Death Of Uninfected Cells Research Articles

Replication of early and recent Zika virus isolates throughout mouse brain development

Fetal infection with Zika virus (ZIKV) can lead to congenital Zika virus syndrome (cZVS), which includes cortical malformations and microcephaly. The aspects of cortical development that are affected during virus infection are unknown. Using organotypic brain slice cultures generated from embryonic mice of various ages, sites of ZIKV replication including the neocortical proliferative zone and radial columns, as well as the developing midbrain, were identified. The infected radial units are surrounded by uninfected cells undergoing apoptosis, suggesting that programmed cell death may limit viral dissemination in the brain and may constrain virus-associated injury. Therefore, a critical aspect of ZIKV-induced neuropathology may be defined by death of uninfected cells. All ZIKV isolates assayed replicated efficiently in early and midgestation cultures, and two isolates examined replicated in late-gestation tissue. Alteration of neocortical cytoarchitecture, such as disruption of the highly elongated basal processes of the radial glial progenitor cells and impairment of postmitotic neuronal migration, were also observed. These data suggest that all lineages of ZIKV tested are neurotropic, and that ZIKV infection interferes with multiple aspects of neurodevelopment that contribute to the complexity of cZVS.

Yeast Dying to Survive

There is evidence that unicellular organisms, yeast in particular, can undergo programmed cell death through a biochemical pathway with similarities to the apoptosis machinery of multicellular organisms. However, the evolutionary advantage of programmed cell death to a unicellular organism is not obvious (to say the least), leading some investigators to question the validity of a yeast programmed cell death pathway. Ivanovska and Hardwick provide an argument in favor of the biological relevance of such a death pathway in the context of cells infected with killer viruses, where the death program may benefit the community rather than a single cell. Most yeast strains are infected with viruses. One common group of double-stranded RNA virus, the M viruses, cause death of uninfected cells but provide immunity to infected cells (through an unknown mechanism). Ivanovska and Hardwick found that such killing appears to rely on components similar to those of apoptotic pathways in higher organisms. In particular, loss of the Fis1 protein, a protein that is thought to function in control of mitochondrial permeability, as do mammalian Bcl-2 family proteins, made cells more susceptible to cell death in an assay of uninfected cells cultured with cells infected with the M1 killer virus. Other components also proposed to mediate a yeast cell death pathway--Yca1, a metacaspase with similarity to mammalian caspases, and Tok1, a plasma membrane potassium channel--were shown to mediate cell death caused by the M1 virus. The M1 virus encodes a toxin, K1. Under proper culture conditions, K1 itself could cause programmed cell death, but through a separate pathway independent of the Yca1 metacaspase. In experiments with long culture conditions designed to simulate competition for survival in the wild, killer virus-infected cells overran cultures with noninfected cells. The authors propose that a primitive mechanism that distinguishes "self" (infected) and "nonself" (uninfected) cells may be evolutionarily advantageous in providing nutrients from the dying cells that enhance survival of the population of cells harboring the killer virus. I. Ivanovska, J. M. Hardwick, Viruses activate a genetically conserved cell death pathway in a unicellular organism. J. Cell Biol. 170 , 391-399 (2005). [Abstract] [Full Text]

Regeneration and tolerance factor prevents bystander T-cell death associated with human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) infection is characterized by a depletion of T cells. This depletion is caused both by the virus-induced death of infected T cells and by the death of uninfected cells (bystander depletion) by a mechanism which is largely uncharacterized. Regeneration and tolerance factor (RTF) is a subunit of the vacuolar ATPase and a protein that is involved with activation and apoptosis. Anti-RTF antibodies mediate apoptosis in T lymphocytes. When anti-RTF was added to lymphocytes from an HIV-positive individual, they underwent larger amounts of apoptosis than cells taken from healthy controls. When lymphocytes were examined by Western blotting, those from HIV-positive individuals exhibited increased levels of expression of the 50-kDa protein (P < 0.001). A 70-kDa protein was the predominant form of RTF in uninfected control lymphocytes, being expressed in 100% of individuals studied. The expression of the 50-kDa protein in HIV-positive individuals correlated with decreased absolute CD4 counts with a sensitivity of 92% and a positive predictive value of 86%. When uninfected lymphocytes were stimulated with anti-CD3 and anti-CD28, no RTF was detected during early stimulation but a 50-kDa protein was expressed during late stimulation. When the susceptibilities of the lymphocytes to anti-RTF-induced apoptosis were measured, they correlated with the size of the RTF protein expressed. The cells were not susceptible to apoptosis when the 70-kDa RTF was present but were susceptible when the 50-kDa RTF was present. We propose that the increase in the levels of the 50-kDa RTF on cells from HIV-positive individuals is important in preventing the cell from undergoing apoptosis.