With great interest I read the recent paper in AJVR by Thompson et al1 on the detection and quantification of equine gamma herpesvirus in gastric lesions in a total of 33 horses. They could not prove their initial hypothesis of a potential link between gamma herpesviruses and a certain subform of the equine gastric ulcer syndrome, equine glandular gastric disease. This is remarkable, as conceded by the authors themselves, since it is in contrast to other studies, namely a recent study2 in straight equine gastric ulcers. As I wrote in a comment on their work,3 referring to our original study4 of human gastric ulcers, it is not only about the mere presence of herpesvirus as such in ulcerative lesions. It is the location relative to the ulcerative lesion and, more importantly, what cell type is harboring the virus. We could demonstrate human herpesvirus (HSV-1) at the margin of gastric ulcers, residing in enterochromaffin (ie, neuroendocrine cells). Recent evidence from rodents suggests that herpesvirus travels along the vagus nerve toward the stomach.5
Looking carefully at the provided histology, the herpesvirus-positive cells seem to be located at the margin of the ulcerative lesions; however, it is difficult to determine the exact cell type at the magnification provided. Trying to link the herpesvirus-positive cells to a certain cell type (eg, neuroendocrine cells) may provide a basis to explain the disparity of the findings in the recent paper. The absolute number, reported to be higher in the nonaffected specimens may not be the relevant figure but the exact location of the virus in relation to the ulcerative lesion.
- 1.↑
Thompson RN, Pearson E, McDonough SP, et al. Equine gamma herpesvirus presence and viral load are not associated with equine glandular gastric disease. Am J Vet Res. Published online March 18, 2024. doi:10.2460/ajvr.23.12.0282
- 2.↑
Pennington MR, Cossic BGA, Perkins GA, Duffy C, Duhamel GE, Van de Walle GR. First demonstration of equid gammaherpesviruses within the gastric mucosal epithelium of horses. Virus Res. 2017;242:30-36. doi:10.1016/j.virusres.2017.09.002
- 3.↑
Löhr M. Pennington LM, et al.: First demonstration of equid gammaherpesviruses within the gastric mucosal epithelium of horses. Virus Research volume 242, 15 October 2017, pages 30-36. Virus Res. 2018;244:116. doi:10.1016/j.virusres.2017.11.016
- 4.↑
Löhr JM, Nelson JA, Oldstone MBA. Is herpes simplex virus associated with peptic ulcer disease? J Virol. 1990;64(5):2168-2174. doi:10.1128/JVI.64.5.2168-2174.1990
- 5.↑
Horn CC, Meyers K, Lim A, et al. Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews. Am J Physiol Regul Integr Comp Physiol. 2014;306(5):R341-R351. doi:10.1152/ajpregu.00413.2013
The authors respond:
Dr. Löhr’s thoughtful letter in response to our recent paper raises the question of whether the location and cell type infected might indicate a potential pathologic connection between gamma herpesvirus infection and glandular gastric disease in horses, despite there being no association between viral load and disease. In human herpesvirus (HSV-1) gastric infections, the virus is reported to infect the neuroendocrine cells,1 which is typical of many alpha herpesviruses.2 High-magnification review of our samples confirms that infected cells were primarily epithelial cells throughout the mucosa and mucosal glands, as well as some smooth muscle cells in the lamina muscularis mucosa. Epithelial tropism has been described for many gamma herpesviruses in humans and horses.3–5 Especially given the samples in which nearly every epithelial cell in the mucosa showed hybridization, we cannot attribute infection to only neuroendocrine-origin cells. Additionally, widespread hybridization was observed in ulcer beds, at the margin of ulcer beds, in inflammatory gastritis lesions, and in normal glandular mucosa. While these findings cannot rule out an influence of equine gamma herpesviruses on glandular ulcer disease, it will be exceeding difficult to tease out a possible connection given the ubiquitous nature of infection.
Joy E. Tomlinson, DVM, PhD, DACVIM
Department of Clinical Studies New Bolton Center, School of Veterinary Medicine, University of Pennsylvania Kennett Sq, PA
Sean P. McDonough, DVM, PhD, DACVP
Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University Ithaca, NY
- 1.↑
Löhr JM, Nelson JA, Oldstone MBA. Is herpes simplex virus associated with peptic ulcer disease? J Virol. 1990;64(5):2168-2174. doi:10.1128/JVI.64.5.2168-2174.1990
- 2.↑
Kramer T, Enquist LW. Directional spread of alphaherpesviruses in the nervous system. Viruses. 2013;5(2):678-707. doi:10.3390/v5020678
- 3.↑
Peters-Kennedy J, Löhr CV, Cossic B, Glaser AL, Duhamel GE. Association of equine gammaherpesvirus-5 with facial lymphohistiocytic interface dermatitis in seven adult horses from the United States. Vet Pathol. 2023;60(6):888-897. doi:10.1177/03009858231197830
- 4.
Williams KJ, Robinson NE, Lim A, et al. Experimental induction of pulmonary fibrosis in horses with the gammaherpesvirus equine herpesvirus 5. PLoS One. 2013;8(10):e77754. doi:10.1371/journal.pone.0077754
- 5.↑
Chandran B, Hutt-Fletcher L. Gammaherpesviruses entry and early events during infection. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge University Press; 2007. https://www.ncbi.nlm.nih.gov/books/NBK47405/897. doi:10.1177/03009858231197830
