Neurotropic infections are not just about the CNS

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CD4+ T Cells Require Either B Cells or CD8+ T Cells to Control Spread and Pathogenesis of a Neurotropic Infection

Text by Andreas C. Solomos, Kevin J. O’Regan, and Glenn F. Rall

Research highlights the old notion of the “immune privileged” central nervous system (CNS) is rapidly being revised as evidence accumulates that the immune system is, in fact, critical for homeostatic CNS surveillance as well direct resolution of neurotropic infections.  Our lab has long used a mouse model in which only CNS neurons are permissive for measles virus (MV) infection, allowing us to directly assess immune-neuron interactions. In this model, neurons of adult, immune competent mice do become infected, but infected animals show no signs of illness because the anti-viral response is rapid and effective.  In contrast, mice that lack adaptive immune cells, T and B lymphocytes, die of unrestricted MV infection by 3 weeks post-challenge.  In this study, we further dissected the roles of the adaptive response, using available immunodeficient mice lacking one or more components of the adaptive response, and/or treated infected mice with antibodies to remove specific immune cell populations. We discovered that mice lacking either B cells or CD8+ cytotoxic T cells could survive infection, but were less able to control MV replication compared to immunocompetent mice.  In contrast, depletion of CD4+ T cells resulted in illness and death in all mice, but required either B cells or CD8+ T cells, implicating a coordinated interplay of adaptive immune cells in resolution of a CNS-restricted infection.

One surprising aspect of this study was that B cells complement CD4+ T cells despite virtually no evidence of these cells in the parenchyma over the course of infection.  This suggests that whatever contribution B cells make to clearance occurs in the periphery, perhaps influencing CD4+ T cells that then migrate to the CNS, or via the production of antiviral antibodies that can percolate into the MV-infected brain.  This observation was the moment we knew we had a compelling story, adding to a growing literature that shows that the periphery plays an important role in shaping CNS immune responses: put simply, neurotropic infections are not just about the CNS.  Additionally, our data implied that viral RNA persists in the brain following infection of immune competent mice, despite the lack of illness or disease.  Thus, the presence of persisting viral RNA in neurons and neuropathology are uncoupled, implicating that some mechanism of viral control must exist in immune competent mice to limit unrestricted viral replication and spread.  Together, we believe these studies underscore an emerging principle in neuroimmunology:  immune responses to neurotropic pathogens are functionally distinct from those that infect the periphery; such differences result in unique pathogenic outcomes, despite using common cellular players and soluble mediators.


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Article figure 5B: Role of CD4+T cells in survival and viral control. NSE-CD46+ (n=21), NSE-CD46+/RAG-2 KO (n=28), NSE-CD46+/MHC-II KO (n=40) or NSE-CD46+ mice injected with CD4-depleting antibody (n=8) or an isotype control (n=5) were challenged IC with 1×104 PFU of MV-Ed and monitored daily for survival.

Introducing the authors


Pictured from left to right the Rall Lab:  Alicia Holmgren, Amanda Purdy, Andreas Solomos, Glenn Rall, Sarah Cavanaugh, Kevin O’Regan, and Christine Matullo

About the research

CD4+ T cells require either B cells or CD8+ T cells to control spread and pathogenesis of a neurotropic infection
Andreas C. Solomos, Kevin J. O’Regan, Glenn F. Rall
Virology, Volume 499, December 2016, Pages 196–202