Ebola Virus Pandemic Shield
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Since it became clear that the outbreak of SARS beginning 2003 is caused by the virus currently known as SARS-coronavirus (SARS-CoV), researchers have tried to find cures for this new virus. It was shown that both shRNAs and siRNAs could efficiently block SARS-CoV replication in tissue culture systems (He et al. 2003 Lu et al. 2004a Wang et al. 2004b Zhang et al. 2004b). In these studies, the main target was the polymerase gene, whereas one paper describes inhibition of SARS-CoV by targeting the spike protein, which is essential for particle formation and entry (Zhang et al. 2004b). Additionally, replication of the newly discovered human coronavirus NL63, HCoV-NL63 (Van der Hoek et al. 2004), could also be inhibited by siRNAs that target the spike gene (Pyrc et al. in preparation). Because SARS is a disease of the upper airways and lungs, it could be relatively easy to administer therapeutic siRNAs. For influenza virus, HRSV and HPIV, it has been shown that virus replication in the...
The first demonstration of RNAi-mediated inhibition of a human pathogenic virus was reported by Bitko and Barik in 2001 (Bitko and Barik 2001). These authors reported a tenfold inhibition of human respiratory syncytial virus (HRSV) replication in vitro using nanomolar concentrations of synthetic siR-NAs that targeted the viral polymerase subunit P and the fusion protein F. Currently, many other studies have described RNAi-mediated inhibition of a large variety of viruses. RNAi-mediated inhibition of HIV-1 has received much attention (see below, Tables 1 and 2). In addition, 17 different RNA viruses, and 10 different DNA viruses have been efficiently targeted by RNAi (Tables 3 and 4). These include important human pathogens such as hepatitis C virus (HCV), dengue (DEN) virus, severe acute respiratory syndrome (SARS) coronavirus, poliovirus, influenza A virus, hepatitis D virus (HDV), human rhinovirus-16 (HRV-16), hepatitis B virus (HBV), herpes simplex virus type-1 (HSV-1), human...
Therapeutically, the use of lentiviral or other stable integrating vector systems may not prove useful in the application of siRNAs in treating transient infections such as influenza or severe acute respiratory syndrome (SARS). One alternative is the use of cationic lipid complexes to systemically or locally de-
(HPIV) and HRSV (Bitko et al. 2005 Ge et al. 2004 Tompkins et al. 2004 Zhang et al. 2005). Due to limitations of anti-influenza vaccines and drugs, there is a real need for novel strategies to inhibit influenza virus. Worldwide, an estimated half million deaths per year are attributed to influenza virus, and there is the continuous threat of the emergence of a novel pandemic strain. To use siRNA as an in vivo therapeutic, it must be delivered efficiently to the appropriate tissue(s), in this case the lungs. Lungs are perhaps the most readily transfectable organs because they are likely the most vascularized tissue in the body. Furthermore, injected materials will first traverse the capillary beds of the lungs upon intravenous administration. Researchers have used polyethyleneimine (PEI) injected intravenously or intratracheally to deliver siRNAs and a lentiviral DNA vector expressing shRNAs (Ge et al. 2004). PEI is a cationic polymer that has been used to deliver DNA into lung cells....
Ge et al. (2003) showed that siRNAs targeting conserved regions (PA and NP) of the influenza genome inhibited virus production in cell culture and in embryonated chicken eggs. Furthermore, RNAi mediated by PA-, NP-, and PB1-specific siRNAs or shRNAs expressed from DNA vectors prevented and treated influenza A virus infection in mice (Ge et al. 2004). In addition, Tompkins et al. (2004) showed that the administration of influenza-specific siRNAs decreased lung virus titers and protected mice from lethal challenge by a variety of influenza A viruses, including the potential pandemic subtypes H5 and H7. This specific inhibition of influenza virus replication requires homology between the siRNAs and gene targets, and is not the result of IFN induction by dsRNAs. For therapeutic applications against the influenza A virus, the siRNAs can be administered via intranasal or pulmonary routes. RNAi is more potent than the antisense approach (Mizuta et al. 1999), and the evaluation of this...
Retroviruses have been colonizing vertebrate hosts for hundreds of millions of years, leaving a calling card of integrated retroviral sequence transmitted between generations (Gifford and Tristem 2003). An early discovery in research into the current HIV-1 pandemic was the finding that this particular retrovirus had a limited host range, being restricted to humans and apes. The barrier to infection in other primate cells was identified in 2004 as being mediated by a protein named TRIM5a, which acted to block HIV-1 replication soon after viral entry into cells and before reverse transcription (Fig. 14.8) (Stremlau et al. 2004).
In 1894, bubonic plague irrupted in Canton, China, and spread to Hong Kong. From this port city, the lethal trio of fleas, rats, and bacteria stowed away on ships heading around the world. As the ensuing pandemic began claiming 12 million lives, two scientists raced to discover the microbe responsible for the Black Death. The winner beat his rival by a matter of days, and the victor's name is now known to every student of microbiology. Alexander Yersin, an eccentric French doctor, shares his name with the plague bacterium, Yersinia pestis. And the loser Kitasato Shibasaburo is no more than a footnote in the chronicles of science. This Japanese microbiologist was, however, a vital link in a chain of events that led to the most diabolical program of entomological warfare ever devised.
However, not all people exposed to HIV become infected, and those who do, progress to AIDS at significantly different rates (Box 14.2). Studies of highly exposed yet persistently seronegative individuals together with prospective cohort studies of groups at risk of HIV exposure have proved highly informative in resolving genetic determinants of disease susceptibility and progression (Kulkarni et al. 2003 O'Brien and Nelson 2004). Genetic variation in genes encoding proteins involved in HIV entry to cells, barriers to retroviral infection within cells, cytokines, and cell mediated and innate immunity have all been shown to be involved in HIV infection and development of AIDS (Fig. 14.2) (O'Brien and Nelson 2004 Heeney et al. 2006). In this chapter some of this remarkable work is reviewed, highlighting the complex relationship between human genetic diversity and viral infection, and the insights such analysis gives into the current AIDS pandemic and our evolutionary history.
The one clear lesson that emerged from our experience in attempting to isolate Apollo-returned lunar samples is that mission controllers are unwilling to risk the certain discomfort of an astronaut - never mind his death - against the remote possibility of a global pandemic. When Apollo 11, the first successful manned lunar-lander, returned to Earth - it was a spaceworthy, but not a very seaworthy, vessel - the agreed-upon quarantine protocol was immediately breached. It was adjudged better to open the Apollo 11 hatch to the air of the Pacific Ocean and, for all we then knew, expose the Earth to lunar pathogens, than to risk three seasick astronauts. So little concern was paid to quarantine that the aircraft-carrier crane scheduled to lift the command module unopened out of the Pacific was discovered at the last moment to be unsafe. Exit from Apollo 11 was required in the open sea.
Since the majority of graptolites lived either in the water column or within the plankton, quite different factors influenced their distribution in contrast to, say, that of the coeval benthos. Provinciality was most marked in the earlier Ordovician (Darriwilian) when two main provinces, the Atlantic and Pacific, were recognized. The Atlantic province, including the then high-latitude regions of Avalonia and Gondwana, was characterized by pendent Didymograptus species. The Pacific province, including low latitude, tropical regions such as the Laurentian margins, was more diverse with isograptids, cardiograptids and oncograptids. The isograptid biofacies, itself, was more pandemic, occupying deeper water and associated with the world's continental margins. During the end-Ordovician extinction events (see p. 169), the Pacific province graptolites suffered particularly badly, and although graptolites again diversified during the Silurian their provinciality developed a different if less...
But while we thrive in a population of 6 billion, our closest relatives are on the brink of extinction. The World Wildlife Fund (www.worldwildlife.org) reports that great apes are all endangered. There are only about 10,000 bonobos left in the wild, down from over 100,000 just twenty years ago. They are being squeezed out of preferred habitats by humans and are also being killed for bush meat to be served at expensive restaurants. Orangutans are stuck on islands that are becoming increasingly deforested. Their numbers are dwindling at 50,000. Jane Goodall reported on her Web site (www.janegoodall.org) that there were only 150,000 chimpanzees left in 2004, but that there should be at least be a million today. Less than 1,000 mountain gorillas have survived to the present day with no help from poachers and deadly Ebola outbreaks.
Modern medical researchers discredit Drake's utopian idea of a disease-free world. They argue that there are not a fixed number of diseases that can be eliminated one by one over time. Disease is part of the same evolutionary process that produced the human race. We evolved together and continue to do so. Medical researchers might wipe out some diseases, but others soon rise to replace them. A generation that has experienced the worldwide spread of AIDS, the ravages ofthe Ebola virus, the threat ofthe human form ofMad Cow Disease (Creutzfeld-Jakob variant), the appearance of SARS, and the possibility of an influenza epidemic appreciates how improbable it is to imagine immortality of the kind proposed by Drake.
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