Route of Infection Influences Zika Virus Shedding in a Guinea Pig Model

Abstract

Due to the recent epidemic of Zika virus (ZIKV) infection and resulting sequelae, as well as concerns about both the sexual and vertical transmission of the virus, renewed attention has been paid to the pathogenesis of this unique arbovirus. Numerous small animal models have been used in various ZIKV pathogenicity studies, however, they are often performed using immunodeficient or immunosuppressed animals, which may impact disease progression in a manner not relevant to immunocompetent humans. The use of immunocompetent animal models, such as macaques, is constrained by small sample sizes and the need for specialized equipment/staff. Here we report the establishment of ZIKV infection in an immunocompetent small animal model, the guinea pig, using both subcutaneous and vaginal routes of infection to mimic mosquito-borne and sexual transmission. Guinea pigs developed clinical signs consistent with mostly asymptomatic and mild disease observed in humans. We demonstrate that the route of infection does not significantly alter viral tissue tropism but does impact mucosal shedding mechanics. We also demonstrate persistent infection in sensory and autonomic ganglia, identifying a previously unrecognized niche of viral persistence that could contribute to viral shedding in secretions. We conclude that the guinea pig represents a useful and relevant model for ZIKV pathogenesis.

Sexual Transmission of Arboviruses: A Systematic Review

“…ZIKV antigen was also detected in the testes of immunocompetent guinea pigs after subcutaneous and intranasal inoculation [124]. A more recent study demonstrated that immunocompetent guinea pigs are susceptible to ZIKV infection after vaginal inoculation, with viral RNA detected in various tissues including the ovaries and uterus [125]. Infectious virus persisted in vaginal secretions for at least 21 days.…”

“…Evidence of ZIKV infection has been detected in the reproductive tracts of several non-murine, non-primate vertebrate species [124][125][126][127]. ZIKV RNA was detected in the testes of tree shrews (Tupaia belangeri) after subcutaneous inoculation [127].…”

Recapitulating Zika Virus Infection in Vagina of Tree Shrew (Tupaia belangeri)

“…Similarly, a constant viremia (10 4.4 -10 6.02 RNA copies/ml) was detected from 2 to 5 dpi in Guinea pigs infected via a subcutaneous and vaginal route which peaked at 3 dpi (Saver et al, 2019). Current study viremia initiation is consistent with detection of ZIKV viremia in Rhesus monkeys (Li X. F. et al, 2016), mice (Zhang N. N. et al, 2016), and Guinea pigs (Saver et al, 2019) but the peak of viremia is only comparable with Rhesus monkeys (Li X. F. et al, 2016). ZIKV shedding in urine, salvia, a low load transient viremia was detected at 1-7 dpi and peaked at 3 dpi which is consistent with the detection of viremia in mice (Zhang N. N. et al, 2016) and tree shrews .…”

“…A transient viremia (10 6.15 RNA copies/ml) was detected at 1 dpi in immunocompetent mice after SC inoculation (Zhang N. N. et al, 2016). Similarly, a constant viremia (10 4.4 -10 6.02 RNA copies/ml) was detected from 2 to 5 dpi in Guinea pigs infected via a subcutaneous and vaginal route which peaked at 3 dpi (Saver et al, 2019). Current study viremia initiation is consistent with detection of ZIKV viremia in Rhesus monkeys (Li X. F. et al, 2016), mice (Zhang N. N. et al, 2016), and Guinea pigs (Saver et al, 2019) but the peak of viremia is only comparable with Rhesus monkeys (Li X. F. et al, 2016).…”

Zika Virus and Host Interactions: From the Bench to the Bedside and Beyond

“…Animals models are critical for understanding viral pathogenesis and testing therapeutic interventions. To this end, Saver et al [ 6 ] inoculated guinea pigs by subcutaneous and vaginal routes to mimic the infected mosquito bite and sexual transmission, respectively. By studying multiple tissues with respect to tropism and persistence, they identified sensory and autonomic ganglia in the nervous system as a potential novel niche of ZIKV persistence.…”