs modeling lethal and non-lethal LF. Viral RNA and infectious virus were detected in all specimen types beginning 8 days post infection, prior to onset of fever. In the pre-clinical and clinical period, virus was isolated from a subset of nasal, oral, genital, and rectal swabs, and from all conjunctival swabs. Overall, conjunctival and nasal specimens most frequently yielded infectious virus. These findings indicate mucosal transmission risk based on virus isolation from various sites early in infection and support potential utility of minimally invasive specimen evaluation by RT-qPCR for LASV diagnostics. |
Defective Interfering Viral Particle Treatment Reduces Clinical Signs and Protects Hamsters from Lethal Nipah Virus Disease.
Welch SR , Spengler JR , Harmon JR , Coleman-McCray JD , Scholte FEM , Genzer SC , Lo MK , Montgomery JM , Nichol ST , Spiropoulou CF . mBio 2022 13 (2) e0329421 Defective interfering particles (DIs) contain a considerably smaller genome than the parental virus but retain replication competency. As DIs can directly or indirectly alter propagation kinetics of the parental virus, they offer a novel approach to antiviral therapy, capitalizing on knowledge from natural infection. However, efforts to translate in vitro inhibition to in vivo screening models remain limited. We investigated the efficacy of virus-like particles containing DI genomes (therapeutic infectious particles [TIPs]) in the Syrian hamster model of lethal Nipah virus (NiV) disease. We found that coadministering a high dose of TIPs intraperitoneally with virus challenge improved clinical course and reduced lethality. To mimic natural exposure, we also evaluated lower-dose TIP delivery and virus challenge intranasally, finding equally efficacious reduction in disease severity and overall lethality. Eliminating TIP replicative capacity decreased efficacy, suggesting protection via direct inhibition. These data provide evidence that TIP-mediated treatment can confer protection against disease and lethal outcome in a robust animal NiV model, supporting further development of TIP treatment for NiV and other high-consequence pathogens. IMPORTANCE Here, we demonstrate that treatment with defective interfering particles (DIs), a natural by-product of viral infection, can significantly improve the clinical course and outcome of viral disease. When present with their parental virus, DIs can directly or indirectly alter viral propagation kinetics and exert potent inhibitory properties in cell culture. We evaluated the efficacy of a selection of virus-like particles containing DI genomes (TIPs) delivered intranasally in a lethal hamster model of Nipah virus disease. We demonstrate significantly improved clinical outcomes, including reduction in both lethality and the appearance of clinical signs. This work provides key efficacy data in a robust model of Nipah virus disease to support further development of TIP-mediated treatment against high-consequence viral pathogens. |
Lassa virus replicon particle vaccine protects strain 13/N guinea pigs against challenge with geographically and genetically diverse viral strains.
Spengler JR , Kainulainen MH , Welch SR , Coleman-McCray JAD , Harmon JR , Condrey JA , Scholte FEM , Nichol ST , Montgomery JM , Albariño CG , Spiropoulou CF . J Infect Dis 2022 226 (9) 1545-1550 Lassa virus (LASV) causes mild to severe hemorrhagic fever disease in humans. Strain 13/N guinea pigs are highly susceptible to infection with LASV strain Josiah (clade IV), providing a critical model system for therapeutics and vaccine development. To develop additional models of disease, we detail the clinical course in guinea pigs infected with 5 geographically and genetically diverse LASV strains. Two of the developed models (LASV clades II and III) were then used to evaluate efficacy of a virus replicon particle (VRP) vaccine against heterologous LASV challenge, demonstrating complete protection against clinical disease after a single vaccination dose. |
The Structure and Immune Regulatory Implications of the Ubiquitin-Like Tandem Domain Within an Avian 2'-5' Oligoadenylate Synthetase-Like Protein.
Shepard JD , Freitas BT , Rodriguez SE , Scholte FEM , Baker K , Hutchison MR , Longo JE , Miller HC , O'Boyle BM , Tandon A , Zhao P , Grimsey NJ , Wells L , Bergeron É , Pegan SD . Front Immunol 2021 12 794664 Post-translational modification of host and viral proteins by ubiquitin and ubiquitin-like proteins plays a key role in a host's ability to mount an effective immune response. Avian species lack a ubiquitin-like protein found in mammals and other non-avian reptiles; interferon stimulated gene product 15 (ISG15). ISG15 serves as a messenger molecule and can be conjugated to both host and viral proteins leading them to be stabilized, degraded, or sequestered. Structurally, ISG15 is comprised of a tandem ubiquitin-like domain (Ubl), which serves as the motif for post-translational modification. The 2'-5' oligoadenylate synthetase-like proteins (OASL) also encode two Ubl domains in series near its C-terminus which binds OASL to retinoic acid inducible gene-I (RIG-I). This protein-protein interaction increases the sensitivity of RIG-I and results in an enhanced production of type 1 interferons and a robust immune response. Unlike human and other mammalian OASL homologues, avian OASLs terminate their tandem Ubl domains with the same LRLRGG motif found in ubiquitin and ISG15, a motif required for their conjugation to proteins. Chickens, however, lack RIG-I, raising the question of structural and functional characteristics of chicken OASL (chOASL). By investigating chOASL, the evolutionary history of viruses with deubiquitinases can be explored and drivers of species specificity for these viruses may be uncovered. Here we show that the chOASL tandem Ubl domains shares structural characteristics with mammalian ISG15, and that chOASL can oligomerize and conjugate to itself. In addition, the ISG15-like features of avian OASLs and how they impact interactions with viral deubiquitinases and deISGylases are explored. |
Diagnostics to support elimination of lymphatic filariasis-Development of two target product profiles
Won KY , Gass K , Biamonte M , Dagne DA , Ducker C , Hanna C , Hoerauf A , Lammie PJ , Njenga SM , Noordin R , Ramaiah KD , Ramzy R , Scholte RGC , Solomon AW , Souza AA , Tappero J , Toubali E , Weil GJ , Williams SA , King JD . PLoS Negl Trop Dis 2021 15 (11) e0009968 As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools. |
Viral replicon particles protect IFNAR(-/-) mice against lethal Crimean-Congo hemorrhagic fever virus challenge three days after vaccination
Spengler JR , Welch SR , Scholte FEM , Rodriguez SE , Harmon JR , Coleman-McCray JD , Nichol ST , Montgomery JM , Bergeron É , Spiropoulou CF . Antiviral Res 2021 191 105090 Crimean-Congo hemorrhagic fever virus (CCHFV) causes mild to severe and fatal disease in humans. Person-to-person transmission is common, necessitating the availability of rapidly deliverable therapeutic and prophylactic interventions to mitigate CCHFV spread. Previously, we showed complete protection using one dose of a viral replicon particle (VRP) vaccine administered 28 days before CCHFV challenge. In order to determine the utility of the VRP vaccine for rapid vaccination protocols, we assessed the efficacy of such vaccination administered at various intervals relative to challenge in IFNAR(-/-) mice. Unvaccinated mice uniformly succumbed to disease by 8 days post infection (dpi). All mice vaccinated 14, 7, or 3 days prior to CCHFV challenge survived infection. Mice vaccinated -14 or -7 dpi were fully protected from clinical disease, whereas mice inoculated -3 dpi developed signs of disease prior to recovering to baseline values 5-9 dpi. These data support the utility of the VRP vaccine for modified short course vaccination protocols to protect against disease and severe outcomes. |
Addressing personal protective equipment (PPE) decontamination: Methylene blue and light inactivates severe acute respiratory coronavirus virus 2 (SARS-CoV-2) on N95 respirators and medical masks with maintenance of integrity and fit.
Lendvay TS , Chen J , Harcourt BH , Scholte FE , Lin YL , Kilinc-Balci FS , Lamb MM , Homdayjanakul K , Cui Y , Price A , Heyne B , Sahni J , Kabra KB , Lin YC , Evans D , Mores CN , Page K , Chu LF , Haubruge E , Thiry E , Ludwig-Begall LF , Wielick C , Clark T , Wagner T , Timm E , Gallagher T , Faris P , Macia N , Mackie CJ , Simmons SM , Reader S , Malott R , Hope K , Davies JM , Tritsch SR , Dams L , Nauwynck H , Willaert JF , De Jaeger S , Liao L , Zhao M , Laperre J , Jolois O , Smit SJ , Patel AN , Mayo M , Parker R , Molloy-Simard V , Lemyre JL , Chu S , Conly JM , Chu MC . Infect Control Hosp Epidemiol 2021 43 (7) 1-83 OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE) underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate SARS-CoV-2-exposed masks and respirators. We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus. DESIGN: The two arms of the study included: 1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment, and 2) PPE treatment with MBL for 5 cycles of decontamination (5CD) to determine maintenance of PPE performance. METHODS: MBL treatment was used to inactivate coronaviruses on three N95 filtering facepiece respirator (FFR) and two medical mask (MM) models. We inoculated FFR and MM materials with three coronaviruses, including SARS-CoV-2, and treated with 10 µM MB and exposed to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5CD using multiple US and international test methods and compared to the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method. RESULTS: Overall, MBL robustly and consistently inactivated all three coronaviruses with 99.8 - to >99.9% virus inactivation across all FFRs and MMs tested. FFR and MM integrity was maintained after 5 cycles of MBL treatment, whereas one FFR model failed after 5 cycles of VHP+O3. CONCLUSIONS: MBL treatment decontaminated respirators and masks by inactivating three tested coronaviruses without compromising integrity through 5CD. MBL decontamination is effective, low-cost and does not require specialized equipment, making it applicable in all-resource settings. |
Cortisol awakening response over the course of humanitarian aid deployment: a prospective cohort study
Qing Y , van Zuiden M , Eriksson C , Lopes Cardozo B , Simon W , Ager A , Snider L , Sabin ML , Scholte W , Kaiser R , Rijnen B , Olff M . Eur J Psychotraumatol 2020 11 (1) 1816649 Background: Internationally deployed humanitarian aid (HA) workers are routinely confronted with potentially traumatic stressors. However, it remains unknown whether HA deployment and related traumatic stress are associated with long-term changes in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, we investigated whether cortisol awakening response (CAR) decreased upon deployment and whether this was moderated by previous and recent trauma exposure and parallel changes in symptom severity and perceived social support. Methods: In this prospective study, n = 86 HA workers (68% females) completed questionnaires regarding trauma exposure, posttraumatic stress disorder (PTSD), anxiety and depressive symptoms and perceived social support, as well as salivary cortisol assessments at awakening and 30 minutes post-awakening at before, early and 3–6 months post-deployment. Results: Linear mixed models showed significantly decreased CAR (b(SE) = −.036(.011), p =.002) and awakening cortisol over time (b(SE) = −.007(.003), p =.014). The extent of awakening cortisol change was significantly moderated by interactions between previous and recent trauma exposure. Also, a steeper awakening cortisol decrease was significantly associated with higher mean anxiety and PTSD symptoms across assessments. No significant effects were found for social support. Conclusions: We observed attenuated CAR and awakening cortisol upon HA deployment, with a dose-response effect between trauma exposure before and during the recent deployment on awakening cortisol. Awakening cortisol change was associated with PTSD and anxiety symptom levels across assessments. Our findings support the need for organizational awareness that work-related exposures may have long-lasting biological effects. Further research assessing symptoms and biological measures in parallel is needed to translate current findings into guidelines on the individual level. |
Integrated survey methodologies for neglected tropical diseases
Harding-Esch EM , Brady MA , Angeles CAC , Fleming FM , Martin DL , McPherson S , Hurtado HM , Nesemann JM , Nwobi BC , Scholte RGC , Taleo F , Talero SL , Solomon AW , Saboyá-Díaz MI . Trans R Soc Trop Med Hyg 2020 115 (2) 124-126 The 2021-2030 Neglected Tropical Diseases road map calls for intensified cross-cutting approaches. By moving away from vertical programming, the integration of platforms and intervention delivery aims to improve efficiency, cost-effectiveness and programme coverage. Drawing on the direct experiences of the authors, this article outlines key elements for successful integrated surveys, the challenges encountered, as well as future opportunities and threats to such surveys. There are multiple advantages. Careful planning should ensure that integration does not result in a process that is less efficient, more expensive or that generates data driving less reliable decisions than conducting multiple disease-specific surveys. |
A single mutation in Crimean-Congo hemorrhagic fever virus discovered in ticks impairs infectivity in human cells.
Hua BL , Scholte FE , Ohlendorf V , Kopp A , Marklewitz M , Drosten C , Nichol ST , Spiropoulou C , Junglen S , Bergeron É . Elife 2020 9 Crimean-Congo Hemorrhagic Fever (CCHF) is the most widely distributed tick-borne viral infection in the world. Strikingly, reported mortality rates for CCHF are extremely variable, ranging from 5 to 80% (1). CCHF virus (CCHFV, Nairoviridae) exhibits extensive genomic sequence diversity across strains (2, 3). It is currently unknown if genomic diversity is a factor contributing to variation in its pathogenicity. We obtained complete genome sequences of CCHFV directly from the tick reservoir. These new strains belong to a solitary lineage named Europe 2 that is circumstantially reputed to be less pathogenic than the epidemic strains from Europe 1 lineage. We identified a single tick-specific amino acid variant in the viral glycoprotein region that dramatically reduces its fusion activity in human cells, providing evidence that a GPC variant, present in ticks, have severely impaired function in human cells. |
How ISG15 combats viral infection.
Freitas BT , Scholte FEM , Bergeron E , Pegan SD . Virus Res 2020 286 198036 Interferon (IFN)-stimulated gene product 15 (ISG15) is a ubiquitin-like protein critical for the control of microbial infections. ISG15 appears to serve a wide variety of functions, which regulate multiple cellular responses contributing to the development of an antiviral state. ISG15 is a versatile molecule directly modulating both host and virus protein function which regulate many signaling pathways, including its own synthesis. Here we review the various roles ISG15 plays in the antiviral immune response, and examine the mechanisms by which viruses attempt to mitigate or exploit ISG15 activity. |
The Crimean-Congo Hemorrhagic Fever Virus NSm Protein is Dispensable for Growth In Vitro and Disease in Ifnar -/- Mice.
Welch SR , Scholte FEM , Spengler JR , Ritter JM , Coleman-McCray JD , Harmon JR , Nichol ST , Zaki SR , Spiropoulou CF , Bergeron E . Microorganisms 2020 8 (5) Crimean-Congo hemorrhagic fever virus (CCHFV) is a tri-segmented, tick-borne nairovirus that causes disease of ranging severity in humans. The CCHFV M segment encodes a complex glycoprotein precursor (GPC) that undergoes extensive endoproteolytic cleavage, giving rise to two structural proteins (Gn and Gc) required for virus attachment and entry, and to multiple non-structural proteins (NSm, GP160, GP85, and GP38). The functions of these non-structural proteins remain largely unclear. Here, we investigate the role of NSm during infection by generating a recombinant CCHFV lacking the complete NSm domain (10200NSm) and observing CCHFV NSm replication in cell lines and pathogenicity in Ifnar(-/-) mice. Our data demonstrate that the NSm domain is dispensable for viral replication in vitro, and, despite the delayed onset of clinical signs, CCHFV lacking this domain caused severe or lethal disease in infected mice. |
Inhibition of Nipah Virus by Defective Interfering Particles.
Welch SR , Tilston NL , Lo MK , Whitmer SLM , Harmon JR , Scholte FEM , Spengler JR , Duprex WP , Nichol ST , Spiropoulou CF . J Infect Dis 2020 221 S460-S470 The error-prone nature of ribonucleic acid (RNA)-dependent RNA polymerases drives the diversity of RNA virus populations. Arising within this diversity is a subset of defective viral genomes that retain replication competency, termed defective interfering (DI) genomes. These defects are caused by aberrant viral polymerase reinitiation on the same viral RNA template (deletion DI species) or the nascent RNA strand (copyback DI species). Defective interfering genomes have previously been shown to alter the dynamics of a viral population by interfering with normal virus replication and/or by stimulating the innate immune response. In this study, we investigated the ability of artificially produced DI genomes to inhibit Nipah virus (NiV), a highly pathogenic biosafety level 4 paramyxovirus. High multiplicity of infection passaging of both NiV clinical isolates and recombinant NiV in Vero cells generated an extensive DI population from which individual DIs were identified using next-generation sequencing techniques. Assays were established to generate and purify both naturally occurring and in silico-designed DIs as fully encapsidated, infectious virus-like particles termed defective interfering particles (DIPs). We demonstrate that several of these NiV DIP candidates reduced NiV titers by up to 4 logs in vitro. These data represent a proof-of-principle that a therapeutic application of DIPs to combat NiV infections may be an alternative source of antiviral control for this disease. |
Griffithsin inhibits Nipah virus entry and fusion and can protect Syrian golden hamsters from lethal Nipah virus challenge
Lo MK , Spengler JR , Krumpe LRH , Welch SR , Chattopadhyay A , Harmon JR , Coleman-McCray JD , Scholte FEM , Hotard AL , Fuqua JL , Rose JK , Nichol ST , Palmer KE , O'Keefe BR , Spiropoulou CF . J Infect Dis 2020 221 S480-S492 Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis and respiratory disease in humans. There is currently no approved therapeutic for human use against NiV infection. Griffithsin (GRFT) is high-mannose oligosaccharide binding lectin that has shown in vivo broad-spectrum activity against viruses including severe acute respiratory syndrome coronavirus, human immunodeficiency virus 1, hepatitis C virus, and Japanese encephalitis virus. In this study, we evaluated the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) against NiV and other viruses from across 4 virus families. The 3mG had comparatively greater potency than GRFT against NiV due to its enhanced ability to block NiV glycoprotein-induced syncytia formation. Our initial in vivo prophylactic evaluation of an oxidation-resistant GRFT (Q-GRFT) showed significant protection against lethal NiV challenge in Syrian golden hamsters. Our results warrant further development of Q-GRFT and 3mG as potential NiV therapeutics. |
Determining the molecular drivers of species-specific interferon-stimulated gene product 15 interactions with nairovirus ovarian tumor domain proteases.
Dzimianski JV , Scholte FEM , Williams IL , Langley C , Freitas BT , Spengler JR , Bergeron E , Pegan SD . PLoS One 2019 14 (12) e0226415 Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection. |
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