Abstract
Clinicoepidemiological data suggest that type 2 diabetes is associated with increased risk of West Nile virus encephalitis (WNVE). However, no experimental studies have elucidated the role of diabetes in WNV neuropathogenesis. Herein, we employed the db/db mouse model to understand WNV immunopathogenesis in diabetics. Nine-week old C57BL/6 WT and db/db mice were inoculated with WNV and mortality, virus burden in the periphery and brain, and antiviral defense responses were analyzed. db/db mice were highly susceptible to WNV disease, exhibited increased tissue tropism and mortality than the wild-type mice, and were unable to clear the infection. Increased and sustained WNV replication was observed in the serum, peripheral tissues and brain of db/db mice, and heightened virus replication in the periphery was correlated with enhanced neuroinvasion and replication of WNV in the brain. WNV infection in db/db mice was associated with enhanced inflammatory response and compromised antiviral immune response characterized by delayed induction of IFN-α, and significantly reduced concentrations of WNV-specific IgM and IgG antibodies. The compromised immune response in db/db mice correlated with increased viremia. These data suggest that delayed immune response coupled with failure to clear the virus leads to increased mortality in db/db mice. In conclusion, this study provides unique mechanistic insight into the immunopathogenesis of WNVE observed in diabetics and can be used to develop therapeutics for the management of WNVE among diabetic patients.
Highlights
It is known that people with type 2 diabetes have higher incidence of bacterial and fungal infections [1,2,3]
Susceptibility of db/db mice to West Nile virus (WNV) disease To investigate the effect of diabetes on WNV pathogenesis, we evaluated the morbidity and mortality of WT and db/db mice after infection with PBS or 10 plaque forming units (PFU) of WNV
Type 2 diabetes is associated with an impaired immune response and increased susceptibility to various pathogens [3,7]
Summary
It is known that people with type 2 diabetes have higher incidence of bacterial and fungal infections [1,2,3]. Virus replication in the periphery and brain of db/db mice To understand how diabetes enhanced the susceptibility of mice to WNV disease, we compared WNV viral load in the peripheral tissues and brain of WT and db/db mice at days 2, 4, 6 and 8 after infection (Fig. 3A–E). By day 4, which corresponds to the peak of WNV infection in spleen, significantly higher virus titer was observed in db/db mice when compared to the WT mice; 46104 vs 86102 PFU/g, p,0.05. Similar to IgM antibodies, overall levels of WNV-specific IgG antibodies were significantly reduced in db/db mice as compared with WT mice at days 6 and 8 after infection (Fig. 5B, p,0.05). Because we observed high virus replication in periphery and brain and low levels of WNV-specific antibodies, we speculated that impaired interferon response in db/ db mice might be the mechanism behind this phenomenon. P,0.05) were only significantly increased at day 8 after infection when compared with the WT mice
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.