Biomedical subjects

Peter M C Wong

Publications and source records attributed to Peter M C Wong.

4 recordsLinked to original sources

PubMed2004

Genetic immune modulation of Ran GTPase against different microbial pathogens.

Septic shock characterized by pro-inflammatory cytokine storm can be induced by a variety of microbial infections. Typical pro-inflammatory cytokines include TNFalpha, IL1 and IL6. Although one or more of them is often expressed in any given microbial infection, usually it is the elevation of one cytokine that becomes predominant at a particular time in a given infection. Here we showed that administration of adenoviral antigens alone led to a predominant elevation of serum IL6 but not TNFalpha Administration of endotoxin together with adenoviral antigens led to elevation of both serum IL6 and TNFalpha. In vivo expression of RanC/d, but not RanT/n or LacZ into peritoneal macrophages rapidly down-modulated the levels of these cytokines in both experimental situations. It also correlated with reduced liver inflammatory damage and increased resistance to septic shock. We conclude that RanC/d can be applied to down-modulating production of cytokines induced by microbial products other than endotoxin and to render resistance to mice against septic shock induced by one or more microbial pathogens. The ability of using RanC/d to down-modulate and RanT/n to up regulate host innate immune response induced by multiple microbial pathogens is illustrated in this study. Incorporation of either or both RanC/d and RanT/n alleles into appropriate vectors will produce genetics vaccines valuable for biodefense and medically important illness in which host immune system against invading agents is severely burdened.

Adenoviridae↗

PubMed2003

Presence of prepackaged mRNA in virions of DNA adenovirus.

Ran GTPase has been shown to be involved in host innate immune response, and two alleles, RanT/n and RanC/d, which differ from each other by a single nucleotide, have opposite effects on host innate immune response. In this study, we showed that although intravenous administration in mice with either Ran cDNA using an identical adenovirus (Ad) vector resulted in no significant difference in vector tissue distribution, intraperitoneal administration resulted in effective vector transduction into peritoneal macrophages, coupled with a striking difference in vector tissue distribution in 2 h or less. We further demonstrated the presence of prepackaged RNA in virions of Ad vectors, in cells actively producing Ad virus particles, and in cells very shortly after Ad infection. Real-time PCR analysis confirmed the presence of prepackaged RNA and estimated the copy number to be one per viral genome. The prepackaged viral mRNA could be used for translation into proteins, as shown by experiments in which the transcriptional inhibitor actinomycin-D was used. Hence, translation of Ran proteins from prepackaged viral mRNA immediately after virus uncoating in the cytoplasm is one mechanism that would account for an early difference in Ad-vector tissue distribution after efficient gene transfer into macrophages.

Adenoviridae↗

PubMed2002

Hypothesis: Ran GTPase-based potential therapeutic interventions against lethal microbial infections.

Host innate immune response represents a vital immediate defense against infections by a diverse group of microorganisms that include bacteria, viruses, and fungi. Many types of cell surface receptors in mammalian cells specifically recognize particular groups of microorganisms and transmit response signals to the nuclei via multiple signal transduction pathways. These signaling pathways must merge at some point and are likely to be redundant, as the host innate immune response to many microorganisms is remarkably similar; it is characterized by the production of proinflammatory cytokines such as TNFalpha, IL-1, and IL-6 by the principal cell types--macrophages and dendritic cells. Since these cytokines influence greatly the magnitude of the cascade of inflammatory events, the proportion and the actual amount of each among the cytokine group may be a characteristic of each type of infections. Immune modulation by systematically up-regulate or down-modulate these cytokines would conceivably have major therapeutic potential. We have recently shown that two alleles of Ran cDNAs--RanT/n and RanC/d--may possess these characteristics. Thus the application of Ran to the treatment of septic shock, lethal anthrax shock, or adenovirus-induced toxicities may open up many interesting possibilities in the future.

Animals↗

PubMedDate not supplied

A functional connection between RanGTP, NF-kappaB and septic shock.

RanGTPase is importantly involved in diverse biological functions, such as nuclear transport, spindle formation during mitosis, DNA replication and cell division. This review summarizes yet another new role of Ran - control of the activity of NF-kappaB in host immune responses. Overexpression of a specific allele of Ran results in preferential accumulation of nuclear RanGTP, downmodulation of proinflammatroy cytokine production and protection against septic shock. Nuclear RanGTP interacts with Exportin1, which in turn binds to IkappaB. Nuclear IkappaB binds to NF-kappaB in the nucleus, inhibiting NF-kappaB transcriptional activation of proinflammatory cytokine genes. Nuclear IkB also functions as an adaptor between NF-kappaB and Exportin1/RanGTP, enhancing export of NF-kappaB to the cytoplasm and further reducing the magnitude of host immune responses. From this picture, it appears that modulation of host immune responses via RanGTPase will have an immense impact on a wide spectrum of emerging infectious diseases, cancer and other genetic diseases.

Animals↗