Persistence of virus-specific immune responses in the central nervous system of mice after West Nile virus infection

Wadsworth Center, New York State Department of Health, Albany, NY, USA.
BMC Immunology (Impact Factor: 2.48). 01/2011; 12(1):6. DOI: 10.1186/1471-2172-12-6
Source: PubMed


West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus.
Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19+ B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4+ and CD8+ T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8+ T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease.
Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi.

Download full-text


Available from: Kristen A Bernard, Aug 14, 2014
  • Source
    • "Two recent WNV persistence studies have employed WNV E-MIA to study the anti-WNV antibody response in the mice after infection [10], [11]. In the first study, MIA was conducted using non heat-inactivated (NHI) sera [10], whereas in the second study, sera were HI at 56°C for 1 hour prior to testing [11]. These two studies detected total anti-WNV antibodies (IgG, IgA and IgM). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunopathogenesis studies employing West Nile virus (WNV) mice model are important for the development of antivirals and vaccines against WNV. Since antibodies produced in mice early during WNV infection are essential for clearing virus from the periphery, it is important to detect early and persistent anti-WNV antibodies. ELISA and plaque reduction neutralization tests are traditionally used for detection of anti-WNV antibodies and WNV-neutralizing antibodies, respectively. Although these assays are sensitive and specific, they are expensive and time consuming. Microsphere immunoassays (MIA) are sensitive, specific, allow for high throughput, are cost effective, require less time to perform than other methods, and require low serum volumes. Several assay parameters such as serum heat-inactivation (HI) and dilution can alter WNV MIA sensitivity. We examined the effect of these parameters on WNV E-protein MIA (WNV E-MIA) for the enhanced detection of anti-WNV IgM and IgG antibodies. WNV E-MIA was conducted using serial dilutions of HI and non-HI (NHI) serum collected at various time points from mice inoculated with WNV. HI significantly enhanced detection of IgM and IgG antibodies as compared to NHI serum. WNV IgM and IgG antibodies in HI sera were detected earlier at day 3 and IgM antibodies persisted up to day 24 after infection. HI serum at 1∶20 dilution was found to be optimal for detection of both IgM and IgG antibodies as compared to higher-serum dilutions. Further, addition of exogenous complement to the HI serum decreased the WNV E-MIA sensitivity. These results suggest that serum-HI and optimal dilution enhance WNV E-MIA sensitivity by eliminating the complement interference, thereby detecting low-titer anti-WNV antibodies during early and late phases of infection. This improved MIA can also be readily employed for detection of low-titer antibodies for detection of other infectious agents and host proteins.
    Full-text · Article · Sep 2012 · PLoS ONE
  • Source
    • "Furthermore, persistence in the CNS and pathological evidence of encephalitis were observed even in mice with subclinical infections. In such cases, the CNS immune response appears to be ineffective in clearing the virus (Stewart et al., 2011). In humans, WNV RNA was recently demonstrated in 5 (20%) of 25 urine samples collected from convalescent WNV patients diagnosed with WNV neuroinvasive disease between 2002 and 2007 (Murray et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The most common neuromuscular manifestation of West Nile virus (WNV) infection is a poliomyelitis syndrome with asymmetric paralysis variably involving one (monoparesis) to four limbs (quadriparesis), with or without brainstem involvement and respiratory failure. This syndrome of acute flaccid paralysis may occur without overt fever or meningoencephalitis. Although involvement of anterior horn cells in the spinal cord and motor neurons in the brainstem are the major sites of pathology responsible for neuromuscular signs, inflammation also may involve skeletal or cardiac muscle (myositis, myocarditis), motor axons (polyradiculitis), and peripheral nerves [Guillain-Barré syndrome (GBS), brachial plexopathy]. In addition, involvement of spinal sympathetic neurons and ganglia provides an explanation for autonomic instability seen in some patients. Many patients also experience prolonged subjective generalized weakness and disabling fatigue. Despite recent evidence that WNV may persist long-term in the central nervous system or periphery in animals, the evidence in humans is controversial. WNV persistence would be of great concern in immunosuppressed patients or in those with prolonged or recurrent symptoms. Support for the contention that WNV can lead to autoimmune disease arises from reports of patients presenting with various neuromuscular diseases that presumably involve autoimmune mechanisms (GBS, other demyelinating neuropathies, myasthenia gravis, brachial plexopathies, stiff-person syndrome, and delayed or recurrent symptoms). Although there is no specific treatment or vaccine currently approved in humans, and the standard remains supportive care, drugs that can alter the cascade of immunobiochemical events leading to neuronal death may be potentially useful (high-dose corticosteroids, interferon preparations, and intravenous immune globulin containing WNV-specific antibodies). Human experience with these agents seems promising based on anecdotal reports.
    Full-text · Article · Mar 2012 · Frontiers in Neurology
  • Source
    • "The role of B-cells has been well established in restricting MCMV in other organs including lungs, spleen and salivary glands [29], but their role in restricting virus reactivation in the brain is unclear. B-lineage cells were detected in the brain as early as 7 d p.i. Similar observations have been made in other viral brain infections where a surprising number of CD138+ cells at 7 d p.i. has been reported [35]. When we assessed the infiltrating immune cells for production of virus-specific antibodies by ELISPOT assay, these virus-specific ASCs were detected for as long as 65 d p.i. Similar trafficking and persistence of ASC in the CNS has been reported in other RNA virus models such as West Nile virus and mouse Alpha-virus infections [12], [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Experimental infection of the mouse brain with murine CMV (MCMV) elicits neuroimmune responses that terminate acute infection while simultaneously preventing extensive bystander damage. Previous studies have determined that CD8(+) T lymphocytes are required to restrict acute, productive MCMV infection within the central nervous system (CNS). In this study, we investigated the contribution of humoral immune responses in control of MCMV brain infection. Utilizing our MCMV brain infection model, we investigated B-lymphocyte-lineage cells and assessed their role in controlling the recovery of reactivated virus from latently infected brain tissue. Brain infiltrating leukocytes were first phenotyped using markers indicative of B-lymphocytes and plasma cells. Results obtained during these studies showed a steady increase in the recruitment of B-lymphocyte-lineage cells into the brain throughout the time-course of viral infection. Further, MCMV-specific antibody secreting cells (ASC) were detected within the infiltrating leukocyte population using an ELISPOT assay. Immunohistochemical studies of brain sections revealed co-localization of CD138(+) cells with either IgG or IgM. Additional immunohistochemical staining for MCMV early antigen 1 (E1, m112-113), a reported marker of viral latency in neurons, confirmed its expression in the brain during latent infection. Finally, using B-cell deficient (Jh(-/-)) mice we demonstrated that B-lymphocytes control recovery of reactivated virus from latently-infected brain tissue. A significantly higher rate of reactivated virus was recovered from the brains of Jh(-/-) mice when compared to Wt animals. Taken together, these results demonstrate that MCMV infection triggers accumulation and persistence of B-lymphocyte-lineage cells within the brain, which produce antibodies and play a significant role in controlling reactivated virus.
    Full-text · Article · Mar 2012 · PLoS ONE
Show more