Elsevier

Journal of Neuroimmunology

Volume 335, 15 October 2019, 577017
Journal of Neuroimmunology

Murine cytomegalovirus infection in mice results in an acute inflammatory reaction in peripheral nerves

https://doi.org/10.1016/j.jneuroim.2019.577017Get rights and content

Highlights

  • MCMV is permissive in the peripheral nerve but not in the spinal cord during acute infection.

  • MCMV infection resulted in an increase of activated CD8+ T cells, and monocyte/macrophages in the blood and sciatic nerves.

  • IFNγ, TNFα, IL-6 and IL-1β expression was increased in the peripheral nerve following acute infection.

  • MCMV infected mice exhibited transient sensory dysfunction at the acute phase.

Abstract

Human cytomegalovirus (CMV) infection is asymptomatic in immunocompetent individuals. However, it can lead to disease in immunodeficient population. Little is known of the mechanisms underlying the pathogenicity of the virus. We investigated the impact of CMV infection on mouse nervous system. Peripheral nerves but not spinal cord was permissive to MCMV during acute infection. Activated CD8+ T cells, monocytes/macrophages and cytokine expression were increased in the blood and sciatic nerves of infected mice, which exhibited transient sensory dysfunction. This study indicates that systemic MCMV infection leads to a dissemination of MCMV into peripheral nerves, which is associated with a local inflammation but not nerve tissue damage in the acute phase.

Introduction

Human cytomegalovirus (HCMV) is a widespread pathogen that affects most of the world's population. Subsequent to initial virus entry and replication, CMV infects many organs and tissues in vivo, but only causes disease at some of these and then only in certain patient populations. It is largely asymptomatic in majority of healthy individuals. However, CMV infection can lead to a significant disease in immunocompromised individuals. HCMV has been considered as a prime viral candidate in the etiology of several immune mediated diseases including, autoimmune peripheral neuropathy such as Guillain-Barre syndrome (GBS), atherosclerosis and inflammatory bowel disease (Chan et al., 2012; Rahbar et al., 2003; Lunn and Hughes, 2011). The mechanisms underlying these diseases are elusive. Many factors influence the pathogenesis of infection and the expression of symptomatic disease. It could be due to direct viral replication in specific organs, arising from either a primary infection or a reactivation of latent endogenous virus. It could also be attributed to the modulating effect of the virus on the host immune response.

CMV has different tissue/organ tropisms. Following acute infection, HCMV and MCMV were found in many types of cells/organs, such as macrophages, spleen, lung, liver and salivary glands where the latter secrete higher levels of virus than others (Cousins et al., 2012; Sweet, 1999). However, no data is available regarding the consequence of a systemic CMV infection on peripheral nerves. It is particularly important, since GBS, a prototypic autoimmune disorder that affects peripheral nerves and roots has been highly associated with CMV infection (10–22%) (Winer et al., 1988). Up to date, no immunologic target molecule from CMV infection has been identified for autoimmune response in peripheral nerves. Underlying mechanisms for CMV-GBS are basically unknown.

Although it is too early to mechanistically link acute CMV infection to GBS, it is nevertheless important to unravel whether MCMV attacks the nervous system following a systemic infection, how the immune system reacts, and whether there is any nervous tissue damage immediately after infection. In this study, we infected C57BL/6 mice via intraperitoneal injection of wild type MCMV and explored nervous tissue damage and systemic immune response. We have focused mainly on CD8+ T cells and macrophages, since our previous animal studies and human data from literature demonstrated the accumulation of activated CD8+ T cells and macrophages in inflammatory demyelinating peripheral nerves (Yang et al., 2014; Kiefer et al., 2000; Sommer et al., 2005; Schmidt et al., 1996). Some evidence of their functional contribution has been documented (kiefer et al., 2000; Yang et al., 2015). Our results revealed that in addition to systemic viral immunity, MCMV attacks peripheral nerves shortly after the infection, leading to a local inflammatory response with minimal impact in the spinal cord. More specifically, the data demonstrated an accumulation of activated CD8+ T cells and macrophages in peripheral nerves, which corresponds to the invasion of the virus in the peripheral nervous system (PNS). However, peripheral nerves are not damaged at this point, mice exhibit transient sensory dysfunction.

Section snippets

Mice

C57BL/6 were purchased from Jackson laboratory. They were housed and bred under specific pathogen free conditions. Male mice, at the age of 8–10 week-old, were used in this study. All procedures were in accordance with the guidelines of the Canadian Council on Animal Care and approved by the animal care committee of McGill University.

Viral infection

Smith strain of MCMV (kindly provided by Dr. Sylvia Vidal) has been described and used in this study (Fodil et al., 2014). Infections were performed using 5 × 104

MCMV immediate early (IE1) mRNA was detected in peripheral nerves following an intraperitoneal inoculation

MCMV IE1 has a critical role in viral replication (Tang and Maul, 2003). Alongside other immediate-early (IE) genes/proteins, IE1 is expressed at the beginning of infection. It is also a prerequisite for progression into the late phase of infectious cycle and the subsequent replication of viral DNA, which is in turn required for entry into the late phase, and virion assembly and release (Nevels et al., 2004; Gawn and Greaves, 2002). To first confirm whether an intraperitoneal injection of MCMV

Discussion

In this study, we investigated the immediate impact (within 2 weeks) of systemic MCMV infection in the blood and in the nervous system of C57BL6 mice. Our results provided clear evidence that in addition to systemic viral immune response, MCMV infection precipitates an acute and transient inflammatory response in the nervous system, with a preference for the PNS. In this acute phase, however, no axonal damage nor demyelination was found in peripheral nerves.

In rodent experimental models of MCMV

Author's contributions

OO, MY, VAGR, XQS and JMH performed experiments; OO, MY, SF and JZ designed the study; OO and JZ wrote the manuscript. All authors read and approved the manuscript.

Declaration of Competing Interest

The authors declare no competing interests.

Acknowledgements

The authors are grateful to Dr. Silvia Vidal (McGill University) for providing WT MCMV for the study. This work was supported by funding from the Canadian Institutes for Health Research (CHIR) (PJT-155929) to J.Z. and S.F., the Louise and Alan Edwards Foundation to J.Z.

References (45)

  • G. Chan et al.

    Human cytomegalovirus stimulates monocyte-to-macrophage differentiation via the temporal regulation of caspase 3

    J. Virol.

    (2012)
  • T. Chomiak et al.

    What is the optimal value of the g-ratio for myelinated fibers in the rat CNS? a theoretical approach

    PLoS One

    (2009)
  • S.W. Cousins et al.

    Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization

    PLoS Pathog.

    (2012)
  • S. Eckhart et al.

    A longitudinal study of circulating lymphocyte subsets in the peripheral blood during the acute tage of Guillain-Barre syndrome

    J. Neurol. Sci.

    (1997)
  • N. Fodil et al.

    Specific dysregulation of IFNgamma production by natural killer cells confers susceptibility to viral infection

    PLoS Pathog.

    (2014)
  • J.M. Gawn et al.

    Absence of IE1 p72 protein function during low-multiplicity infection by human Cytomegalovirus results in a broad Block to viral delayed-early gene expression

    J. Virol.

    (2002)
  • D.A. Goukassian et al.

    Tumor necrosis factor-alpha receptor p75 is required in ischemia-induced neovascularization

    Circulation

    (2007)
  • R.D. Hadden et al.

    Preceeding infections, immune factors, and outcome in Guillain-Barre syndrome, the plasma exchange/sandoglobulin Guillain-Barre syndrome trial group

    Neurology

    (2001)
  • D. Henson et al.

    Mouse cytomegalovirus. Necrosis of infected and morphologically normal submaxillary gland acinar cells during termination of chronic infection

    Am. J. Pathol.

    (1972)
  • A. Khalili-Shirazi et al.

    Antiganglioside antibodies in Guillain-Barre syndrome after a recent cytomegalovirus infection

    J Neurol Neurosurg.

    (1999)
  • R. kiefer et al.

    The role of macrophages in immune mediated damage to the peripheral nervous system

    Prog. Neurobiol.

    (2000)
  • P. Klenerman et al.

    T cell responses to cytomegalovirus

    Nat. Rev. Immunol.

    (2016)
  • Cited by (4)

    • Construction of a mouse model of Posner-Schlossman syndrome by anterior chamber infection with cytomegalovirus

      2022, Experimental Eye Research
      Citation Excerpt :

      Oladiran et al. investigated the effect of MCMV infection on the nervous system of mice and found that peripheral nerves were permissive to MCMV during acute infection, which was associated with local inflammation but not nerve tissue damage in the acute phase. Moreover, levels of activated CD8+ T cells, monocytes/macrophages, and cytokines expression increased in the blood and sciatic nerves of infected mice, which exhibited transient sensory dysfunction in the acute phase; however, no axonal damage or demyelination was found in peripheral nerves(Oladiran et al., 2019). It is known that AC structures are richly innervated by sensory- and autonomic-nerve endings(May et al., 2005; McDougal and Gamlin, 2015; Nomura and Smelser, 1974; Selbach et al., 2000).

    View full text