Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine gamma-herpesvirus 68 (MHV-68) is a natural pathogen of small rodents and insectivores (mice, voles and shrews). The primary infection is characterized by virus replication in lung epithelial cells and the establishment of a latent infection in B lymphocytes. The virus is also observed to persist in lung epithelial cells, dendritic cells and macrophages. Splenomegaly is observed two weeks after infection, in which there is a CD4+ T-cell-mediated expansion of B and T cells in the spleen. At three weeks post-infection an infectious mononucleosis-like syndrome is observed involving a major expansion of Vbeta4+CD8+ T cells. Later in the course of persistent infection, ca. 10% of mice develop lymphoproliferative disease characterized as lymphomas of B-cell origin. The genome from MHV-68 strain g2.4 has been sequenced and contains ca. 73 genes, the majority of which are collinear and homologous to other gamma-herpesviruses. The genome includes cellular homologues for a complement-regulatory protein, Bcl-2, cyclin D and interleukin-8 receptor and a set of novel genes M1 to M4. The function of these genes in the context of latent infections, evasion of immune responses and virus-mediated pathologies is discussed. Both innate and adaptive immune responses play an active role in limiting virus infection. The absence of type I interferon (IFN) results in a lethal MHV-68 infection, emphasizing the central role of these cytokines at the initial stages of infection. In contrast, type II IFN is not essential for the recovery from infection in the lung, but a failure of type II IFN receptor signalling results in the atrophy of lymphoid tissue associated with virus persistence. Splenic atrophy appears to be the result of immunopathology, since in the absence of CD8+ T cells no pathology occurs. CD8+ T cells play a major role in recovery from the primary infection, and also in regulating latently infected cells expressing the M2 gene product. CD4+ T cells have a key role in surveillance against virus recurrences in the lung, in part mediated through 'help' in the genesis of neutralizing antibodies. In the absence of CD4+ T cells, virus-specific CD8+ T cells are able to control the primary infection in the respiratory tract, yet surprisingly the memory CD8+ T cells generated are unable to inhibit virus recurrences in the lung. This could be explained in part by the observations that this virus can downregulate major histocompatibility complex class I expression and also restrict inflammatory cell responses by producing a chemokine-binding protein (M3 gene product). MHV-68 provides an excellent model to explore methods for controlling gamma-herpesvirus infection through vaccination and chemotherapy. Vaccination with gp150 (a homologue of gp350 of Epstein-Barr virus) results in a reduction in splenomegaly and virus latency but does not block replication in the lung, nor the establishment of a latent infection. Even when lung virus infection is greatly reduced following the action of CD8+ T cells, induced via a prime-boost vaccination strategy, a latent infection is established. Potent antiviral compounds such as the nucleoside analogue 2'deoxy-5-ethyl-beta-4'-thiouridine, which disrupts virus replication in vivo, cannot inhibit the establishment of a latent infection. Clearly, devising strategies to interrupt the establishment of latent virus infections may well prove impossible with existing methods.
 ...
PMID:Natural history of murine gamma-herpesvirus infection. 1131 14

Normal C57BL/6 mice infected with 106 colony-forming units of a highly virulent strain of Mycobacterium avium developed a progressive infection characterized by loss of T cells from the tissues and infiltration with high numbers of heavily infected macrophages. In contrast, when C57BL/6 mice were infected with 102 colony-forming units of the same strain they retained T cells and T-cell reactivity in the tissues, and granulomas evolved into large masses that, at 4 months of infection, exhibited central necrosis. The development of these necrotic lesions did not occur in nude mice, nor in mice genetically deficient in CD4, interleukin-12 (IL-12) p40, interferon-gamma (IFN-gamma) and CD40 and were reduced in mice deficient in CD54 or IL-6. They were less numerous but bigger in mice deficient in IL-10 or the inducible nitric oxide synthase, correlating with the increased resistance to mycobacterial proliferation of these strains as compared to control mice. The appearance of necrosis was not affected in mice deficient in CD8alpha, T-cell receptor delta, tumour necrosis factor receptor p55, and perforin, nor was it affected in mice over-expressing bcl2. The appearance of necrosis could be prevented by administering antibodies specific for CD4, IL-12p40, or IFN-gamma from the second month of infection when organized granulomas were already found. Our results show that the immunological mediators involved in the induction of protective immunity are also major players in the immunopathology associated with mycobacteriosis.
 ...
PMID:Immunological basis of the development of necrotic lesions following Mycobacterium avium infection. 1215 23

It is known that TNF-alpha (TNF) exerts distinct tissue-protective or -destructive effects in the pathogenesis of T cell-dependent immunopathology, depending on the context and amount of cytokine produced. To better understand the cellular mechanisms underlying the regulation of T cells by TNF, we have analyzed the role of TNF in regulating various facets of the antigen-specific CD8 T cell response to lymphocytic choriomeningitis virus (LCMV) in mice. We show that expansion and differentiation of virus-specific effector CD8 T cells and LCMV clearance are not dependent on TNF. Instead, we demonstrate that TNF limits the duration of the effector phase of the CD8 T cell response by regulating apoptosis and not proliferation of effector cells in vivo. We further show that attenuation of effector cell apoptosis induced by TNF deficiency led to a substantial increase in the number of virus-specific memory CD8 T cells without affecting their function. The enhancement in the number of memory CD8 T cells in TNF-deficient (TNF-/-) mice was not associated with up-regulation of IL-7Ralpha or Bcl-2 in effector cells, which indicated that TNF might limit differentiation of memory cells from IL-7R(lo) effector cells. Collectively, these data are strongly suggestive of a role for TNF in down-regulating CD8 T cell responses and the establishment of CD8 T cell memory during an acute viral infection. These findings further our understanding of the regulation of CD8 T cell homeostasis and have implications in vaccine development and clinical use of anti-TNF therapies to treat T cell-dependent, inflammatory disorders.
 ...
PMID:A role for TNF in limiting the duration of CTL effector phase and magnitude of CD8 T cell memory. 1770 95

Pathogen clearance and host resilience/tolerance to infection are both important factors in surviving an infection. Cells of the myeloid lineage play important roles in both of these processes. Neutrophils, monocytes, macrophages, and dendritic cells all have important roles in initiation of the immune response and clearance of bacterial pathogens. If these cells are not properly regulated they can result in excessive inflammation and immunopathology leading to decreased host resilience. Programmed cell death (PCD) is one possible mechanism that myeloid cells may use to prevent excessive inflammation. Myeloid cell subsets play roles in tissue repair, immune response resolution, and maintenance of homeostasis, so excessive PCD may also influence host resilience in this way. In addition, myeloid cell death is one mechanism used to control pathogen replication and dissemination. Many of these functions for PCD have been well defined in vitro, but the role in vivo is less well understood. We created a mouse that constitutively expresses the pro-survival B-cell lymphoma (bcl)-2 protein in myeloid cells (CD68(bcl2tg), thus decreasing PCD specifically in myeloid cells. Using this mouse model we explored the impact that decreased cell death of these cells has on infection with two different bacterial pathogens, Legionella pneumophila and Streptococcus pyogenes. Both of these pathogens target multiple cell death pathways in myeloid cells, and the expression of bcl2 resulted in decreased PCD after infection. We examined both pathogen clearance and host resilience and found that myeloid cell death was crucial for host resilience. Surprisingly, the decreased myeloid PCD had minimal impact on pathogen clearance. These data indicate that the most important role of PCD during infection with these bacteria is to minimize inflammation and increase host resilience, not to aid in the clearance or prevent the spread of the pathogen.
 ...
PMID:The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes. 2885 75

Control of chronic CNS infection with the parasite Toxoplasma gondii requires ongoing T cell responses in the brain. Immunosuppressive cytokines are also important for preventing lethal immunopathology during chronic infection. To explore the loss of suppressive cytokines exclusively during the chronic phase of infection, we blocked IL-10R in chronically infected mice. Consistent with previous reports, IL-10R blockade led to severe, fatal tissue destruction associated with widespread changes in the inflammatory response, including increased APC activation, expansion of CD4+ T cells, and neutrophil recruitment to the brain. We then sought to identify regulatory mechanisms contributing to IL-10 production, focusing on ICOS, a molecule implicated in IL-10 production. Unexpectedly, ICOS ligand (ICOSL) blockade led to a local expansion of effector T cells in the brain without affecting IL-10 production or APC activation. Instead, we found that ICOSL blockade led to changes in T cells associated with their proliferation and survival. We observed increased expression of IL-2-associated signaling molecules CD25, STAT5 phosphorylation, Ki67, and Bcl-2 in T cells in the brain, along with decreased apoptosis. Interestingly, increases in CD25 and Bcl-2 were not observed following IL-10R blockade. Also, unlike IL-10R blockade, ICOSL blockade led to an expansion of both CD8+ and CD4+ T cells in the brain, with no expansion of peripheral T cells or neutrophil recruitment to the brain and no severe tissue destruction. Overall, these results suggest that IL-10 and ICOS differentially regulate T cell responses in the brain during chronic T. gondii infection.
 ...
PMID:IL-10 and ICOS Differentially Regulate T Cell Responses in the Brain during Chronic Toxoplasma gondii Infection. 3071 97