Human antibody modification of enterovirus D68 infection

Project Summary/Abstract
Acute flaccid myelitis (AFM) is a poliomyelitis-like illness of children that emerged in the US in 2014.
Since then, AFM outbreaks occur August-October every other year, concurrent with outbreaks of enterovirus
D68 (EV-D68) infection. Increasing evidence now indicates that EV-D68 is a principal cause of AFM. EV-D68,
in the same Enterovirus genus as poliovirus, primarily causes respiratory tract infections. However, the
mechanisms of EV-D68 neuropathogenesis and the characteristics of the human immune response to EV-D68
are poorly understood. This five-year research career development award will provide training and
development of the skills necessary for the PI to establish an independent research program focused on
understanding how EV-D68 causes respiratory and neurologic disease and how human antibodies modify this
pathogenesis. Currently the PI is an Assistant Professor on the tenure track in Pediatric Infectious Diseases
and Microbiology & Immunology at the University of North Carolina at Chapel Hill School of Medicine. His
training to date has focused on the isolation and characterization of human monoclonal antibodies (mAbs) from
subjects with prior EV-D68 infection. He will supplement this experience with further training in developing in
vivo mouse and ex vivo human tissue models of EV-D68 infection with which to study the pathogenesis of this
virus and how human antibodies, both monoclonal and polyclonal, modify pathogenesis. The short-term goal of
the proposed studies is to test the central hypothesis that human antibodies prevent EV-D68 from causing
AFM but do not protect against respiratory disease. The PI will be mentored by national experts in the study of
picornaviruses (Drs. Craig Cameron and Stanley Lemon), human airway epithelial cultures (Dr. Raymond
Pickles), mouse models of virus infection (Dr. Mark Heise), and human antibodies (Dr. James Crowe, Jr.). The
specific aims are to 1) determine how EV-D68-specific human antibodies modify virus-induced respiratory
disease and AFM in a mouse model of infection, to test the hypothesis that antibodies efficiently preclude EV-
D68 from causing AFM by preventing dissemination to the CNS; and 2) investigate factors that determine the
efficacy of antibody at inhibiting EV-D68 infection in differentiated primary human airway epithelial cells at an
air-liquid interface, to test the hypothesis that antibodies poorly protect against initial respiratory mucosal
infection. Overall, these studies will help determine whether EV-D68 neutralizing antibodies are a mechanistic
correlate of protection from AFM by pinpointing the quantity and quality of antibodies capable of restricting EV-
D68 infection to the respiratory tract. Industry collaborators are developing protective mAbs made by the PI as
human therapeutic agents, which would be the only available targeted therapy for children with EV-D68
infection. Thus, these studies directly translate to importance in human health in addition to contributing to a
more fundamental understanding of disease.