Microglial response to murine leukemia virus-induced encephalopathy is a good indicator of neuronal perturbations

Abstract

The neuronal pathology caused by neonatal infection of rats with the PVC-211 murine leukemia virus (PVC-211 MuLV) and its underlying mechanisms are not well defined even though a loss of neurons and spongiform neurodegeneration has been reported to accompany the disease. Here we sought to identify sites of neurodegeneration using microglial reactivity as an indirect marker and to characterize microglial activation during disease progression. Using a panel of microglial antibodies including Iba1, OX-42, ED1, and anti-ferritin, we have studied the response of microglial cells to neonatal CNS infection with PVC-211 at post-infection survival times 7, 14, 21, and 28 days. We found that microglial activation occurred primarily in the spinal cord and brainstem where it gradually increased in intensity over the time course of this study. Other brain areas were relatively unremarkable in their microglial reaction to viral infection within this time frame. However, presence of activated microglial cells was not correlated directly with presence of viral glycoprotein (gp70), which was expressed in endothelial cells throughout the CNS. Although double labeling of microglia with Iba1 and ED1 revealed numerous actively phagocytic microglia during disease progression, not all activated microglia were ED1-positive. In addition to the intense microglial activation, we found increased ferritin expression sporadically throughout the virus-infected brain. The ferritin-positive cells were mostly microglia that exhibited dystrophic changes and likely represented a degenerating subpopulation of microglial cells. Thus, activated microglia can co-exist with degenerating microglia in the same brain region. We attempted to localize degenerating neurons or neurites using FluoroJade, anti-tau, and anti-alpha synuclein staining, but none of these procedures yielded results to indicate obvious neuronal pathology. We conclude that the visualization of microglial activation is a more sensitive measure of neuronal perturbations than direct detection of neuronal pathology which may be subtle and not produce overt degenerative changes.

Persistent retroviral infection with MoMuLV influences neuropathological signature and phenotype of prion disease

“…The spatial distribution of the virus within the CNS (e.g. parenchyma or blood vessels) is not well defined [84]. In this study, we did not address modes of MoMuLV replication in brain parenchyma.…”

“…Mice infected with MoMuLV alone did not show any clinical signs of disease or neuropatholgical alterations. Here, it is important to note that the administration of virus to young mice and not to mid-gestation or newborn mice, inhibits disease induction (both the common T-cell lymphoma/leukemia and a very rare spongiform encephalopathy induced by mutant forms of MoMuLV) by reducing virus spread at a critical developing window in both the thymus and CNS [4,55,61,84]. Furthermore, the development of paresis in MoMuLV ?…”

“…Certain MoMuLV variants may induce spongiform encephalopathies with clinical manifestations in defined mouse strains when virus is administered at mid-gestation or to newborn animals [4,55,61,84]. However, in our experimental setting, mice inoculated with MoMuLV only did not show any signs of clinical manifest retrovirus a Different representative brain regions were analyzed for astrogliosis (GFAP), microgliosis (Iba-1) or spongiosis (HE).…”

Microglial pathology

“…In situations where there is sudden entry of iron into the CNS parenchyma, for example during intracerebral hemorrhages, it is of critical importance that the iron be sequestered rapidly and effectively, and this is a critical function of microglial first responders. Experimental studies in animals have shown that when microhemorrhages occur or when there is CNS trauma, microglia not only become positive for ferritin they also become dystrophic [ 143 , 144 ]. The strong correlation between ferritin positivity and dystrophy, reflected in findings from both human brains as well as from experimental studies, strongly suggest that sequestration of iron is a hazardous activity that can cause damage to microglial cells.…”

Induction of Microglia Activation after Infection with the Non-Neurotropic A/CA/04/2009 H1N1 Influenza Virus

“…In general, microglial induction is thought to be protective, with the goal of eliminating the encountered pathological species. However, this activation can also have unintended consequences, leading to neurotoxicity [ 12 ]. For this reason, mechanisms exist to deactivate the microglial response.…”