Frog Virus 3 dissemination in the brain of tadpoles, but not in adult Xenopus, involves blood brain barrier dysfunction

Abstract

While increasing evidence points to a key role of monocytes in amphibian host defenses, monocytes are also thought to be important in the dissemination and persistent infection caused by ranavirus. However, little is known about the fate of infected macrophages or if ranavirus exploits immune privileged organs, such as the brain, in order to establish a reservoir. The amphibian Xenopus laevis and Frog Virus 3 (FV3) were established as an experimental platform for investigating in vivo whether ranavirus could disseminate to the brain. Our data show that the FV3 infection alters the BBB integrity, possibly mediated by an inflammatory response, which leads to viral dissemination into the central nervous system in X. laevis tadpole but not adult. Furthermore, our data suggest that the macrophages play a major role in viral dissemination by carrying the virus into the neural tissues.

Xenopus-FV3 host-pathogen interactions and immune evasion

“…Considering the indiscriminate infection mode and apparent absence of specific cellular receptor(s) requirement, we have proposed that macrophages with their ability to acquire exogenous particles and antigens through various pathways such as micropinocytosis and phagocytosis represent an advantageous cellular target for viral dissemination and persistence into the host. Consistent with this postulate, dissemination of FV3 into the X. laevis tadpole brain is associated with and can be promoted by macrophages infiltration into brain tissue (De Jesus Andino et al, 2016). Furthermore, accumulating evidence indicates that macrophages are critical for viral persistence in asymptomatic adult X. laevis (Robert et al, 2007).…”

“…Since larval peritoneal macrophages are particularly susceptible to FV3 infection (De Jesus Andino et al, 2012) and that FV3 is able to disseminate in tadpole brain (De Jesus Andino et al, 2016), we thought to first examine the ability of knock-out (KO) recombinant FV3 Δ64R- or Δ52L-FV3 compared to FV3-WT to actively infect these sites and induce host antiviral responses. Accordingly, we determined the viral loads and expression of several key host antiviral genes in peritoneal leukocytes, brain and kidneys of tadpoles at different times postinfection.…”

A novel approach to wildlife transcriptomics provides evidence of disease‐mediated differential expression and changes to the microbiome of amphibian populations

“…Little is known about how ranaviruses impact the development of the nervous system, but it is known that the brain is an important site of infection (De Jesús Andino, Jones, Maggirwar, & Robert, ) and neural development and proliferation of nerve cells are often negatively impacted by viral infection (Cordeiro, Tsimis, & Burd, ; Tsutsui, ). Ranavirus infection has also been shown to impact whole organism development of larval amphibians (St‐Amour, Garner, Schulte‐Hostedde, & Lesbarrères, ) and to increase developmental rates (Warne, Crespi, & Brunner, ).…”

Using Xenopus to understand human disease and developmental disorders

“…Humanized mutations are easily introduced via expression vectors or established in founder lines, and the anatomy, function, and molecular regulation of most organs are highly similar across the tetrapods (amphibian, reptiles, avians and mammals). This approach has been used to investigate: aniridia (Nakayama et al, ); blood–brain barrier dysfunction (De Jesús Andino, Jones, Maggirwar, & Robert, ); congenital heart disease (Bhattacharya, Marfo, Li, Lane, & Khokha, ); demyelination diseases (Sekizar et al, ); holoprosencephaly (Nakayama et al, ); Huntington's disease (Haremaki, Deglincerti, & Brivanlou, ); myasthenia gravis (Yeo, Lim, Fukami, Yuki, & Lee, ); pneumonia (Walentek et al, ); and tumor progression (Hardwick & Philpott, ). We anticipate that similar contributions to human disease will rapidly expand due to the ease of performing these types of experiments in Xenopus .…”