Lymphocytic choriomeningitis (LCM) virus (LCMV), a mouse pathogen and prototypical member of the arenavirus family, has been invaluable for key discoveries in both immunology and viral pathogenesis (reviewed in references 4
). For example, LCMV was used to define T-cell receptor-class I major histocompatibility complex interactions, to establish the relative immunodominance of viral epitopes, and to dissect the events leading to CD8+
T-cell-mediated cytotoxicity (reviewed in reference 3
). More recently, the generation, diversity, and exhaustion of memory T cells were established by using LCMV-challenged mice (2
). In addition to revealing seminal aspects of host immunity, LCMV has also been used to define novel ways by which viruses trigger disease. For example, transgenic mice expressing an LCMV protein were used to show that autoimmune disease can result from cross-reactivity between viral antigens and self-antigens following infection (“molecular mimicry”) (20
), a process that was later shown to occur in humans following herpes simplex virus type 1 ocular infection (32
). Moreover, LCMV-mediated suppression of cellular genes, including those encoding growth hormones (15
), neurotransmitters (17
), and synaptic proteins (9
), implicated novel roles for persisting, noncytopathic viruses in chronic disease.
One attribute that makes LCMV so useful is that vastly different pathogenic outcomes can be achieved in mice by varying both host and viral parameters (e.g., the route of inoculation, dose and viral strain, mouse strain, age, and immunocompetence). As a result, LCMV infection can result in asymptomatic clearance and immunity, lifelong persistent infection, or rapid death (LCM). While much is known about the first two of these outcomes, less is known about the basis of the lethal, immune-mediated disease that occurs following intracerebral (i.c.) challenge of immunocompetent mice. In this instance, the delivery of as few as 1 PFU of LCMV into the brain results in infection of the meninges, leptomeninges, and ependyma as well as the cerebrospinal fluid (CSF)-producing choroid plexus cells within the ventricles (3
). A rapid expansion of virus-specific CD8+
T cells occurs in secondary lymphoid organs, which then migrate through the CSF to the infected central nervous system (CNS) (7
); the peak of infiltration (6 to 7 days postinfection [dpi]) coincides with characteristic seizures that immediately precede death.
T cells are essential for lethal disease (as CD8-deficient mice survive i.c. LCMV challenge [12
]), the events that contribute to fatal neuropathology are not fully established. Studies using knockout (KO) mice lacking key immune mediators (e.g., perforin [PFN], gamma interferon, granzyme B, Fas, and tumor necrosis factor alpha) indicated that no single deficiency of any of these effector molecules could fully prevent disease (14
). Interestingly, disease onset occurs ~2 to 3 days later in PFN KO mice than in wild-type animals, which has been attributed to the reduced capacity of PFN KO effector CD8+
T cells to secrete proinflammatory cytokines, resulting in a delayed recruitment of other effector cells to the CNS. Nevertheless, the CD8+
T-cell effector function(s) that causes death in LCMV-infected mice remains unknown.
Indeed, even the issue of whether CD8+
T cells act directly or indirectly has been questioned: a recent report using two-photon microscopy to visualize events that occur in the meninges following infection showed that the infiltration of CD8+
T cells coincided with the entry of neutrophils and monocytes, which those authors speculated play a role in fatal disease (14
). The depletion of both neutrophils and monocytes, but not either cell population alone, delayed lethality somewhat, arguing that while CD8+
T cells are important, they may serve primarily a chemotactic role for other hematogenous effector populations.
Independent of the cells that are responsible for pathogenesis, the timing and order of events that lead to lethal LCM, as well as the specific basis of mortality, remain poorly defined. Previous reports suggested that the loss of integrity of blood-brain barrier (BBB) permeability may be important (1
), although it is not known how early postinfection this occurs or what role increased barrier permeability plays in LCM disease (1
). Alternatively, we hypothesized that the destruction of the cells lining the ventricles could result in edema and increased intracranial pressure, triggering events that then lead to the sudden onset of seizures and death in virus-challenged mice.
Here, we identify novel anatomical changes that are coincident with seizures and death in LCMV-infected mice; these events are consistent with uncal herniation resulting from ventricular leakage and edema. Thus, while BBB damage is apparent, we propose that ventricular failure, which is more temporally associated with fatal choriomeningitis, is the causative basis of this classic immunopathological disease.