Brain Trauma Enhances Transient Cytomegalovirus Invasion of the Brain Only in Mice That Are Immunodeficient

Abstract

Cytomegalovirus (CMV) is one of the most common viral pathogens leading to neurological dysfunction in individuals with depressed immune systems. How CMV enters the brain remains an open question. The hypothesis that brain injury may enhance the entrance of CMV into the brain was tested. Insertion of a sterile needle into the brain caused a dramatic increase in mouse CMV in the brains of immunodeficient SCID mice inoculated peripherally within an hour of injury and examined 1 week later; peripheral inoculation 48 h after injury and a 1-week survival resulted in only a modest infection at the site of injury. In contrast, uninjured SCID mice, as well as injured immunocompetent control mice, showed little sign of viral infection at the same time intervals. Direct inoculation of the brain resulted in widespread dispersal and enhanced replication of mCMV in SCID brains tested 1 week later but not in parallel control brains. Differential viremia was unlikely to account for the greater viral load in the SCID brain, since increased mCMV in the blood of SCID compared to controls was not detected until a longer interval. These data suggest that brain injury enhances CMV invasion of the brain, but only when the adaptive immune system is compromised, and that the brain's ability to resist viral infection recovers rapidly after injury.Cytomegalovirus (CMV) is a common virus found in the majority of adult humans. In contrast to the normal mature brain, where CMV infections are uncommon (15, 16), in individuals compromised by human immunodeficiency virus (2,22,30) or during medical immunosuppression associated with organ transplants (10, 21), CMV infections are common. CMV acts as an opportunistic virus that is associated with substantial complications once it has entered the central nervous system (CNS) (1,10,11,15,30,32,33,34). A number of mechanisms keep viruses such as CMV out of the brain; however, once inside the brain, viruses can spread rapidly, particularly within the ventricular systems. Outside the brain, T-and antibodygenerating B lymphocytes of the adaptive immune system, as well as other cells of the systemic immune system, including natural killer and macrophage/monocytes, fight and reduce CMV infections (1,4,8,23). The factors that influence CMV entrance into the adult brain have not been clearly elucidated. In the fetal human brain, in the absence of a developed bloodbrain barrier (BBB), CMV can enter the brain and cause substantial neurological disease (1,3,9).Mouse and human CMV each have genomes of 235 kb of double-stranded DNA, have similar tissue affinity, similar viral morphology and biology, similar ability to achieve long-term latency, and colinear gene sequences with different nucleotide sequences within many genes (15,16,25), suggesting that mouse CMV (mCMV) in many respects parallels its human counterpart.A number of papers studying CMV dispersal in normal and immunocompromised mice reported CMV infection in a number of peripheral organs but did not report CMV in the brain (16,20,23). When a CMV wit...

Polio, Still Lurking in the Shadows

“…A number of models of PV penetration of the CNS are based on the view that an intermediate step between gut and spinal cord infection requires the virus to move from the gut, possibly via the lymphatic system, into the blood stream (viremia). From there it might directly cross the blood brain barrier (BBB) into the CNS and initiate infection of neurons; it is, however, unusual for a virus, even a small one such as PV, to diffuse cross the BBB, although minor transient injury may enhance penetration of some viruses into the CNS (van den Pol,2009). Other potential mechanisms of PV movement across the BBB include direct infection of the endothelial cells, transendothelial transport, a Trojan horse infection of macrophage or dendritic cells that express the PVR and can be productively infected (Wahid et al,2005) or other immune cells that subsequently enter the brain, or entry through one of the regions of the brain such as the area postrema or median eminence with weak BBBs and subsequent diffusion or transport within the brain (Tyler and Nathanson,2001; Couderc et al,1990; Freistadt et al,1993; Pfeiffer,2010).…”