Exploring animal models of two 21st century pandemics: Zika virus and SARS-CoV-2

Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the etiologic agents responsible for the two major pandemics of the 21st century (so far). By virtue of its capacity for mosquito-borne, sexual, and vertical transmission, as well as its association with congenital Zika syndrome (CZS), ZIKV remains a significant global public health risk. Mounting evidence identifies the male reproductive tract as a significant ZIKV reservoir; however, data regarding the duration of ZIKV persistence, potential for sexual transmission, and male genitourinary sequelae remain sparse. Furthermore, while microcephaly is a well-documented, extreme manifestation of CZS, there are cases of normocephalic newborns with confirmed prenatal ZIKV exposure but no observable congenital defects exhibiting neurologic deficits and behavioral abnormalities over time. These and other long-term developmental sequelae to prenatal ZIKV infection are not well described.I addressed these gaps in knowledge using archived tissues from 1) 51 ZIKV-inoculated male macaques from past collaborative research projects; and 2) two juvenile rhesus macaque infants exposed prenatally to ZIKV. In the male macaque cohort, I identified persistent ZIKV RNA and infectious virus in testis, epididymis, seminal vesicle, and prostate gland of sexually mature male macaques, with detection as late as 60 days post-inoculation. ZIKV RNA localized primarily to testicular stem cells/sperm precursors and epithelial cells, including Sertoli cells, epididymal duct epithelium, and glandular epithelia of the seminal vesicle and prostate gland. ZIKV infection was associated with microscopic evidence of inflammation in the epididymis and prostate gland of sexually mature males, which could have significant effects on male fertility. In the two juvenile macaques, I identified CNS microcalcifications and macrostructural developmental abnormalities within the CNS visual pathway, specifically disorganization, blending of layers, laminar discontinuities, and regions of low cell density within the lateral geniculate nucleus.COVID-19 disease, caused by SARS-CoV-2, varies from asymptomatic to severe respiratory disease, progressing to acute respiratory distress syndrome (ARDS), multiorgan dysfunction, and death in a subset of patients. Clinical evidence of coagulopathy and microscopic indicators of pulmonary vascular damage are increasingly reported; however, published autopsy data in human patients remain relatively scarce and SARS-CoV-2 induced vascular lesions have not been fully characterized. I used a previously described Syrian golden hamster model of COVID-19 disease to demonstrate that regions of active SARS-CoV-2 induced pulmonary inflammation exhibit ultrastructural evidence of endothelial injury with platelet marginalization and marked perivascular and subendothelial mononuclear inflammation composed primarily of macrophages. SARS-CoV-2 antigen/RNA was not associated with affected blood vessels. Taken together, these findings suggest that the prominent microscopic vascular lesions in SARS-CoV-2 inoculated hamsters (and by extrapolation, humans) are primarily due to indirect endothelial damage, likely secondary to immune dysfunction.These studies emphasize the importance of animal models such as nonhuman primates and hamsters to study pathogenesis of emerging viral diseases