Mapping spatiotemporal dynamics during enterovirus infection across cells and tissues

Project Summary
Human enterovirus (HEV) infections primarily affect infant and adolescent populations, causing a
wide range of clinical manifestations that commonly include respiratory illness and
mucocutaneous lesions, or hand, foot and mouth disease. In some cases, the infection is life-
threatening. The clinical manifestations are a function of their tropism. For example, some HEVs,
including EV-A71 and EV-D68, are associated with serious neurological symptoms due to
invasion and damage of central nervous tissues. Others, such CVB3, are implicated in respiratory
symptoms and cardiomyopathy. This proposal aims to take an integrative approach to understand
how tissues, and cells within these tissues, respond to infection by CVB3 and the emerging
pathogens EV-D68 and EV-A71. We will determine the temporal and spatial dynamics of HEV
infection using recent advances in genomics: (i) We will profile single-cell transcriptomes to
quantify viral replication levels and the host response to infection across cells and tissues over
the course of infection. (ii) Given that intra-host adaptation appears to be important in infection,
in parallel, we will map the mutational spectrum of the replicating viruses using a novel ultra-deep
sequencing approach. We will use new innovative technologies, such as ultra-deep virus
population sequencing, deep learning and single-cell analysis to increase our basic understanding
of the pathogenesis of enteroviruses A, B and D. Finally, given that innate immunity is a major
determinant of tissue tropism, we will use mice with deletions of specific type-I IFN subtypes to
determine the significance of interferon diversity in controlling HEV infections. These data will
enable us to determine cell types that HEVs infect, the response that the host mounts against
them in each cell and tissue, and the viral mutants that emerge in different tissues. Understanding
pathogenesis is critically needed for developing effective and broadly-acting countermeasures
and to inform the development of effective and broad-spectrum vaccines and antiviral
compounds.

Grant Number: 5R01AI169460-05
NIH Institute/Center: NIH
Principal Investigator: Raul Andino