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In 1998 an outbreak of fatal encephalitis among pig farm workers in Malaysia and Singapore led to the discovery of Nipah henipavirus (NiV), a novel paramyxovirus closely related to Hendra henipavirus with case fatality rates of nearly 40%. Following its initial emergence nearly annual outbreaks of NiV have occurred in Bangladesh with a different, NiV Bangladesh, genotype, where the role of pigs in its transmission remains unknown. The present study provides the first report on susceptibility of domestic pigs to NiV Bangladesh following experimental infection, characterizing acute and long-term phases of disease and pathogenesis. All pigs were successfully infected with NiV Bangladesh following oronasal inoculation, with viral shedding confirmed by a novel genotype-specific qRT-PCR in oral, nasal and rectal excretions and dissemination from the upper respiratory tract to the brain, lungs, and associated lymphatic tissues. Unlike previous NiV Malaysia findings in pigs, clinical signs were absent, viremia was undetectable throughout the study, and only low level neutralizing antibody titers were measured by 28/29 days post-NiV-B infection. Results obtained highlight the need for continued and enhanced NiV surveillance in pigs in endemic and at-risk regions, and raise questions regarding applicability of current serological assays to detect animals with previous NiV-B exposure.

Objectives Mouse models have delivered variable recapitulation of Kyasanur Forest disease (KFD) pathology and consistently demonstrated neurological involvement which may be a limited feature of human disease. With the purpose of more accurately modelling human disease progression we infected several small-mammalian models: guinea pigs, hamsters and ferrets with a titered infectious dose of Kyasanur Forest disease virus (KFDV). Clinical indicators of disease severity were observed for seventeen days, on day eighteen a visual post-mortem analysis of visceral organs was conducted. Viral load in selected tissues was measured to infer disease signs and the establishment of viral replication. Data description Daily monitoring did not reveal any observable signs of illness; weight loss was minimal across species and gross pathology did not indicate severe viral infection. Tissue specific tropism and establishment of viral infection was monitored by quantitative real-time polymerase chain reaction (qRT-PCR). No viral replication was detected in ferrets (n = 0/3), but was present in the spleen of guinea pigs (n = 3/3) and the brain of hamsters (n = 3/3). Low levels of viral RNA were detected in multiple hamster tissues (kidney, liver, lung and spleen) suggesting the possibility of viral tropism and possible adaptation to the host. No serological tests were performed.

Severe acute respiratory syndrome (SARS) is characterized by a risk of nosocomial transmission; however, the risk of airborne transmission of SARS is unknown. During the Toronto outbreaks of SARS, we investigated environmental contamination in SARS units, by employing novel air sampling and conventional surface swabbing. Two polymerase chain reaction (PCR)–positive air samples were obtained from a room occupied by a patient with SARS, indicating the presence of the virus in the air of the room. In addition, several PCR-positive swab samples were recovered from frequently touched surfaces in rooms occupied by patients with SARS (a bed table and a television remote control) and in a nurses’ station used by staff (a medication refrigerator door). These data provide the first experimental confirmation of viral aerosol generation by a patient with SARS, indicating the possibility of airborne droplet transmission, which emphasizes the need for adequate respiratory protection, as well as for strict surface hygiene practices

The ‘Spanish’ influenza pandemic of 1918–19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people 1 died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin 2 (HA) and neuraminidase 3 (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal 4 , 5 . Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic 6 .

Filoviruses, such as Ebola virus (EBOV) and Marburg virus, are causative agents of unpredictable outbreaks of severe hemorrhagic fevers in humans and non-human primates. For infection, filoviral particles need to be internalized and delivered to intracellular vesicles containing cathepsin proteases and the viral receptor Niemann-Pick C1. Previous studies have shown that EBOV triggers macropinocytosis of the viral particles in a glycoprotein (GP)-dependent manner, but the molecular events required for filovirus internalization remain mostly unknown. Here we report that the diacylglycerol kinase inhibitor, R-59-022, blocks EBOV GP-mediated entry into Vero cells and bone marrow-derived macrophages. Investigation of the mode of action of the inhibitor revealed that it blocked an early step in entry, more specifically, the internalization of the viral particles via macropinocytosis. Finally, R-59-022 blocked viral entry mediated by a panel of pathogenic filovirus GPs and inhibited growth of replicative Ebola virus. Taken together, our studies suggest that R-59-022 could be used as a tool to investigate macropinocytic uptake of filoviruses and could be a starting point for the development of pan-filoviral therapeutics.

The development of adenoviral vectors based on non-human serotypes such as the chimpanzee adenovirus simian adenovirus 24 (AdC7) may allow for their utilization in populations harboring neutralizing antibodies to common human serotypes. Because adenoviral vectors can be used to generate potent T cell responses, they may be useful as vaccines against pandemic influenza such as may be caused by the H5N1 strains that are currently endemic in avian populations. The influenza nucleoprotein (NP) is known to provide MHC Class I restricted epitopes that are effective in evoking a cytolytic response. Because there is only low sequence variation in NP sequences between different influenza strains, a T cell vaccine may provide heterosubtypic protection against a spectrum of influenza A strains. An AdC7 vector expressing the influenza A/Puerto Rico/8/34 NP was tested for its efficacy in protecting BALB/c mice against two H5N1 strains and compared to a conventional human adenovirus serotype 5 vaccine. The AdC7 NP vaccine elicited a strong anti-NP T cell response. When tested in a mouse challenge model, there was improved survival following challenge with two strains of H5N1 that have caused human outbreaks, Vietnam/1203/04 and Hong Kong/483/97, although the improved survival reached statistical significance only with the strain from Vietnam.

This study compared teicoplanin with vancomycin without and with gentamicin and/or rifampin for treatment of experimental endocarditis due to methicillin-resistant Staphylococcus epidermidis. In rabbits treated for three days and killed 12 hr after the last doses of antimicrobial agents, no significant difference in reducing bacterial titers of vegetations was detected between vancomycin and teicoplanin without and with gentamicin and/or rifampin. Addition of gentamicin and/or rifampin to vancomycin or teicoplanin significantly reduced bacterial titers of vegetations compared with vancomycin or teicoplanin alone. Addition of rifampin alone or gentamicin plus rifampin was significantly more effective than addition of gentamicin alone. In rabbits treated for three days and killed seven days after the last doses of antimicrobial agents, no significant difference in sterilizing vegetations was detected between vancomycin and teicoplanin with gentamicin and/or rifampin. However, there was a trend (probably due to the longer elimination half-life of teicoplanin in serum) that clearly favored teicoplanin over vancomycin. Teicoplanin plus rifampin without or with gentamicin is at least as effective as vancomycin plus rifampin without or with gentamicin for treatment of experimental endocarditis due to methicillin-resistant S. epidermidis.

Vancomycin was evaluated with and without gentamicin and/or rifampin in therapy for endocarditis due to methicillin-resistant Staphylococcus epidermidis in rabbits. Vancomyin (30 mg/kg iv every 12 hr), gentamicin (3.5 mg/kg im every 8 hr), rifampin (20 mg/kg im every 12 hr), combinations of vancomycin plus gentamicin, vancomycin plus rifampin, and vancomycin plus gentamicin plus rifampin were injected for two days, and the number of bacteria in vegetations was determined. Ratios of minimal inhibitory concentrations to minimal bactericidal concentrations (μg/ml) for S. epidermidis were 3.1:25 for vancomycin, 0.2:0.8 for gentamicin, and 0.4:0.4 for rifampin. After two days of therapy, mean log colony-forming units ± SD in vegetations were 7.1 ± 1.5 (none of eight animals were sterile) for vancomycin; 4.6 ± 2.2 (two of nine) for gentamicin; 4.5 ± 2.2 (two of eight) for rifampin; 3.3 ± 1.3 (three of 10) for vancomycin plus gentamicin; 2.7 ± 1.2 (three of nine) for vancomycin plus rifampin; 2.1 ± 0.2 (eight of nine) for vancomycin plus gentamicin plus rifampin; and 8.1 ± 1.3 (none of 12) for the control group. Gentamicin, rifampin, vancomycin plus gentamicin, and vancomycin plus rifampin were significantly more effective than was vancomycin; vancomycin plus rifampin was more effective than was gentamicin alone; and the combination of vancomycin plus gentamicin plus rifampin was more effective than were the drugs administered alone or in the combinations vancomycin plus gentamicin and vancomycin plus rifampin. Two days of treatment followed by seven days of no treatment resulted in 71%, 29%, and 14% sterile vegetations in rabbits receiving the combination therapy vancomycin plus gentamicin plus rifampin, vancomycin plus rifampin, and vancomycin plus gentamicin, respectively.

Widespread circulation of SARS-CoV-2 in humans raises the theoretical risk of reverse zoonosis events with wildlife, reintroductions of SARS-CoV-2 into permissive nondomesticated animals. Here we report that North American deer mice ( Peromyscus maniculatus ) are susceptible to SARS-CoV-2 infection following intranasal exposure to a human isolate, resulting in viral replication in the upper and lower respiratory tract with little or no signs of disease. Further, shed infectious virus is detectable in nasal washes, oropharyngeal and rectal swabs, and viral RNA is detectable in feces and occasionally urine. We further show that deer mice are capable of transmitting SARS-CoV-2 to naïve deer mice through direct contact. The extent to which these observations may translate to wild deer mouse populations remains unclear, and the risk of reverse zoonosis and/or the potential for the establishment of Peromyscus rodents as a North American reservoir for SARS-CoV-2 remains unknown. Deer mice are natural hosts for a number of human pathogens. Here, Griffin et al. report that intranasal exposure of the North American deer mouse to SARS-CoV-2 results in virus replication and shedding, despite causing only mild or asymptomatic illness. Additionally, infected deer mice can transmit SARS-CoV-2 to naïve deer mice.

Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics. Here, Parzych et al describe the development of a DNA-delivered SARS-CoV-2 mAb cocktail displaying synergistic RBD binding that confers broad neutralizing activity against variants of concern and prophylactic efficacy in multiple small animal models.