Biology subjects

McMillen, C. M.

Publications and source records attributed to McMillen, C. M..

3 recordsLinked to original sources

bioRxiv2020

SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts

Vaccines are urgently needed to combat the global coronavirus disease 2019 (COVID-19) pandemic, and testing of candidate vaccines in an appropriate non-human primate (NHP) model is a critical step in the process. Infection of African green monkeys (AGM) with a low passage human isolate of SARS-CoV-2 by aerosol or mucosal exposure resulted in mild clinical infection with a transient decrease in lung tidal volume. Imaging with human clinical-grade 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) co-registered with computed tomography (CT) revealed pulmonary lesions at 4 days post-infection (dpi) that resolved over time. Infectious virus was shed from both respiratory and gastrointestinal (GI) tracts in all animals in a biphasic manner, first between 2-7 dpi followed by a recrudescence at 14-21 dpi. Viral RNA (vRNA) was found throughout both respiratory and gastrointestinal systems at necropsy with higher levels of vRNA found within the GI tract tissues. All animals seroconverted simultaneously for IgM and IgG, which has also been documented in human COVID-19 cases. Young AGM represent an excellent species to study mild/subclinical COVID-19 disease and have shed light on unknown aspects of long-term virus shedding. They are ideally suited for preclinical evaluation of candidate vaccines and therapeutic interventions. One Sentence SummarySubclinical infection of African green monkeys infected with SARS-CoV-2 results in prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts.

microbiology↗

bioRxiv2020

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients

SARS-CoV-2, the causative agent of COVID-19, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

microbiology↗

bioRxiv2018

Rift Valley fever virus induces fetal demise through direct placental infection

Rift Valley fever virus (RVFV) infections in pregnant livestock are associated with high rates of fetal demise and have been linked to miscarriage in pregnant women. To address how acute RVFV infection during pregnancy causes detrimental effects on the fetus, we developed an immunocompetent pregnant rodent model of RVFV infection. We found that pregnant rats were more susceptible to RVFV-induced death than their non-pregnant counterparts and that RVFV infection resulted in intrauterine fetal death and severe congenital abnormalities, even in pups from infected asymptomatic pregnant rats. Virus distribution in infected dams was widespread, with a previously unrecognized preference for infection, replication, and tissue damage in the placenta. In human mid-gestation placental tissue, RVFV directly infected placental chorionic villi, with replication detected in the outermost syncytial layer. Our work identifies direct placental infection by RVFV as a mechanism for vertical transmission and points to the teratogenic potential of this virus in humans. This is the first time vertical transmission of RVFV has been shown in species other than livestock. This study highlights the potential impact of a future epidemic of this emerging mosquito-borne virus.

microbiology↗