Establishment of a non-lethal model of antibody-dependent enhancement of infection in A129 mice based on a non-mouse-adapted dengue virus strain.
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ABSTRACT:
SUBMITTER: Wang H
PROVIDER: S-EPMC10559087 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Establishment of a non-lethal model of antibody-dependent enhancement of infection in A129 mice based on a non-mouse-adapted dengue virus strain.
Wang Han H Long Ming-Wang MW Zhang Li L Pan Yue Y Chen Jun-Ying JY Feng Kai K Sun Qiang-Ming QM
Zoological research 20230901 5
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Project description:Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcgamma receptors (FcgammaR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcgammaR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.
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Project description:In search of a mouse model for use in evaluating dengue vaccines, we assessed A129 mice that lacked IFN-α/β receptors, rendering them susceptible to dengue virus (DENV) infection. To our knowledge, no reports have evaluated dengue vaccine efficiency using A129 mice. A129 mice were given a single intraperitoneal (IP) or subcutaneous (SC) injection of the vaccine, Dengvaxia. After 14 days of immunization via the IP or SC injection of Dengvaxia, the A129 mice exhibited notably elevated levels of anti-DENV immunoglobulin G and neutralizing antibodies (NAb) targeting all four DENV serotypes, with DENV-4 displaying the highest NAb levels. After challenge with DENV-2, Dengvaxia and mock-immunized mice survived, while only the mock group exhibited signs of morbidity. Viral genome levels in the serum and tissues (excluding the brain) were considerably lower in the immunized mice compared to those in the mock group. The SC administration of Dengvaxia resulted in lower viremia levels than IP administration did. Therefore, given that A129 mice manifest dengue-related morbidity, including viremia in the serum and other tissues, these mice represent a valuable model for investigating novel dengue vaccines and antiviral drugs and for exploring dengue pathogenesis.
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Project description:Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are severe disease manifestations that can occur following sequential infection with different dengue virus serotypes (DENV1-4). At present, there are no licensed therapies to treat DENV-induced disease. DHF and DSS are thought to be mediated by serotype cross-reactive antibodies that facilitate antibody-dependent enhancement (ADE) by binding to viral antigens and then Fcγ receptors (FcγR) on target myeloid cells. Using genetically engineered DENV-specific antibodies, it has been shown that the interaction between the Fc portion of serotype cross-reactive antibodies and FcγR is required to induce ADE. Additionally, it was demonstrated that these antibodies were as neutralizing as their non-modified variants, were incapable of inducing ADE, and were therapeutic following a lethal, antibody-enhanced infection. Therefore, we hypothesized that avian IgY, which do not interact with mammalian FcγR, would provide a novel therapy for DENV-induced disease. We demonstrate here that goose-derived anti-DENV2 IgY neutralized DENV2 and did not induce ADE in vitro. Anti-DENV2 IgY was also protective in vivo when administered 24 hours following a lethal DENV2 infection. We were also able to demonstrate via epitope mapping that both full-length and alternatively spliced anti-DENV2 IgY recognized different epitopes, including epitopes that have not been previously identified. These observations provide evidence for the potential therapeutic applications of goose-derived anti-DENV2 IgY.
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Project description:UnlabelledInfections with Marburg virus (MARV) and Ebola virus (EBOV) cause severe hemorrhagic fever in humans and nonhuman primates (NHPs) with fatality rates up to 90%. A number of experimental vaccine and treatment platforms have previously been shown to be protective against EBOV infection. However, the rate of development for prophylactics and therapeutics against MARV has been lower in comparison, possibly because a small-animal model is not widely available. Here we report the development of a mouse model for studying the pathogenesis of MARV Angola (MARV/Ang), the most virulent strain of MARV. Infection with the wild-type virus does not cause disease in mice, but the adapted virus (MARV/Ang-MA) recovered from liver homogenates after 24 serial passages in severe combined immunodeficient (SCID) mice caused severe disease when administered intranasally (i.n.) or intraperitoneally (i.p.). The median lethal dose (LD50) was determined to be 0.015 50% TCID50 (tissue culture infective dose) of MARV/Ang-MA in SCID mice, and i.p. infection at a dose of 1,000× LD50 resulted in death between 6 and 8 days postinfection in SCID mice. Similar results were obtained with immunocompetent BALB/c and C57BL/6 mice challenged i.p. with 2,000× LD50 of MARV/Ang-MA. Virological and pathological analyses of MARV/Ang-MA-infected BALB/c mice revealed that the associated pathology was reminiscent of observations made in NHPs with MARV/Ang. MARV/Ang-MA-infected mice showed most of the clinical hallmarks observed with Marburg hemorrhagic fever, including lymphopenia, thrombocytopenia, marked liver damage, and uncontrolled viremia. Virus titers reached 10(8) TCID50/ml in the blood and between 10(6) and 10(10) TCID50/g tissue in the intestines, kidney, lungs, brain, spleen, and liver. This model provides an important tool to screen candidate vaccines and therapeutics against MARV infections.ImportanceThe Angola strain of Marburg virus (MARV/Ang) was responsible for the largest outbreak ever documented for Marburg viruses. With a 90% fatality rate, it is similar to Ebola virus, which makes it one of the most lethal viruses known to humans. There are currently no approved interventions for Marburg virus, in part because a small-animal model that is vulnerable to MARV/Ang infection is not available to screen and test potential vaccines and therapeutics in a quick and economical manner. To address this need, we have adapted MARV/Ang so that it causes illness in mice resulting in death. The signs of disease in these mice are reminiscent of wild-type MARV/Ang infections in humans and nonhuman primates. We believe that this will be of help in accelerating the development of life-saving measures against Marburg virus infections.
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Project description:Human primary monocytes were differentiated for 6days in the presence of M-CSF. The resulting macrophages were infected with dengue virus serotype 2, strain 16681 under the following conditions: Mock, Multiplicity of infection (MOI) 1 without antibodies, MOI 1 with 40ng/mL of irrelevant human antibody, MOI 1 with infection enhancing antibody (40ng/mL of a human monoclonal antibody against dengue), and either MOI 5 or MOI 2.5. Total cell RNA was isolated at 2h post infection or 24h post infection.
2014-12-30 | E-MTAB-3138 | biostudies-arrayexpress
Project description:Mayaro (MAYV) and chikungunya viruses (CHIKV) are vector-borne arthritogenic alphaviruses that cause acute febrile illnesses. CHIKV is widespread and has recently caused large urban outbreaks, whereas the distribution of MAYV is restricted to tropical areas in South America with small and sporadic outbreaks. Because MAYV and CHIKV are closely related and have high amino acid similarity, we investigated whether vaccination against one could provide cross-protection against the other. We vaccinated A129 mice (IFNAR -/-) with vaccines based on chimpanzee adenoviral vectors encoding the structural proteins of either MAYV or CHIKV. ChAdOx1 May is a novel vaccine against MAYV, whereas ChAdOx1 Chik is a vaccine against CHIKV already undergoing early phase I clinical trials. We demonstrate that ChAdOx1 May was able to afford full protection against MAYV challenge in mice, with most samples yielding neutralizing PRNT80 antibody titers of 1:258. ChAdOx1 May also provided partial cross-protection against CHIKV, with protection being assessed using the following parameters: survival, weight loss, foot swelling and viremia. Reciprocally, ChAdOx1 Chik vaccination reduced MAYV viral load, as well as morbidity and lethality caused by this virus, but did not protect against foot swelling. The cross-protection observed is likely to be, at least in part, secondary to cross-neutralizing antibodies induced by both vaccines. In summary, our findings suggest that ChAdOx1 Chik and ChAdOx1 May vaccines are not only efficacious against CHIKV and MAYV, respectively, but also afford partial heterologous cross-protection.
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2006-12-15 | GSE6530 | GEO
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