Abstract
Ocular complications of Ebola virus disease are well-documented and long-term sequelae in survivors are common and lead to considerable morbidity. However, little is currently known ...regarding EBOV's tropism and replication kinetics within the eye. To date, limited studies have utilized in vitro infections of ocular cell lines and analyses of archived pathology samples to investigate these issues. Here, we employed ex vivo cultures of cynomolgus macaque eyes to determine the tropism of EBOV in 7 different ocular tissues: cornea, anterior sclera with bulbar conjunctiva, ciliary body, iris, lens, neural retina, and retina pigment epithelium. We report that, except for neural retina, all tissues supported EBOV replication. Retina pigment epithelium produced the fastest growth and highest viral RNA loads, although the differences were not statistically significant. Immunohistochemical staining confirmed and further characterized infection. This study demonstrates that EBOV has a broad tropism within the eye.
Dysregulated inflammation dominated by chemokine expression is a key feature of disease following infection with the globally important human pathogens Zika virus (ZIKV) and dengue virus, but a ...mechanistic understanding of how pro-inflammatory responses are initiated is lacking. Mitophagy is a quality-control mechanism that regulates innate immune signaling and cytokine production through selective degradation of damaged mitochondria. Here, we demonstrate that ZIKV nonstructural protein 5 (NS5) antagonizes mitophagy by binding to the host protein Ajuba and preventing its translocation to depolarized mitochondria where it is required for PINK1 activation and downstream signaling. Consequent mitophagy suppression amplifies the production of pro-inflammatory chemokines through protein kinase R (PKR) sensing of mitochondrial RNA. In Ajuba−/− mice, ZIKV induces early expression of pro-inflammatory chemokines associated with significantly enhanced dissemination to tissues. This work identifies Ajuba as a critical regulator of mitophagy and demonstrates a role for mitophagy in limiting systemic inflammation following infection by globally important human viruses.
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•Zika virus antagonizes mitophagy by inhibiting Ajuba translocation to mitochondria•Viral suppression of mitophagy amplifies proinflammatory chemokine expression•Chemokine expression is dependent on PKR sensing of mitochondrial dsRNA•Suppressed mitophagy amplifies early chemokines and viral tissue burden in vivo
Inflammation characterized by chemokine expression is a key feature of Zika virus infection in humans. Here, Ponia et al. demonstrate that Zika virus antagonizes mitophagy. Retention of damaged mitochondria in infected cells amplifies chemokine expression by PKR-mediated sensing of mitochondrial dsRNA.
Filoviruses are among the most pathogenic infectious agents known to human, with high destructive potential, as evidenced by the recent Ebola virus epidemic in West Africa. As members of the ...filovirus family, marburgviruses have caused similar devastating outbreaks, albeit with lower case numbers. In this study we compare the pathogenesis of Ravn virus (RAVV) and Marburg virus (MARV) strains Angola, Musoke, and Ozolin in rhesus and cynomolgus macaques, the 2 nonhuman primate species most commonly used in filovirus research. Our results reveal the most pathogenic MARV strain to be Angola, followed by Musoke, whereas Ozolin is the least pathogenic. We also demonstrate that RAVV is highly pathogenic in cynomolgus macaques but less pathogenic in rhesus macaques. Our results demonstrate a preferential infection of endothelial cells by MARVs; in addition, analysis of tissue samples suggests that lymphocyte and hepatocyte apoptosis might play a role in MARV pathogenicity. This information expands our knowledge about pathogenicity and virulence of marburgviruses.
Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of ...NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication.
Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in a human with severe pneumonia in 2012. Since then, infections have been detected in >1500 individuals, with disease ...severity ranging from asymptomatic to severe, fatal pneumonia. To elucidate the pathogenesis of this virus and investigate mechanisms underlying disease severity variation in the absence of autopsy data, a rhesus macaque and common marmoset model of MERS-CoV disease were analyzed. Rhesus macaques developed mild disease, and common marmosets exhibited moderate to severe, potentially lethal, disease. Both nonhuman primate species exhibited respiratory clinical signs after inoculation, which were more severe and of longer duration in the marmosets, and developed bronchointerstitial pneumonia. In marmosets, the pneumonia was more extensive, with development of severe airway lesions. Quantitative analysis showed significantly higher levels of pulmonary neutrophil infiltration and higher amounts of pulmonary viral antigen in marmosets. Pulmonary expression of the MERS-CoV receptor, dipeptidyl peptidase 4, was similar in marmosets and macaques. These results suggest that increased virus replication and the local immune response to MERS-CoV infection likely play a role in pulmonary pathology severity. Together, the rhesus macaque and common marmoset models of MERS-CoV span the wide range of disease severity reported in MERS-CoV–infected humans, which will aid in investigating MERS-CoV disease pathogenesis.
Nigeria continues to experience ever increasing annual outbreaks of Lassa fever (LF). The World Health Organization has recently declared Lassa virus (LASV) as a priority pathogen for accelerated ...research leading to a renewed international effort to develop relevant animal models of disease and effective countermeasures to reduce LF morbidity and mortality in endemic West African countries. A limiting factor in evaluating medical countermeasures against LF is a lack of well characterized animal models outside of those based on infection with LASV strain Josiah originating form Sierra Leone, circa 1976. Here we genetically characterize five recent LASV isolates collected from the 2018 outbreak in Nigeria. Three isolates were further evaluated in vivo and despite being closely related and from the same spatial / geographic region of Nigeria, only one of the three isolates proved lethal in strain 13 guinea pigs and non-human primates (NHP). Additionally, this isolate exhibited atypical pathogenesis characteristics in the NHP model, most notably respiratory failure, not commonly described in hemorrhagic cases of LF. These results suggest that there is considerable phenotypic heterogeneity in LASV infections in Nigeria, which leads to a multitude of pathogenesis characteristics that could account for differences between subclinical and lethal LF infections. Most importantly, the development of disease models using currently circulating LASV strains in West Africa are critical for the evaluation of potential vaccines and medical countermeasures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Kyasanur Forest disease virus (KFDV) is an endemic arbovirus in western India mainly transmitted by hard ticks of the genus
Haemaphysalis
. KFDV causes Kyasanur Forest disease (KFD), a syndrome ...including fever, gastrointestinal symptoms, and hemorrhages. There are no approved treatments, and the efficacy of the only vaccine licensed in India has recently been questioned. Here, we studied the protective efficacy of a vesicular stomatitis virus (VSV)–based vaccine expressing the KFDV precursor membrane and envelope proteins (VSV-KFDV) in pigtailed macaques. VSV-KFDV vaccination was found to be safe and elicited strong humoral and cellular immune responses. A single-dose vaccination reduced KFDV loads and pathology and protected macaques from KFD-like disease. Furthermore, VSV-KFDV elicited cross-reactive neutralizing immune responses to Alkhurma hemorrhagic fever virus, a KFDV variant found in Saudi Arabia.
VSV-KFDV is safe, mediates strong immune responses and provides efficacy against KFDV challenge in a nonhuman primate model.
The 2022 mpox virus (MPXV) outbreak was sustained by human-to-human transmission; however, it is currently unclear which factors lead to sustained transmission of MPXV. Here we present Mastomys ...natalensis as a model for MPXV transmission after intraperitoneal, rectal, vaginal, aerosol and transdermal inoculation with an early 2022 human outbreak isolate (Clade IIb). Virus shedding and tissue replication were route dependent and occurred in the presence of self-resolving localized skin, lung, reproductive tract or rectal lesions. Mucosal inoculation via the rectal, vaginal and aerosol routes led to increased shedding, replication and a pro-inflammatory T cell profile compared with skin inoculation. Contact transmission was higher from rectally inoculated animals. This suggests that transmission might be sustained by increased susceptibility of the anal and genital mucosae for infection and subsequent virus release.
Background: Nipah virus (NiV) causes recurrent outbreaks of lethal respiratory and neurological disease in Southeast Asia. The World Health Organization considers the development of an effective ...vaccine against NiV a priority. Methods: We produced two NiV vaccine candidates using the licensed VSV-EBOV vaccine as a backbone and tested its efficacy against lethal homologous and heterologous NiV challenge with Nipah virus Bangladesh and Nipah virus Malaysia, respectively, in the African green monkey model. Findings: The VSV-EBOV vaccine expressing NiV glycoprotein G (VSV-NiVG) induced high neutralising antibody titers and afforded complete protection from homologous and heterologous challenge. The VSV-EBOV vaccine expressing NiV fusion protein F (VSV-NiVF) induced a lower humoral response and afforded complete homologous protection, but only partial heterologous protection. Both vaccines reduced virus shedding from the upper respiratory tract, and virus replication in the lungs and central nervous system. None of the protected animals vaccinated with VSV-NiVG or VSV-NiVF showed histological lesions in the CNS, but one VSV-NiVF-vaccinated animal that was not protected developed severe meningoencephalitis. Interpretation: The VSV-NiVG vaccine offers broad protection against NiV disease. Funding: This study was supported by the Intramural Research Program, NIAID, NIH.
Nipah virus (NiV) causes recurrent outbreaks of lethal respiratory and neurological disease in Southeast Asia. The World Health Organization considers the development of an effective vaccine against ...NiV a priority.
We produced two NiV vaccine candidates using the licensed VSV-EBOV vaccine as a backbone and tested its efficacy against lethal homologous and heterologous NiV challenge with Nipah virus Bangladesh and Nipah virus Malaysia, respectively, in the African green monkey model.
The VSV-EBOV vaccine expressing NiV glycoprotein G (VSV-NiVG) induced high neutralising antibody titers and afforded complete protection from homologous and heterologous challenge. The VSV-EBOV vaccine expressing NiV fusion protein F (VSV-NiVF) induced a lower humoral response and afforded complete homologous protection, but only partial heterologous protection. Both vaccines reduced virus shedding from the upper respiratory tract, and virus replication in the lungs and central nervous system. None of the protected animals vaccinated with VSV-NiVG or VSV-NiVF showed histological lesions in the CNS, but one VSV-NiVF-vaccinated animal that was not protected developed severe meningoencephalitis.
The VSV-NiVG vaccine offers broad protection against NiV disease.
This study was supported by the Intramural Research Program, NIAID, NIH.
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