7 research outputs found
Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity
The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis
Noise, nonlinearity and seasonality: the epidemics of whooping cough revisited
Understanding the mechanisms that generate oscillations in the incidence of
childhood infectious diseases has preoccupied epidemiologists and population
ecologists for nearly two centuries. This body of work has generated simple yet
powerful explanations for the epidemics of measles and chickenpox, while the
dynamics of other infectious diseases, such as whooping cough, have proved more
challenging to decipher. A number of authors have, in recent years, proposed
that the noisy and somewhat irregular epidemics of whooping cough may arise due
to stochasticity and its interaction with nonlinearity in transmission and
seasonal variation in contact rates. The reason underlying the susceptibility of
whooping cough dynamics to noise and the precise nature of its transient
dynamics remain poorly understood. Here we use household data on the incubation
period in order to parametrize more realistic distributions of the latent and
infectious periods. We demonstrate that previously reported phenomena result
from transients following the interaction between the stable annual attractor
and unstable multiennial solutions
Reconstructing susceptible and recruitment dynamics from measles epidemic data
Dynamical epidemic studies are often based on the reported number of cases. For various purposes it would be helpful to have information about the numbers of susceptibles, but these data are rarely available. We show that under general theoretical assumptions it is possible to reconstruct, up to linear scaling parameters, the dynamics of the susceptible class, as well as the rate of recruitment to the susceptible class, based only on case report data. We demonstrate that susceptible data reconstructed by our method improve the performance of forecasting models. Our estimate of susceptible class dynamics also can be used to estimate the age distribution of recruitment into the susceptible class, if the birth rate is known from independent data. Simulation experiments show that the reconstruction is robust to errors in the reporting scheme. This work was motivated by measles in large developed-world cities prior to immunization programs; our theoretical assumptions are empirically justified for measles but should also be applicable to some other diseases with permanent immunity.Mathematical epidemiology, measles, susceptibility, forecasting, modeling,