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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Infect Dis. Nov 25, 2015; 5(4): 67-76
Published online Nov 25, 2015. doi: 10.5495/wjcid.v5.i4.67
Interplay between rabies virus and the mammalian immune system
Nicholas Johnson, Adam F Cunningham
Nicholas Johnson, Animal and Plant Health Agency, Surrey KT15 3NB, United Kingdom
Adam F Cunningham, Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham BT15 2TT, United Kingdom
Author contributions: Both authors wrote the paper.
Supported by The European Union Seventh Framework Programme through project ANTIGONE: Anticipating the global onset of novel epidemics, No. 278976.
Conflict-of-interest statement: The authors declare that no competing interest exists.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nicholas Johnson, PhD, Animal and Plant Health Agency, Woodham Lane, Surrey KT15 3NB, United Kingdom. nick.johnson@apha.gsi.gov.uk
Telephone: +44-19-32357724 Fax: +44-19-32357237
Received: June 2, 2015
Peer-review started: June 3, 2015
First decision: August 8, 2015
Revised: September 23, 2015
Accepted: November 13, 2015
Article in press: November 17, 2015
Published online: November 25, 2015
Processing time: 177 Days and 23.8 Hours
Abstract

Rabies is a disease caused following infection of the brain by the rabies virus (RABV). The principle mechanism of transmission is through a bite wound. The virus infects peripheral nerves and moves to the central nervous system (CNS). There appears to be little involvement of other organ systems and little detectable immune stimulation prior to infection of the CNS. This failure of the mammalian immune system to respond to rabies virus infection leads, in the overwhelming majority of cases, to death of the host. To some extent, this failure is likely due to the exclusive replication of RABV in neurons and the limited ability to generate, sufficiently rapidly, an anti-viral antibody response in situ. This is reflected in the ability of post-exposure vaccination, when given early after infection, to prevent disease. The lack of immune stimulation during RABV infection preceding neural invasion is the Achilles heel of the immune response. Whilst many viruses infect the brain, causing encephalitis and neuronal deficit, none are as consistently fatal to the host as RABV. This is in part due to prior replication of many viruses in peripheral, non-neural tissue by other viruses that allows timely activation of the immune response before the host is overwhelmed. Our current understanding of the correlates of protection for rabies suggests that it is the action of neutralising antibodies that prevent infection and control spread of RABV. Furthermore, it tells us that the induction of immunity can protect and understanding how and why this happens is critical to controlling infection. However, the paradigm of antibody development suggests that antigen presentation overwhelmingly occurs in lymphoid tissue (germinal and non-germinal centres) and these are external to the CNS. In addition, the blood-brain-barrier may provide a block to the delivery of immune effectors (antibodies/plasma B-cells) entering where they are needed. Alternatively, there may be insufficient antigen exposure after natural infection to mount an effective response or the virus actively suppresses immune function. To improve our ability to treat this fatal infection it is imperative to understand how immunity to RABV develops and functions so that parameters of protection are better defined.

Keywords: Rabies virus; Immune stimulation; Central nervous system; Vaccination; Blood-brain-barrier

Core tip: Rabies is a devastating disease in developing countries with a very high case-fatality rate. The delayed immune response to infection with rabies virus could be a defining factor in poor prognosis following infection. Understanding the reasons for this muted response and identifying ways to manipulate immune effectors may lead to new therapeutic approaches to the treatment of rabies. This article reviews the reasons for the apparent failure of the immune response and identifies areas for therapeutic development.