Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality.
Herpes simplex virus 1 (HSV-1), a leading cause of genital herpes, infects oral or genital mucosal epithelial cells before infecting the peripheral sensory nervous system. The spread of HSV-1 beyond the sensory nervous system and the resulting broader spectrum of disease are not well understood. Using a mouse model of genital herpes, we found that HSV-1-infection-associated lethality correlated with severe fecal and urinary retention. No inflammation or infection of the brain was evident. Instead, HSV-1 spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system (ENS) in the colon. ENS infection led to robust viral gene transcription, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons, ultimately resulting in permanent loss of peristalsis and the development of toxic megacolon. Laxative treatment rescued mice from lethality following genital HSV-1 infection. These results reveal an unexpected pathogenesis of HSV associated with ENS infection.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
William
W
Khoury-Hanold
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Brian
B
Yordy
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Philip
P
Kong
Department of Molecular Biophysics and Biochemistry, W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT 06520, USA.
Yong
Y
Kong
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
William
W
Ge
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Klara
K
Szigeti-Buck
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Alexandra
A
Ralevski
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Tamas L
TL
Horvath
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: akiko.iwasaki@yale.edu.
Akiko
A
Iwasaki
D000818:Animals; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000473:pathology / Q000821:virology*; D005260:Female; D005724:Ganglia / Q000473:pathology / Q000648:ultrastructure / Q000821:virology; D005727:Ganglia, Spinal / Q000473:pathology / Q000821:virology; D016679:Genome, Viral; D006558:Herpes Genitalis / Q000473:pathology / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D007422:Intestines / Q000821:virology; D008532:Megacolon, Toxic / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology / Q000821:virology*; D009504:Neutrophils / Q000821:virology; D009619:Nociceptors / Q000821:virology; D014621:Vagina / Q000821:virology; D014623:Vaginal Diseases / Q000473:pathology / Q000821:virology*; D014779:Virus Replication / Q000502:physiology