First isolation, in-vivo and genomic characterization of zoonotic variegated squirrel Bornavirus 1 (VSBV-1) isolates

Variegated squirrel bornavirus 1 (VSBV-1) is a recently discovered zoonotic virus that causes severe encephalitis in humans. VSBV-1 was found in a fatal human infection, and screening tests revealed that captive exotic squirrels were involved. Variable squirrels (Sciurus variegatoides) and red-tailed squirrels (Sciurus granatensis) have been tested positive for VSBV-1. The authors successfully isolated the virus from the brain and kidney of VSBV-1-infected squirrels. The isolated VSBV-1 sequence had more than 99% similarity to the original squirrels-based viral sequence. Lewis rats inoculated with VSBV-1, regardless of age or route of infection, showed no clinical signs and did not shed the virus. Viral RNA was detected in the cerebrum, cerebellum, and spinal cord of neonatal rats inoculated with VSBV-1 in the brain. As a result, VSBV-1 may infect Lewis rats, but further studies are needed before it can be used as an experimental model.
(SM)

Ginkgolic acid inhibits orthopneumo‑ and metapneumovirus infectivity

Pneumoviridae family viruses are enveloped, single-stranded, negative-sense RNA viruses belonging to two genera: orthopneumovirus and metapneumovirus. The human respiratory syncytial virus (hRSV) and the human metapneumovirus (hMPV), members of the two genera, are important human respiratory pathogens. Ginkgo biloba extracts from the leaves and fruits of the Ginkgo biloba contain various chemical compounds, including Ginkgolic Acid (GA). GA, and in particular GA C15:1, which is the major compound found in these extracts, has been widely researched as a therapeutic option for various human diseases including viral infections. This research reports the antiviral activity of GA against two members of the Pneumoviridae family: hRSV and hMPV. GA can make the inhibition of infectivity occurs during the entry step in the early stage of the viruses’ life cycle with no effect on late events such as viral replication, gene expression, and viral assembly and release. Overall, the ability of GA to inhibit the infectivity of two members from the Pneumoviridae family, hRSV and hMPV, hints that the drug may have a broader range of action and can be used to treat other members of this family.
(DKW)

Respiratory Syncytial virus glycoprotein G impedes CX3CR1-activation by CX3CL1 and monocyte function

The Respiratory Syncytial Virus (RSV) soluble G protein (sG) exhibits structural and functional similarities to the chemokine fractalkine (CX3CL1). It contains a mucin-like domain, a CX3C motif, and interacts with the CX3CR1 receptor expressed on immune and epithelial cells. This study aimed to elucidate the biological implications of RSV sG's interaction with CX3CR1. Wild-type (WT) and CX3C motif-deficient (CX3C mutant) RSV sG proteins were produced to evaluate their effects on CX3CR1 signaling in monocytic cells. While neither WT nor CX3C mutant sG directly activated CX3CR1 signaling, WT sG competitively inhibited CX3CL1 binding to CX3CR1. This inhibition reduced CX3CL1-induced CX3CR1 activation, monocyte migration, and adhesion. The CX3C motif was essential for this competitive blocking, as the CX3C mutant sG showed minimal impact on CX3CR1 functions. These findings suggest that RSV sG-mediated blockade of CX3CR1 signaling may help the virus evade host immune responses.
(SN)

Long-term Elevation of Complement Factors in Cerebrospinal Fluid of Patients With Borna Disease Virus 1 Encephalitis

Borna disease virus type 1 (BoDV-1) is a highly neurotropic enveloped RNA virus with liner, non-segmented, single-stranded, negative-sense genome of approximately 8.9 kb. BoDV-1 causes a rare but severe form of encephalitis. The mortality rate is very high and no effective countermeasures have been established. Recent research has shown increases in inflammatory cytokines and chemokines such as IF-γ, IL-6, IL-12p40, CCL-2 and CCL-5. However, there is a lack of data on the role of the complement system during BoDV-1 infection. This study showed that the cerebrospinal fluid samples of patients infected with BoDV-1 showed elevated levels of all complement pathway factors and activation of the complement cascade. In patients with BoDV-1 encephalitis, a negative correlation has been shown to exist between the concentration of specific complement factors in CSF and survival rate. The measurement of complement factors in CSF from patients with BoDV-1 encephalitis may help to identify additional diagnostic markers, prognostic markers, or target for treatment.
(TT)

Therapeutic efficacy JNJ-49214698, an RSV fusion inhibitor, in RSV-infected neonatal lambs

Exceedingly cases of lower respiratory tract infection (ALRTI) in high-risk of infants, that is driven by respiratory syncytial virus (RSV) are raising global concern. It is including high hospitalization rate and hospital residence time. Beside the application of RSV vaccine, with no effective direct antivirals, currently, the therapeutic agents are also widely developed. JNJ-49214698 is an RSV inhibitor that targeting the major virulence factor, viral fusion (F) protein. The experiment uses neonatal lambs as animal model due to it has similar innate and adaptive immune response in human, then it was infected with RSV strain M37 (wild type) to induce ALRTI clinical symptoms. The administration of 25mg/kg JNJ-4921498 once daily within 5 days reduce the incidence and duration of RSV-associated symptoms, reduce RSV titer and infection, inhibit RSV-induced lung pathology and cellular immune response of neonatal lambs. Thus, the development of RSV inhibitor as therapeutic agent can be used as new drug of choice for RSV treatment in human.
(INV)

Longitudinal proteome-wide antibody profiling in Marburg virus survivors identifies wing domain immunogen for vaccine design.

Few data exist on the quality of polyclonal antibody responses generated following MARV infection of survivors and its evolution over time. In this report, the researchers analyzed MARV proteome-wide antibody repertoire longitudinally for five years post MARV infection approximately every six months in ten human survivors during the convalescent phase. IgM vs. IgG vs. IgA epitope diversity, antibody binding, antibody affinity maturation, and Fc-receptor interaction to MARV proteins revealed differential kinetics. MARV-neutralizing antibody durability is poor in survivors. MARV infection elicits a broad epitope repertoire covering GP, VP40, VP30, and VP24 dominant responses persisting up to 5 years after MARV exposure. However, with time, the IgM and IgA repertoire decreases. IgG-recognizing antigenic sites mainly in the amino-terminus, wing domain, and GP2-heptad repeat are made from MARV-GP. Notably, MARV infection induces strong long-lived FcɣRI, FcɣRIIA, and FcɣRIIIA IgG-Fc receptor pairings. Unconventional neutralizing antibodies against MARV are induced by immunization with the immunodominant MARV epitopes, exposing the conserved wing region between GP1 and GP2. previously, it was noted that MARV infection bestows a diverse, long persistent, non-neutralizing, IgG antibody repertoire that disturbs disease by fcɣr activity. These findings, in addition to identifying neutralizing immunogens within the wing domain, can facilitate the rational engineering of effective therapeutics and vaccines against the Marburg virus.
(SN)

Attempted Transmission of Marburg Virus by Bat-Associated Fleas Thaumapsylla breviceps breviceps (Ischnopsyllidae: Thaumapsyllinae) to the Egyptian Rousette Bat (Rousettus aegyptiacus)

The Egyptian rousette bat (ERB; Rousettus aegyptiacus) has been implicated as a reservoir host for Marburg virus (MARV) and it has been suggested to be associated with the transmission of MARV to humans. However, the mechanism by which MARV are maintained within the ERB population is not understood. Bats are hosts to many external parasites, including fleas but little is known about these host-vector-pathogen interactions. Sufficient MARV RNA were detected in fleas sucked from ERBs with viremia due to MARV inoculation. Bats in contact with flea-parasitized MARV-infected bats didn’t exhibit viremia. Bats parasitized with MARV-inoculated fleas did not show viremia or seroconversion until 38 days after infection. These results suggest that fleas don’t appear to be involved in the biological transmission of MARV, but may well be involved in mechanical transmission.
(SM)

Novel filoviruses: indication of a global threat or cause to reassess our risk perception

In 1967, Marburg virus (MARV), a Filovirus from Filoviridae family is firstly discovered. Followed by Ebola virus (EBOV) and Sudan virus (SUDV) that previously known as responsible in severe human health. Despite of comprising different genus, these viruses have similar clinical pattern: hemorrhagic fever and multi organ failure. To date, there are novel filoviruses has been discovered: Bombali virus, Lloviu virus, Mengla virus, Tapajos virus, Fiwi virus, Kander virus, Huangjiao virus, Oberland virus, Xiland virus, Lotschberg virus, Blue spotted goatfish filovirus, John dory filovirus from diverse hosts all over the world with genome-based studies. The finding emphasizes the possibility of future global threat. Geographic distribution of the viruses among the world with known cases of autochthonous filovirus diseases in bats are within 9.1-100% in Australia, 1.4-100% in Asia, 2.8-14.3% in Central America, 0.4-9.5% in Africa, and 12.2-36.5% in Europe. Given the much more wide-spread distribution of filoviruses that is being revealed by genomic and serological studies, researchers are expected to increasingly detect these viruses also outside areas that have been classically considered as filovirus endemic regions.
(INV)

Hippo signaling pathway regulates Ebola virus transcription and egress

Ebola (EBOV) virus is an emerging pathogen of the Filoviridae family that causes sporadic and global outbreaks of acute hemorrhagic fever in humans, resulting in mortality rates as high as 90%. Filoviruses can establish chronic/persistent infections in immunologically privileged sites and their re-emergence can cause long-term sequelae or death. Identifying and characterizing filovirus-host interactions that impact the virus lifecycle can be exploited as potential targets for developing host-oriented countermeasures and represent a potential way forward. This research reveals how key effector YAP and core kinases LATS1/2 of the Hippo pathway intersect with the EBOV lifecycle. Hippo signaling-regulated YAP localization and activity shape the cellular environment towards one that either inhibits (Hippo ON) or promotes (Hippo OFF) viral egress. LATS2 indirectly regulates egress by phosphorylating AMOTp130; whereas, LATS1/2 kinases directly regulate EBOV transcription by interacting with EBOV NP and phosphorylating EBOV VP30. This research provides mechanistic insights into the diverse Hippo pathway-mediated control of several stages of the EBOV lifecycle, potentially leading to identifying and exploiting antiviral targets for building host-oriented countermeasures against EBOV and similar infections.
(DKW)

Antibody-dependent enhancement of Ebola virus infection

Ebola virus, which belongs to the Filoviridae family, is known as pathogen that causes acute, highly fatal hemorrhagic diseases in human. Ebola virus is a negative-stranded RNA virus with a filamentous envelope. Its genome encodes eight proteins, and two of which are glycoproteins (GP) that are important for Ebola virus infection. One is the envelope GP, which is responsible for binding to the receptor and fusion of viral and host cell membrane, and the other is the non-structural secreted GP released from the infected cell. There are four different strains of Ebola virus: Zaire, Sudan, Ivory Coast, and Reston. Plasma or serum from patients in the convalescent stage of Zaire strain infection promoted infection of kidney cells in nonhuman primates with Zaire strain. This promotion was mediated by antibodies to GP and the complement component C1q. This shows that human Ebola Zaire virus infection induces antibodies that increase the infectivity of virus. This suggests a new mechanism for antibody-dependent enhancement of Ebola virus infection, which explain the devastating Ebola outbreaks in human populations.
(TT)