photo credit: James D. Gathany/CDC
Over 200 million people are infected by malaria each year, and the majority of the 627,000 deaths per year are children younger than five. The disease is carried by mosquitos who act as vectors for the parasite. It’s only transmitted to humans by female mosquitoes, as they’re the only ones who bite. A team of researchers led by Andrea Crisanti of the Imperial College London managed to genetically modify mosquitos to produce 95% male offspring, eliminating mosquito populations along with the risk of malaria. The results of the study were published in Nature Communications.
In most species of mosquito, the females need a blood meal in order to acquire the nutrients to create viable eggs. When she does, she can lay about 200 eggs at a time in water, and up to 3,000 eggs over the course of her lifetime. About half of those offspring will be daughters, many of whom will live long enough to produce that amount of offspring also. For humans living near mosquitos carrying the parasite that causes malaria, those numbers of female mosquitos present a very real threat.
But what if the numbers could be skewed so that the sex ratio favors males, who are harmless to humans? This is exactly what Crisanti’s team set out to do with Anopheles gambiae, a species of mosquito endemic to sub-Saharan Africa, where 95% of malaria deaths occur. The researchers modified the males with the enzyme I-Ppol, which excises the X chromosome during spermatogenesis. This renders sperm that would produce daughters to be non-functional, while the sperm that will create male offspring are unaffected. As a result, about 95% of the resulting offspring are male.
Next, modified males were introduced to five caged wild-type populations. As the males mated with the females, they passed along the same mutation until it dominated the population. For four of the five populations, it took only six generations for the mosquitos to die out due to a lack of females.
“What is most promising about our results is that they are self-sustaining,” co-author Nikolai Windbichler said in a press release. “Once modified mosquitoes are introduced, males will start to produce mainly sons, and their sons will do the same, so essentially the mosquitoes carry out the work for us.”
This study was the first to successfully manipulate mosquito sex ratios, and it was done in a big way. The researchers hope that this information will be used to develop genetic mutations to be used in the wild, bringing large populations of mosquitos to their knees.
“The research is still in its early days, but I am really hopeful that this new approach could ultimately lead to a cheap and effective way to eliminate malaria from entire regions,” added lead author Roberto Galizi. “Our goal is to enable people to live freely without the threat of this deadly disease.”
Of course, while eradicating the mosquitos would be fantastic for eliminating the threat of malaria, what other affects would it have? Wouldn’t there be harsh consequences for the ecosystem? After all, mosquitos have been on the planet for about 100 million years and represent 3,500 species. As it turns out, mosquitos wouldn’t really be missed if they were to disappear. While mosquitos can act as pollinators as well as a food source for other animals, their absence would be merely a temporary setback before another species filled the niche. Of course, there is a gamble in assuming the replacement organism would be harmless.
“Malaria is debilitating and often fatal and we need to find new ways of tackling it. We think our innovative approach is a huge step forward. For the very first time, we have been able to inhibit the production of female offspring in the laboratory and this provides a new means to eliminate the disease,” Crisanti explained.
Each year, sub-Saharan Africa loses about $12 billion in economic productivity due to malarial infections. Considering developed areas in these countries have per capita incomes of about US$1500, this would have very real implications for the quality of life for people in those areas. Eliminating that disease would also allow doctors and hospitals to address other health concerns, and the environment would likely benefit from not having to use insecticides.
Galizi, R. et al. 2014. ‘A synthetic sex ratio distortion system for the control of the human malaria mosquito’. Nature Communications, 10 June 2014.
Researchers at Albert Einstein College of Medicine of Yeshiva University have helped identify a cellular protein that is critical for infection by the deadly Ebola virus. The findings, published in the August 24 online edition of Nature, suggest a possible strategy for blocking infection due to Ebola virus, one of the world’s most lethal viruses and a potential bioterrorism agent.
The study was a collaborative effort involving scientists from Einstein, the Whitehead Institute for Biomedical Research, Harvard Medical School, and the U.S. Army Medical Research Institute of Infectious Diseases
Ebola virus is notorious for killing up to 90 percent of the people it infects. Ebola hemorrhagic fever — the severe, usually fatal disease that Ebola virus causes in humans and in nonhuman primates — first emerged in 1976 in villages along the Ebola River in the Sudan and the Democratic Republic of the Congo, Africa. Since then, about two dozen outbreaks have occurred.
This drawing illustrates the sequence of events from the time the Ebola virus first enters the host cell (top) until the virus gains its release into the cytoplasm, where it can multiply (bottom). Researchers have shown that Ebola exists in the lysosome and enters the cytoplasm by interacting with NPC1 protein molecules (orange) embedded in the lysosomal membrane. (Credit: Image courtesy of Albert Einstein College of Medicine) (right)
Though Ebola and Marburg hemorrhagic fevers are fortunately rare diseases, “even small outbreaks of Ebola or Marburg virus can cause fear and panic,” said co-senior author Kartik Chandran, Ph.D., assistant professor of microbiology & immunology at Einstein “And then there’s the worry that these viruses could be used for bioterrorism.”
Ebola virus’s ability to enter cells is reminiscent of the Trojan Horse used by the ancient Greeks to defeat their archenemies. Ebola virus binds to the host cell’s outer membrane, and a portion of host cell membrane then surrounds the virus and pinches off, creating an endosome — a membrane-bound bubble inside the cell (see image). Endosomes carry their viral stowaways deep within the cell and eventually mature into lysosomes — tiny enzyme-filled structures that digest and recycle cellular debris.
The viruses captive in the lysosome manage to escape destruction by exploiting components of the cell to gain entry to the cytoplasm, the substance between the cell membrane and the nucleus where the virus can replicate. But the identities of many of these components have remained unknown.
In seeking the answer, Einstein researchers and colleagues searched for proteins that Ebola virus might exploit to enter the cell’s cytoplasm. One such cellular protein, known as Niemann-Pick C1 (NPC1), stood out.
“We found that if your cells don’t make this protein, they cannot be infected by Ebola virus,” said Dr. Chandran. “Obviously it’s very early days, but we think our discovery has created a real therapeutic opportunity.” At present, there are no drugs available to treat people who have been infected with Ebola virus or approved vaccines to prevent illness.”
The NPC1 protein is embedded within cell membranes, where it helps transport cholesterol within the cell. However, the absence of NPC1 due to gene mutations causes a rare degenerative disorder called Niemann-Pick disease, in which cells become clogged up with cholesterol and eventually die.
To confirm their finding that NPC1 is crucial for Ebola virus infection, the researchers challenged mice carrying a mutation in NPC1 with Ebola virus. Remarkably, most of these mutant mice survived the challenge with this normally deadly virus. Similarly, fibroblast cells (found in connective tissue) from people with Niemann-Pick disease were resistant to Ebola virus infection, as were human cells from other organs that were manipulated to reduce the amount of NPC1 they contained.
The researchers also tested whether other major viruses need NPC1 to infect human cells. Only Ebola virus and its close relative, Marburg virus, were found to require the presence of NPC1 protein for infection. Like Ebola virus, Marburg virus also needs NPC1 to kill mice.
“Our work suggests that these viruses need NPC1, which is embedded in the lysosomal membrane, to escape from the lysosome into the cytoplasm,” said Dr. Chandran. “We are now testing that hypothesis in the laboratory.”
The discovery of NPC1’s crucial role in Ebola infection raises the possibility that Ebola and Marburg virus outbreaks could be thwarted by a drug that blocks the action of NPC1. “Even though such a treatment would also block the cholesterol transport pathway, we think it would be tolerable,” said Dr. Chandran. “Most outbreaks are short-lived, so treatment would be needed for only a short time.” Einstein, in conjunction with the Whitehead Institute of Biomedical Research and Harvard Medical School, has filed a patent application related to this research that is available for licensing to partners interested in further developing and commercializing this technology.
Remarkably, an anti-Ebola virus inhibitor Dr. Chandran found as a postdoctoral fellow at the Brigham and Women’s Hospital in Boston, MA turns out to be just such an NPC1 blocker, as described in a separate manuscript by Côté and co-workers to be published in the same issue of Nature.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Jan E. Carette, Matthijs Raaben, Anthony C. Wong, Andrew S. Herbert, Gregor Obernosterer, Nirupama Mulherkar, Ana I. Kuehne, Philip J. Kranzusch, April M. Griffin, Gordon Ruthel, Paola Dal Cin, John M. Dye, Sean P. Whelan, Kartik Chandran, Thijn R. Brummelkamp. Ebola virus entry requires the cholesterol transporter Niemann–Pick C1. Nature, 2011; DOI: 10.1038/nature10348
“Malaria tertiana is the form of malaria that science needs to focus on in more detail in future.” These are the words of Harald Noedl from the Institute of Specific Prophylaxis and Tropical Medicine at the Medical University of Vienna, spoken as part of World Malaria Day on Wednesday, 25th April. In a multi-centre study, the MedUni Vienna team, led by Harald Noedl, is working on an improved and more straightforward treatment of this form of malaria.
Although malaria tropica, which currently kills around 655,000 people a year (around 2,000 people every day), has increasingly been repressed as a result of more research, malaria tertiana may well develop into the main problem of the future in many countries, says Noedl. The problem does not so much involve the (low) mortality rate from malaria tertiana, but rather the often protracted period of illness that can occur as a result of the condition. This is because if the malaria tertiana pathogens are not killed with targeted therapy, they can remain dormant in the human liver for months or even years, and cause recurrent relapses.
Conventional therapy involves administering chloroquine for three days, followed by two weeks of primaquine therapy. “However unlike in Europe, compliance with medications in tropical countries is often very poor,” explains the malaria expert from the MedUni Vienna. Many patients would discontinue the medication after just a few days.
As a consequence, the pathogens will survive in the liver and can cause an outbreak of malaria tertiana at any time which is as infectious as the other two forms of malaria. This makes patients a constant source of infection for their environment and the new condition is often no longer associated with the previous episode of malaria and therefore treated incorrectly. Says Noedl: “This makes patients, most of whom are the poorest of the poor, constantly ill, preventing them from working. It’s a fatal vicious circle.”
In a multi-centre study involving the MedUni Vienna, scientists are well on their way to establishing a new substance (tafenoquine). The advantage of this is that the drug only has to be taken for a maximum of three days. Tafenoquine is currently undergoing clinical trials.
MedUni Vienna and new malaria focus in Africa
Since 2006, the Center for Geographic Medicine at the MedUni Vienna’s MARIB research center, led by Harald Noedl, has been working on malaria research in Bangladesh. More than 20,000 patients have been treated free of charge since. In 2012, the MedUni expanded its malaria focus to include Africa, and in particular Ethiopia. There, the MedUni team is cooperating with the University of Gondar in the north west of the country. Says Noedl: “We are keen to further the MedUni Vienna’s position as a leading centre for malaria expertise, lead multi-center studies and establish a global malaria network.”
Two Novartis AG leukemia drugs, Gleevec and Tasigna, fought the deadly Ebola virus in laboratory experiments, suggesting the products could be used against a disease for which there are no treatments.
The two medicines stopped the release of viral particles from infected cells in lab dishes, a step that in a person may prevent Ebola from spreading in the body and give the immune system time to control it, researchers from the U.S. National Institute of Allergy and Infectious Diseases wrote in the journal Science Translational Medicine today.
There’s no cure and no vaccine for Ebola, a virus that causes high fever, diarrhea, vomiting and internal and external bleeding. Death can ensue within days, and outbreaks in Africa have recorded fatality rates of as much as 90 percent, according to the World Health Organization.
In some forms of leukemia, Gleevec and Tasigna reduce levels of a protein called Bcr-Abl that causes malignant white blood cells to multiply.
The researchers found that Ebola uses a related protein called c-Abl1 tyrosine kinase to regulate its own reproduction. They showed that by blocking c-Abl1, Tasigna may reduce the pathogen’s ability to replicate by as much as 10,000-fold. In addition to showing how the two drugs might be used to treat infected patients, the findings also suggest that new medicines could be developed to target c-Abl1, they wrote.
Gleevec and Tasigna, also known as imatinib and nilotinib, earned Basel, Switzerland-based Novartis a combined $5.45 billion in sales last year. Gleevec is sold as Glivec outside the U.S.
Source: Yahoo! Health
Some cancer drugs used to treat patients with leukemia may also help stop the Ebola virus and give the body time to control the infection before it turns deadly, US researchers said on Wednesday.
The much-feared Ebola virus emerged in Africa in the 1970s and can incite a hemorrhagic fever which causes a person to bleed to death in up to 90 percent of cases.
While rare, the Ebola virus is considered a potential weapon for bioterrorists because it is so highly contagious, so lethal and has no standard treatment.
But a pair of well-known drugs that have been used to treat leukemia — known as nilotinib and imatinib — appear to have some success in stopping the virus from replicating in human cells.
Lead researcher Mayra Garcia of the US National Institute of Allergy and Infectious Diseases and colleagues reported their finding in Wednesday’s edition of the journal Science Translational Medicine.
By experimenting with human embryonic kidney cells in a lab, they found that a protein called c-Abl1 tyrosine kinase was a key regulator in whether the Ebola virus could replicate or not.
The leukemia drugs work by stopping that protein’s activity. In turn, a viral protein called VP40 stopped the release of viral particles from the infected cells, a process known as filovirus budding.
“Drugs that target filovirus budding would be expected to reduce the spread of infection, giving the immune system time to control the infection,” the study authors wrote.
“Our results suggest that short-term administration of nilotinib or imatinib may be useful in treating Ebola virus infections.”
Imatinib, which is marketed as Gleevec and Glivec, is used to treat chronic myelogenous leukemia in humans, a disease which is caused by dysregulation of c-Abl enzyme.
Nilotinib, also known as Tasigna, has been used in chronic myelogenous leukemia patients who are resistant to imatinib.
Both “have reasonable safety profiles, although some cardiac toxicity has been reported with long-term administration in a small number of patients,” the study added.
According to the UN’s World Health Organization (WHO), about 1,850 cases of Ebola, with some 1,200 deaths, have occurred since 1976.
The virus has a natural reservoir in several species of African fruit bat. Gorillas and other non-human primates are also susceptible to the disease.