RESUMO
We identified a cluster of mpox exposures among key populations in Kenya through retrospective serologic screening. We identified strong seropositivity among sex workers and gay, bisexual, and other men who have sex with men. These findings demonstrate the need for increased mpox surveillance among mpox-endemic and mpox-endemic-adjacent regions in Africa.
Assuntos
Anticorpos Antivirais , Orthopoxvirus , Humanos , Quênia/epidemiologia , Estudos Soroepidemiológicos , Masculino , Anticorpos Antivirais/sangue , Estudos Retrospectivos , Adulto , Orthopoxvirus/imunologia , Feminino , Infecções por Poxviridae/epidemiologia , Infecções por Poxviridae/imunologia , Adulto Jovem , Pessoa de Meia-Idade , AdolescenteRESUMO
PURPOSE OF REVIEW: To highlight the clinical features of mpox with an emphasis on ocular manifestations and to review treatment options for this re-emerging infectious disease. RECENT FINDINGS: Ocular involvement of mpox varies by clade. The most recent 2022 outbreak appears to be associated with fewer conjunctivitis cases compared to previous outbreaks. However, the ocular findings occurring during this newly emerging clade can be visually threatening and include cases of keratitis, rapidly progressing scleritis, and necrotizing periorbital rashes. SUMMARY: Ocular mpox is an important clinical feature of systemic mpox virus (MPXV) infection. Heightened clinical suspicion allows for a timely diagnosis and the initiation of antiviral treatment, when appropriate. Randomized clinical trials for mpox systemic and ocular treatment efficacy are lacking. Prior clinical experience with smallpox and in-vitro mpox data support the use of systemic antivirals such as tecovirimat, cidofovir, brincidofovir and topical use of trifluridine in ocular mpox management, though treatment-resistant infection can occur and portend a poor prognosis.
Assuntos
Antivirais , Infecções Oculares Virais , Humanos , Antivirais/uso terapêutico , Infecções Oculares Virais/diagnóstico , Infecções Oculares Virais/virologia , Infecções Oculares Virais/tratamento farmacológico , Orthopoxvirus , Esclerite/diagnóstico , Esclerite/tratamento farmacológico , Esclerite/etiologiaRESUMO
We assessed early antibody responses after two doses of JYNNEOS (IMVANEX) mpox vaccine in the District of Columbia (D.C.) in persons at high risk for mpox without characteristic lesions or rash. Participants with PCR mpox negative specimens (oral swab, blood, and/or rectal swab) on the day of receipt of the first vaccine dose and who provided a baseline (day 0) serum sample and at least one serum sample at â¼28, â¼42-56 days, or 180 days post vaccination were included in this analysis. Orthopoxvirus (OPXV)-specific IgG and IgM ELISAs and neutralizing antibody titers were performed, and longitudinal serologic responses were examined. Based on participants' IgG and IgM antibody levels at baseline, they were categorized as naïve or non-naïve. Linear mixed effects regression models were conducted to determine if IgG antibody response over time varied by age, sex, HIV status, and route of administration for both naïve and non-naïve participants. Among both naïve and non-naïve participants IgG seropositivity rates increased until day 42-56, with 89.4 % of naïve and 92.1 % of non-naïve participants having detectable IgG antibodies. The proportion of naive participants with detectable IgG antibodies declined by day 180 (67.7 %) but remained high among non-naïve participants (94.4 %). Neutralizing antibody titers displayed a similar pattern, increasing initially post vaccination but declining by day 180 among naïve participants. There were no significant serologic response differences by age, sex, or HIV status. Serologic response did vary by route of vaccine administration, with those receiving a combination of intradermal and subcutaneous doses displaying significantly higher IgG values than those receiving both doses intradermally. These analyses provide initial insights into the immunogenicity of a two-dose JYNNEOS PEP regimen in individuals at high risk of mpox exposure in the United States.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Imunoglobulina G , Imunoglobulina M , Humanos , Masculino , Feminino , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Imunoglobulina G/sangue , Adulto , Anticorpos Neutralizantes/sangue , Pessoa de Meia-Idade , Adulto Jovem , Imunoglobulina M/sangue , Vacina Antivariólica/imunologia , Vacina Antivariólica/administração & dosagem , Adolescente , Orthopoxvirus/imunologia , Vacínia/imunologia , Vacinação/métodos , Estudos de CoortesRESUMO
Poxviruses are large (200-450 nm) and enveloped viruses carrying double-stranded DNA genome with an epidermal cell-specific adaptation. The genus Orthopoxvirus within Poxviridae family constitutes several medically and veterinary important viruses including variola (smallpox), vaccinia, monkeypox virus (MPXV), and cowpox. The monkeypox disease (mpox) has recently emerged as a public health emergency caused by MPXV. An increasing number of human cases of MPXV have been documented in non-endemic nations without any known history of contact with animals brought in from endemic and enzootic regions, nor have they involved travel to an area where the virus was typically prevalent. Here, we review the MPXV replication, virus pathobiology, mechanism of viral infection transmission, virus evasion the host innate immunity and antiviral therapies against Mpox. Moreover, preventive measures including vaccination were discussed and concluded that cross-protection against MPXV may be possible using antibodies that are directed against an Orthopoxvirus. Despite the lack of a specialised antiviral medication, several compounds such as Cidofovir and Ribavirin warrant consideration against mpox.
Assuntos
Monkeypox virus , Mpox , Orthopoxvirus , Humanos , Animais , Monkeypox virus/genética , Monkeypox virus/patogenicidade , Monkeypox virus/imunologia , Orthopoxvirus/genética , Orthopoxvirus/imunologia , Orthopoxvirus/classificação , Mpox/virologia , Mpox/transmissão , Mpox/epidemiologia , Antivirais/uso terapêutico , Antivirais/farmacologia , Replicação Viral , Infecções por Poxviridae/virologia , Infecções por Poxviridae/transmissão , Infecções por Poxviridae/prevenção & controle , Infecções por Poxviridae/imunologiaRESUMO
Since May 2022, the multi-country outbreak of monkeypox (mpox) has raised a great concern worldwide. Early detection of mpox virus infection is recognized as an efficient way to prevent mpox transmission. Mpox specific detection methods reported up to now are based on the SNPs among mpox virus and other orthopoxviruses. We have therefore developed a real-time PCR based mpox detection method targeting mpox virus specific sequences (N3R and B18Rplus). We have also optimized an orthopoxvirus detection system which targets the highly conserved E9L and D6R genes. The mpox and orthopoxvirus real-time PCR assays have a high sensitivity (1 copy/reaction) and specificity. Mpox viral DNA and clinical samples from mpox patients are detected with the mpox detection system. Furthermore, we have established a multiplex real-time PCR detection system allowing simultaneous and efficient detection of mpox and orthopoxvirus infections.
Assuntos
Monkeypox virus , Mpox , Reação em Cadeia da Polimerase Multiplex , Orthopoxvirus , Infecções por Poxviridae , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Orthopoxvirus/genética , Orthopoxvirus/isolamento & purificação , Humanos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Monkeypox virus/genética , Monkeypox virus/isolamento & purificação , Infecções por Poxviridae/diagnóstico , Infecções por Poxviridae/virologia , Infecções por Poxviridae/veterinária , Mpox/diagnóstico , Mpox/virologia , Técnicas de Diagnóstico Molecular/métodosRESUMO
The recent outbreak of mpox epidemic, caused by monkeypox virus (MPXV), poses a new threat to global public health. Here, we initially assessed the preexisting antibody level to the MPXV B6 protein in vaccinia vaccinees born before the end of the immunization program and then identified two monoclonal antibodies (MAbs), hMB621 and hMB668, targeting distinct epitopes on B6, from one vaccinee. Binding assays demonstrate that both MAbs exhibit broad binding abilities to B6 and its orthologs in vaccinia (VACV), variola (VARV) and cowpox viruses (CPXV). Neutralizing assays reveal that the two MAbs showed potent neutralization against VACV. Animal experiments using a BALB/c female mouse model indicate that the two MAbs showed effective protection against VACV via intraperitoneal injection. Additionally, we determined the complex structure of B6 and hMB668, revealing the structural feature of B6 and the epitope of hMB668. Collectively, our study provides two promising antibody candidates for the treatment of orthopoxvirus infections, including mpox.
Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , Epitopos , Camundongos Endogâmicos BALB C , Animais , Humanos , Feminino , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Camundongos , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Monkeypox virus/imunologia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/prevenção & controle , Vaccinia virus/imunologia , Orthopoxvirus/imunologia , Mpox/imunologia , Mpox/prevenção & controleRESUMO
In 2022, an unprecedented outbreak of mpox raged in several nations. Sequences from the 2022 outbreak reveal a higher nucleotide substitution if compared with the estimated rate for orthopoxviruses. Recently, intra-lesion SNVs (single nucleotide variants) have been described, and these have been suggested as possible sources of genetic variation. Until now, it has not been clear if the presence of several SNVs could represents the result of local mutagenesis or a possible co-infection. We investigated the significance of SNVs through whole-genome sequencing analysis of four unrelated mpox cases. In addition to the known mutations harboured by the circulating strains of virus (MPXV), 7 novel mutations were identified, including SNVs located in genes that are involved in immune evasion mechanisms and/or viral fitness, six of these appeared to be APOBEC3-driven. Interestingly, three patients exhibited the coexistence of mutated and wild-type alleles for five non-synonymous variants. In addition, two patients, apparently unrelated, showed an analogous pattern for two novel mutations, albeit with divergent frequencies. The coexistence of mixed viral populations, harbouring non-synonymous mutations in patients, supports the hypothesis of possible co-infection. Additional investigations of larger clinical cohorts are essential to validating intra-patient viral genome heterogeneity and determining the possibility of co-presence events of slightly divergent MPXV strains.
Assuntos
Surtos de Doenças , Genoma Viral , Mutação , Sequenciamento Completo do Genoma , Humanos , Itália/epidemiologia , Masculino , Orthopoxvirus/genética , Orthopoxvirus/classificação , Infecções por Poxviridae/virologia , Infecções por Poxviridae/epidemiologia , Infecções por Poxviridae/veterinária , Feminino , Coinfecção/virologia , Coinfecção/epidemiologia , Filogenia , Polimorfismo de Nucleotídeo Único , Pessoa de Meia-Idade , Variação GenéticaRESUMO
In May 2022, mpox began to spread worldwide, posing a serious threat to human public health. Modified Vaccinia Ankara-Bavaria Nordic (MVA-BN) is a live attenuated orthopoxvirus vaccine that has been authorized by the U.S. Food and Drug Administration as the vaccine of choice for the prevention of mpox. In this study, we conducted a meta-analysis of all currently published literature on the efficacy and safety of the MVA-BN vaccine in the real world, showing that the MVA-BN vaccine is effective and safe, with efficacy of up to 75% with a single dose and up to 80% with a two-dose vaccine. Meanwhile, we found that subcutaneous injection has lower local and systemic adverse events than intradermal injection, regardless of single- or two-dose vaccination, and subcutaneous injection is better tolerated in children, the elderly, or people with underlying medical conditions. These results have important reference value for clinical practice.
Assuntos
Eficácia de Vacinas , Vacinas Atenuadas , Humanos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Infecções por Poxviridae/prevenção & controle , Infecções por Poxviridae/imunologia , Vaccinia virus/imunologia , Vaccinia virus/genética , Vacinação , Injeções Subcutâneas , Injeções Intradérmicas , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Orthopoxvirus/imunologia , Orthopoxvirus/genética , CriançaAssuntos
Orthopoxvirus , Infecções por Poxviridae , Zoonoses , Orthopoxvirus/genética , Animais , Infecções por Poxviridae/virologia , Infecções por Poxviridae/epidemiologia , Humanos , Zoonoses/virologia , Zoonoses/transmissão , Zoonoses/epidemiologia , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/virologia , Doenças Transmissíveis Emergentes/transmissãoRESUMO
The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly caused by genomic changes in subclade IIb MPXV. Key genomic changes could occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and are often dismissed as uninformative. Here, using a combination of highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204, and OPG208, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability.
Assuntos
Mpox , Orthopoxvirus , Poxviridae , Humanos , Monkeypox virus/genética , Genômica , Mpox/genéticaRESUMO
The eradication of smallpox was officially declared by the WHO in 1980, leading to discontinuation of the vaccination campaign against the virus. Consequently, immunity against smallpox and related orthopoxviruses like Monkeypox virus gradually declines, highlighting the need for efficient countermeasures not only for the prevention, but also for the treatment of already exposed individuals. We have recently developed human-like monoclonal antibodies (mAbs) from vaccinia virus-immunized non-human primates. Two mAbs, MV33 and EV42, targeting the two infectious forms of the virus, were selected for in vivo evaluation, based on their in vitro neutralization potency. A single dose of either MV33 or EV42 administered three days post-infection (dpi) to BALB/c female mice provides full protection against lethal ectromelia virus challenge. Importantly, a combination of both mAbs confers full protection even when provided five dpi. Whole-body bioimaging and viral load analysis reveal that combination of the two mAbs allows for faster and more efficient clearance of the virus from target organs compared to either MV33 or EV42 separately. The combined mAbs treatment further confers post-exposure protection against the currently circulating Monkeypox virus in Cast/EiJ female mice, highlighting their therapeutic potential against other orthopoxviruses.
Assuntos
Orthopoxvirus , Infecções por Poxviridae , Varíola , Vacínia , Humanos , Feminino , Animais , Camundongos , Anticorpos Monoclonais , Infecções por Poxviridae/prevenção & controle , Vaccinia virus , Anticorpos AntiviraisRESUMO
OBJECTIVES: The aim was to estimate the effect of reported history of smallpox vaccination prior to 1980 on clinical expression of mpox. METHODS: We included all confirmed mpox cases identified by the national mpox surveillance system in France between May and July 2022. Cases tested positive for monkeypox virus or orthopoxviruses by PCR. Cases were interviewed by phone using a questionnaire documenting demographics, symptoms and exposures. To estimate the effect of smallpox vaccination on the presence of marked mpox symptoms (association of fever, lymphadenopathy and extensive mucocutaneous lesions), we estimated prevalence ratios (PRs) and 95% CIs using Poisson regression models with robust standard errors. RESULTS: There were 1888 confirmed mpox cases with date of symptom onset between 7 May and 31 July 2022. Overall, 7% (93/1394) presented marked mpox symptoms. Among patients who provided information about their vaccination status, 14% (207/1469) reported smallpox vaccination prior to 1980. The proportion of cases with marked symptoms was 2% (3/170) among those reporting smallpox vaccination prior to 1980 and 8% (76/974) among those who reported no vaccination. The proportion of marked symptoms was four times lower among cases reporting previous smallpox vaccination than in cases reporting no vaccination (PR, 0.24; 95% CI: 0.08-0.76). There was no evidence of an effect of smallpox vaccination on development of complications (PR, 0.65; 95% CI: 0.35-1.22) or hospitalization due to mpox (PR, 0.64; 95% CI: 0.23-1.80). DISCUSSION: Our results suggest that smallpox vaccination during childhood attenuated the clinical expression of monkeypox virus infection, but there was no evidence of an effect on complications or hospitalization.
Assuntos
Vacina Antivariólica , Vacinação , Humanos , França/epidemiologia , Masculino , Feminino , Adulto , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Criança , Vacinação/estatística & dados numéricos , Mpox/epidemiologia , Pré-Escolar , Idoso , Lactente , Monkeypox virus/genética , Prevalência , Orthopoxvirus/genética , Varíola/epidemiologia , Varíola/prevenção & controleRESUMO
BACKGROUND: After the eradication of smallpox, there have been no specific public health measures for any Orthopoxviruses (OPXVs). Therefore, it is necessary to countermeasure OPXV infections after Mpox (formerly monkeypox) occurrences, such as the latest global outbreak in 2022-2023. This study aimed to provide crucial insights for the development of effective public health policy making against mpox in populations residing in regions where the virus is not prevalent. METHODS: This study used enzyme-linked immunosorbent assays (ELISA) to examine smallpox and mpox antibodies in Koreans with three different age groups. We analyzed 56 sera obtained from a tertiary care hospital in South Korea between September 2022 and April 2023. Plasma levels of antibodies against the viral proteins of smallpox (variola cytokine response-modifying protein B) and MPXV (A29) were measured using enzyme-linked immunosorbent assays. RESULTS: Plasma samples from participants in their early 40 s and older exhibited higher reactivity to viral antigens than those from younger participants. Furthermore, there was a strong positive correlation in antibody positivity for the two different viruses across the sera. CONCLUSIONS: The presence of low antibody levels in participants Ë40 years may hinder their ability to defend against OPXV. Therefore, it is imperative to implement effective public health measures to mitigate the transmission of OPXV within the community. These findings serve as fundamental information for devising strategies to combat mpox efficiently, particularly in regions where the virus is not prevalent.
Assuntos
Anticorpos Antivirais , Ensaio de Imunoadsorção Enzimática , Orthopoxvirus , Humanos , Adulto , Anticorpos Antivirais/sangue , República da Coreia/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Feminino , Orthopoxvirus/imunologia , Fatores Etários , Saúde Pública , Idoso , Adolescente , Formação de Anticorpos , Varíola/prevenção & controle , Varíola/imunologia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/epidemiologia , Mpox/epidemiologia , Mpox/imunologiaRESUMO
BACKGROUND: Limited data are available on Mpox breakthrough infections. PURPOSE: The purpose of this study is to investigate a Mpox breakthrough outbreak in 3 vaccinated individuals. METHODS: Study participants provided informed consent. Serology testing was performed in one involved individual (ID-1) using an in-house assay detecting anti-orthopoxvirus IgG. Whole genome sequencing (WGS) was carried out and compared with the reference sequence ON563414.3 ( https://www.ncbi.nlm.nih.gov/nuccore/ON563414.3/ ). RESULTS: Three individuals vaccinated with modified vaccinia Ankara-Bavaria Nordic contracted Mpox following one sexual intercourse event. One of them (ID-1) had received only one vaccine dose, while the other two were fully vaccinated. ID-1 presented to the sexual health clinic of the Universitair Ziekenhuis Brussel with proctitis related to Mpox. Despite one vaccination, serology testing Three months post vaccine showed absence of Mpox virus (MPXV) specific antibodies in ID-1. In contrast, 2 weeks after the sexual intercourse, seroconversion occurred. Whole genome sequencing of the isolated MPXV showed, compared with the reference sequence, a total of seven single nucleotide variants with four of them indicating protein amino-acid changes. CONCLUSION: Incomplete MPXV vaccination as well as MPXV variants might result in breakthrough infections. Preventive measures, such as MPVX vaccination, could maintain immunity in individuals with higher risk of MPXV infection, and might lower disease severity.
Assuntos
Anticorpos Antivirais , Surtos de Doenças , Humanos , Masculino , Anticorpos Antivirais/sangue , Adulto , Feminino , Sequenciamento Completo do Genoma , Vacinação , Infecções por Poxviridae/epidemiologia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/virologia , Orthopoxvirus/imunologia , Orthopoxvirus/genética , Pessoa de Meia-IdadeRESUMO
AIMS: To evaluate whether antibodies specific for the vaccinia virus (VV) are still detectable after at least 45 years from immunization. To confirm that VV-specific antibodies are endowed with the capacity to neutralize Mpox virus (MPXV) in vitro. To test a possible role of polyclonal non-specific activation in the maintenance of immunologic memory. METHODS: Sera were collected from the following groups: smallpox-vaccinated individuals with or without latent tuberculosis infection (LTBI), unvaccinated donors, and convalescent individuals after MPXV infection. Supernatant of VV- or MPXV-infected Vero cells were inactivated and used as antigens in ELISA or in Western blot (WB) analyses. An MPXV plaque reduction neutralization test (PRNT) was optimized and performed on study samples. VV- and PPD-specific memory T cells were measured by flow cytometry. RESULTS: None of the smallpox unvaccinated donors tested positive in ELISA or WB analysis and their sera were unable to neutralize MPXV in vitro. Sera from all the individuals convalescing from an MPXV infection tested positive for anti-VV or MPXV IgG with high titers and showed MPXV in vitro neutralization capacity. Sera from most of the vaccinated individuals showed IgG anti-VV and anti-MPXV at high titers. WB analyses showed that positive sera from vaccinated or convalescent individuals recognized both VV and MPXV antigens. Higher VV-specific IgG titer and specific T cells were observed in LTBI individuals. CONCLUSIONS: ELISA and WB performed using supernatant of VV- or MPXV-infected cells are suitable to identify individuals vaccinated against smallpox at more than 45 years from immunization and individuals convalescing from a recent MPXV infection. ELISA and WB results show a good correlation with PRNT. Data confirm that a smallpox vaccination induces a long-lasting memory in terms of specific IgG and that antibodies raised against VV may neutralize MPXV in vitro. Finally, higher titers of VV-specific antibodies and higher frequency of VV-specific memory T cells in LTBI individuals suggest a role of polyclonal non-specific activation in the maintenance of immunologic memory.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Linfócitos B , Reações Cruzadas , Vacina Antivariólica , Vaccinia virus , Adulto , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Chlorocebus aethiops , Reações Cruzadas/imunologia , Ensaio de Imunoadsorção Enzimática , Memória Imunológica , Ativação Linfocitária , Testes de Neutralização , Orthopoxvirus/imunologia , Varíola/imunologia , Varíola/prevenção & controle , Vacina Antivariólica/imunologia , Linfócitos T/imunologia , Vacinação , Vaccinia virus/imunologia , Células Vero , Monkeypox virus/imunologiaAssuntos
Orthopoxvirus , Infecções por Poxviridae , Animais , Humanos , Regiões Árticas/epidemiologia , Doenças Transmissíveis Emergentes/virologia , Doenças Transmissíveis Emergentes/epidemiologia , Orthopoxvirus/isolamento & purificação , Infecções por Poxviridae/virologia , Infecções por Poxviridae/diagnósticoRESUMO
Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a restriction factor for VACV and herpes simplex virus type 1. Here, we report that HDAC5 promotes interferon regulatory factor 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss of HDAC5-mediated IRF3 activation is restored by re-introduction of HDAC5 but not HDAC1 or HDAC4. The antiviral activity of HDAC5 is antagonized by VACV protein C6 and orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, and variola. Infection by many of these viruses induces proteasomal degradation of HDAC5, and expression of C6 alone can induce HDAC5 degradation. Mechanistically, C6 binds to the dimerization domain of HDAC5 and prevents homodimerization and heterodimerization with HDAC4. Overall, this study describes HDAC5 as a positive regulator of IRF3 activation and provides mechanistic insight into how the poxviral protein C6 binds to HDAC5 to antagonize its function.
Assuntos
Orthopoxvirus , Vírus da Varíola , Monkeypox virus/metabolismo , Vírus da Varíola/metabolismo , Orthopoxvirus/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Vaccinia virus/fisiologia , Histona Desacetilases/metabolismoRESUMO
The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses.