Addressing vaccine-preventable encephalitis in vulnerable populations.

PURPOSE OF REVIEW: Vaccinations have been pivotal in lowering the global disease burden of vaccine-preventable encephalitides, including Japanese encephalitis, tick-borne encephalitis, measles encephalitis, and rabies encephalitis, among others. RECENT FINDINGS: Populations vulnerable to vaccine-preventable infections that may lead to encephalitis include those living in endemic and rural areas, military members, migrants, refugees, international travelers, younger and older persons, pregnant women, the immunocompromised, outdoor, healthcare and laboratory workers, and the homeless. There is scope for improving the availability and distribution of vaccinations, vaccine equity, surveillance of vaccine-preventable encephalitides, and public education and information. SUMMARY: Addressing these gaps in vaccination strategies will allow for improved vaccination coverage and lead to better health outcomes for those most at risk for vaccine-preventable encephalitis.

Japanese encephalitis virus persists in the human reproductive epithelium and porcine reproductive tissues.

Japanese encephalitis virus (JEV) is the emerging and geographically expanding flavivirus and the major causative agent of encephalitis in humans in Asia. There are risks of JEV introduction into the Americas given a large population of amplifying hosts-pigs and wild boars, and insect vectors-Culex mosquitoes. There are emerging concerns about vector-free ways of flavivirus transmission, for example sexual and transplacental Zika virus transmissions, which may change flavivirus epidemiology and expand the geographical range to territories with no insect vectors. It is unknown whether JEV has tropism in the female lower reproductive tract and the potential for sexual transmission in humans. While clinical outcomes of transplacental JEV infection are described in humans and pigs, cellular targets and tissue tropism in the upper reproductive tract are also unknown. Here, we studied JEV infection phenotypes and host transcriptional responses in human reproductive epithelial cells. We found that JEV caused persistent infection and cytopathology in the vaginal epithelium, endometrial epithelium, and trophoblast. Human vaginal epithelial cells infected with JEV had altered transcriptional responses associated with inflammation and disruption of epithelial barrier function. Also, using pigs-the native amplifying host for JEV, we confirmed JEV tropism in the female lower and upper reproductive tracts. We discovered that JEV persists in the vaginal mucosa for at least 28 days and pigs shed the virus in vaginal secretions. We also found JEV persistence in the endometrium and placenta with transplacental and fetal infections. Altogether, we discovered that JEV targets the vaginal epithelium and has the potential for sexual transmission in humans. We also contributed to a better understanding of JEV pathogenesis during transplacental infection. Further studies are needed to better understand the interactions of JEV with reproductive tissues, how persistent infection affects female reproductive functions, and the risks for non-vector transmission.

Identifying Japanese Encephalitis Virus Using Metatranscriptomic Sequencing, Xinjiang, China.

The treat of infectious disease epidemics has increased the critical need for continuous broad-ranging surveillance of pathogens with outbreak potential. Using metatranscriptomic sequencing of blood samples, we identified several cases of Japanese encephalitis virus infection from Xinjiang Uyghur Autonomous Region, China. This discovery highlights the risk for known viral diseases even in nonendemic areas.

Safety profile comparison of chimeric live attenuated and Vero cell-derived inactivated Japanese encephalitis vaccines through an active surveillance system in Australia.

Limited information is available about post-marketing safety of Japanese encephalitis (JE) vaccines. Using data from SmartVax, an active surveillance system for monitoring vaccine safety, adverse events following immunizations (AEFIs) were compared between the two JE vaccines available in Australia (a chimeric live attenuated vaccine [Imojev] and a Vero cell-derived inactivated vaccine [JEspect]). Data from 2756 patients (1855 Imojev and 901 JEspect) were included. Overall (7.0%), systemic (2.8%), and local (1.9%) AEFIs were uncommon. There were no significant differences in the odds of overall (OR = 1.27; 95%CI: 0.91-1.77), systemic (OR = 1.23; 95%CI: 0.74-2.06), or local (OR = 1.20; 95%CI: 0.65-2.22) AEFIs with Imojev compared to JEspect. There was an increase in odds of overall AEFI in patients aged <5 years (OR = 2.39; 95%CI: 1.10-5.19) compared to those aged >50 years. Both JE vaccines available in Australia are safe and well tolerated. Odds of AEFIs were age-dependent, young children should be carefully observed for AEFIs after vaccination.

High-resolution intracranial vessel wall imaging in cerebral viral infections evaluations.

PURPOSE: Vascular complications can be seen in various viral CNS infections. Variable neuro-imaging findings have been described in the literature elucidating the parenchymal changes with vascular involvement. Vessel wall imaging (VWI) can help to detect these vascular involvements. We aimed to describe the role and usefulness of VWI in the evaluation of various viral CNS infections. METHODS: In this prospective study, we included 15 cases of various diagnosed viral CNS infections (varicella, HIV encephalopathy, HSV encephalitis, Japanese encephalitis, dengue, COVID-19). VWI and time-of-flight MR angiography (TOF MRA) were included in imaging protocol. All cases were evaluated for the presence of cerebral parenchymal changes, vascular enhancement, and vascular stenosis. RESULTS: We found infarctions in all 5 cases of varicella, 1 case of HIV encephalopathy, and 1 case of COVID-19 encephalopathy. All these cases also showed vascular enhancement and stenosis on VWI. The rest of the cases, including 1 case of HIV encephalopathy, 3 cases of herpes encephalitis, 2 cases of dengue, and 2 cases of Japanese encephalitis did not have any vascular complication, and also did not show vascular enhancement or stenosis. CONCLUSION: VWI can be useful in the detection of vascular involvement in various viral infections of CNS which show a relatively higher cerebrovascular complication rate like varicella, HIV encephalopathy, and COVID-19. However, VWI may not be useful in the routine evaluation of other viral infections like herpes, dengue, and Japanese encephalitis, which have a very low rate of cerebrovascular complication rate.

C-type lectins and extracellular vesicles in virus-induced NETosis.

Dysregulated formation of neutrophil extracellular traps (NETs) is observed in acute viral infections. Moreover, NETs contribute to the pathogenesis of acute viral infections, including those caused by the dengue virus (DV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Furthermore, excessive NET formation (NETosis) is associated with disease severity in patients suffering from SARS-CoV-2-induced multiple organ injuries. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and other members of C-type lectin family (L-SIGN, LSECtin, CLEC10A) have been reported to interact with viral glycans to facilitate virus spreading and exacerbates inflammatory reactions. Moreover, spleen tyrosine kinase (Syk)-coupled C-type lectin member 5A (CLEC5A) has been shown as the pattern recognition receptor for members of flaviviruses, and is responsible for DV-induced cytokine storm and Japanese encephalomyelitis virus (JEV)-induced neuronal inflammation. Moreover, DV activates platelets via CLEC2 to release extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs). The DV-activated EXOs (DV-EXOs) and MVs (DV-MVs) stimulate CLEC5A and Toll-like receptor 2 (TLR2), respectively, to enhance NET formation and inflammatory reactions. Thus, EVs from virus-activated platelets (PLT-EVs) are potent endogenous danger signals, and blockade of C-type lectins is a promising strategy to attenuate virus-induced NETosis and intravascular coagulopathy.

Aglycone polyether ionophores as broad-spectrum agents inhibit multiple enveloped viruses including SARS-CoV-2 in vitro and successfully cure JEV infected mice (preprint)

Infections with zoonotic viruses, such as flaviviruses, influenza virus, and the SARS-CoV-2 pandemic coronavirus constitute an increasing global risk. Hence, an urgent need exists for the development of broad-spectrum antivirals to prevent such outbreaks. Here, we show that the maduramycin and CP-80,219 aglycone polyether ionophores exhibit effective broad-spectrum antiviral activity, against various viruses, including Japanese encephalitis virus (JEV), Dengue virus (DENV), Zika virus (ZIKV), and Chikungunya virus (CHIKV), while also exhibiting promising activity against PR8 influenza virus and SARS-CoV-2. Moreover, liposome-encapsulated maduramycin and CP-80,219 provide full protection for mice from infection with JEV in vivo. Mechanistic studies suggest that aglycone polyether ionophores primarily inhibit the viral replication step without blocking endosome acidification to promote the fusion between viral and cellular membranes. The successful application of liposomes containing aglycone polyether ionophores in JEV-infected mice offers hope to the development of broad-spectrum antiviral drugs like penicillin back to 1940s.