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Posts Tagged ‘infection’

Highly Aggressive New Strain Of HIV Is Spreading Through Cuba

February 18, 2015 Leave a comment

Given the deadly global rampage that HIV has been on for the past few decades, you’re all probably familiar with the virus. But you may not be aware that there are two types of HIV—HIV-1 and HIV-2—with the former being significantly more prevalent worldwide. The most common type of HIV-1 is then further divided into distinct subtypes, some of which are associated with a more rapid progression to AIDS. If these different viruses meet in an infected person, for example if someone infected with one subtype is exposed to a different one, they can exchange bits of their genetic material to create a new virus.

One of these so called “circulating recombinant forms” is currently spreading through Cuba, and it’s unfortunately extremely aggressive. Individuals infected with this hybrid virus, which is a mix of three different HIV-1 subtypes, progress to AIDS more than three times faster than average. Now, scientists have scrutinized this particularly pathogenic strain, which has yielded insight into the traits that have bestowed it with this deadly efficiency. The findings have been published in EBioMedicine.

Before HIV can get inside our cells, it first needs to bind to receptors on the surface called CD4. While this is an essential first step, it’s insufficient to get the virus inside. This is where anchoring points, called coreceptors, come in, which HIV also has to latch onto to gain entry. There are two coreceptors, CCR5 and CXCR4, and around 90% of newly transmitted HIV uses the former.

CXCR4-using viruses emerge in around 50% of individuals, but this usually takes around five years from infection. These viruses are associated with a more pronounced depletion of immune cells, but whether this shift in coreceptor preference is a cause or consequence of disease progression is unknown. Interestingly, however, the aggressive recombinant currently spreading through Cuba starts to use CXCR4 very early on in infection, and researchers think this is likely contributing to the observed rapid progression to AIDS.

To find this out, researchers examined 73 recently infected patients in Cuba, 52 who had rapidly progressed to AIDS within three years and 21 without AIDS. Then, they compared the blood of these individuals with 22 patients who had progressed to AIDS after the period typically expected, which is around 10-15 years without treatment.

They found that all those who had progressed to AIDS within three years of infection were infected with a recombinant called CRF19, which is a mixture of subtypes A, D and G. Interestingly, infection with A/D recombinants has previously been reported to result in rapid progression to AIDS, but no CRFs had been exclusively associated with rapid progression. Furthermore, those infected with CRF19 had abnormally high levels of an immune response molecule called RANTES, which acts by binding to CCR5. Without this coreceptor available for binding, CRF19 may have been forced to bypass that anchor point and go straight for CXCR4. Since the switch to CXCR4 usage is associated with progression to AIDS, this could explain why those infected with CRF19 developed AIDS so early on.

Another reason that CRF19 might be so pathogenic is that it has an enzyme, called protease, from subtype D, which is known to be very efficient. This enzyme helps the virus form mature particles, which is an essential stage in the virus life cycle.

Via KU Leuven and EBioMedicine

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Nanotechnology against malaria parasites

December 13, 2014 Leave a comment

After maturation, malaria parasites (yellow) are leaving an infected red blood cell and are efficiently blocked by nanomimics (blue). (Fig: Modified with permission from ACS)

Malaria parasites invade human red blood cells, they then disrupt them and infect others. Researchers at the University of Basel and the Swiss Tropical and Public Health Institute have now developed so-called nanomimics of host cell membranes that trick the parasites. This could lead to novel treatment and vaccination strategies in the fight against malaria and other infectious diseases. Their research results have been published in the scientific journal ACS Nano.

For many infectious diseases no vaccine currently exists. In addition, resistance against currently used drugs is spreading rapidly. To fight these diseases, innovative strategies using new mechanisms of action are needed. The  Plasmodium falciparum that is transmitted by the Anopheles mosquito is such an example. Malaria is still responsible for more than 600,000 deaths annually, especially affecting children in Africa (WHO, 2012).

Artificial bubbles with receptors

Malaria parasites normally invade human red  in which they hide and reproduce. They then make the host cell burst and infect new cells. Using nanomimics, this cycle can now be effectively disrupted: The egressing parasites now bind to the nanomimics instead of the red blood cells.

Researchers of groups led by Prof. Wolfgang Meier, Prof. Cornelia Palivan (both at the University of Basel) and Prof. Hans-Peter Beck (Swiss TPH) have successfully designed and tested host cell nanomimics. For this, they developed a simple procedure to produce polymer vesicles – small artificial bubbles – with host cell receptors on the surface. The preparation of such polymer vesicles with water-soluble host receptors was done by using a mixture of two different block copolymers. In aqueous solution, the nanomimics spontaneously form by self-assembly.

Blocking parasites efficiently

Usually, the malaria parasites destroy their host cells after 48 hours and then infect new . At this stage, they have to bind specific host cell receptors. Nanomimics are now able to bind the egressing parasites, thus blocking the invasion of new cells. The parasites are no longer able to invade host cells, however, they are fully accessible to the immune system.

The researchers examined the interaction of nanomimics with malaria parasites in detail by using fluorescence and electron microscopy. A large number of nanomimics were able to bind to the parasites and the reduction of infection through the nanomimics was 100-fold higher when compared to a soluble form of the host cell receptors. In other words: In order to block all , a 100 times higher concentration of soluble host  is needed, than when the receptors are presented on the surface of nanomimics.

“Our results could lead to new alternative treatment and vaccines strategies in the future”, says Adrian Najer first-author of the study. Since many other pathogens use the same  receptor for invasion, the nanomimics might also be used against other . The research project was funded by the Swiss National Science Foundation and the NCCR “Molecular Systems Engineering”.

More information: Adrian Najer, Dalin Wu, Andrej Bieri, Françoise Brand, Cornelia G. Palivan, Hans-Peter Beck, and Wolfgang Meier. “Nanomimics of Host Cell Membranes Block Invasion and Expose Invasive Malaria Parasites.” ACS Nano, Publication Date (Web): November 29, 2014 | DOI: 10.1021/nn5054206

GM Mosquitos Could Eradicate Wild Populations By Only Producing Male Offspring


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.

 

REFERENCE:

Galizi, R. et al. 2014. ‘A synthetic sex ratio distortion system for the control of the human malaria mosquito’. Nature Communications, 10 June 2014.

New virus isolated from patients with severe brain infections


Researchers have identified a new virus in patients with severe brain infections in Vietnam. Further research is needed to determine whether the virus is responsible for the symptoms of disease.

The virus was found in a total of 28 out of 644 patients with severe brain infections in the study, corresponding to around 4%, but not in any of the 122 patients with non-infectious brain disorders that were tested.

Infections of the brain and central nervous system are often fatal and patients who do survive, often young children and young adults, are left severely disabled. Brain infections can be caused by a range of bacterial, parasitic, fungal and viral agents, however, doctors fail to find the cause of the infection in more than half of cases despite extensive diagnostic efforts. Not knowing the causes of these brain infections makes public health and treatment interventions impossible.

Researchers at the Oxford University Clinical Research Unit, Wellcome Trust South East Asia Major Overseas Programme and the Academic Medical Center, University of Amsterdam identified the virus, tentatively named CyCV-VN, in the fluid around the brain of two patients with brain infections of unknown cause. The virus was subsequently detected in an additional 26 out of 642 patients with brain infections of known and unknown causes.

Using next-generation gene sequencing techniques, the team sequenced the entire genetic material of the virus, confirming that it represents a new species that has not been isolated before. They found that it belongs to a family of viruses called the Circoviridae, which have previously only been associated with disease in animals, including birds and pigs.

Dr Rogier van Doorn, Head of Emerging Infections at the Wellcome Trust Vietnam Research Programme and Oxford University Clinical Research Unit Hospital for Tropical Diseases in Vietnam, explains: “We don’t yet know whether this virus is responsible for causing the serious brain infections we see in these patients, but finding an infectious agent like this in a normally sterile environment like the fluid around the brain is extremely important. We need to understand the potential threat of this virus to human and animal health.”

The researchers were not able to detect CyCV-VN in blood samples from the patients but it was present in 8 out of 188 fecal samples from healthy children. The virus was also detected in more than half of fecal samples from chickens and pigs taken from the local area of one of the patients from whom the virus was initially isolated, which may suggest an animal source of infection.

Dr Le Van Tan, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, said: “The evidence so far seems to suggest that CyCV-VN may have crossed into humans from animals, another example of a potential zoonotic infection. However, detecting the virus in human samples is not in itself sufficient evidence to prove that the virus is causing disease, particularly since the virus could also be detected in patients with other known viral or bacterial causes of brain infection. While detection of this virus in the fluid around the brain is certainly remarkable, it could still be that it doesn’t cause any harm. Clearly we need to do more work to understand the role this virus may play in these severe infections.”

The researchers are currently trying to grow the virus in the laboratory using cell culture techniques in order to develop a blood assay to test for antibody responses in patient samples, which would indicate that the patients had mounted an immune response against the virus. Such a test could also be used to study how many people in the population have been exposed to CyCV-VN without showing symptoms of disease.

The team are collaborating with scientists across South East Asia and in the Netherlands to determine whether CyCV-VN can be detected in patient samples from other countries and better understand its geographical distribution.

Professor Menno de Jong, head of the Department of Medical Microbiology of the Academic Medical Centre in Amsterdam said: “Our research shows the importance of continuing efforts to find novel causes of important infectious diseases and the strength of current technology in aid of these efforts.”

Journal reference: L.V. Tan et al . Identification of a new cyclovirus in cerebrospinal fluid of patients with acute central nervous system infections. mBio, June 2013. DOI: 10.1128/mBio.00231-13

The above story is reprinted from materials provided by Wellcome Trust, via MedicalXpress.

Malaria drug treatment breakthrough

April 6, 2013 1 comment

An international study, involving researchers from Griffith University’s Eskitis Institute, has discovered a molecule which could form the basis of powerful new anti-malaria drugs.

Professor Vicky Avery from Griffith University’s Eskitis Institute is co-author of the paper “Quinolone-3-Diarylethers: a new class of drugs for a new era of malaria eradication” which has been published in the journal Science Translational Medicine.

“The 4(1H)-quinolone-3- diarylethers are selective potent inhibitors of the parasite mitochondrial cytochrome bc1 complex,” Professor Avery said.

“These compounds are highly active against the types of malaria parasites which infect humans, Plasmodium falciparum and Plasmodium vivax,” she said.

“What is really exciting about this study is that a new class of drugs based on the 4(1H)- quinolone-3- diarylethers would target the malaria parasite at different stages of its lifecycle.”

This provides the potential to not only kill the parasite in people who are infected, thus treating the clinical symptoms of the disease, but also to reduce transmission rates.

“Just one of these properties would be of great benefit but to achieve both would really make a difference in reducing the disease burden on developing nations,” Professor Avery said.

“There is also the real possibility that we could begin to impact on the incidence and spread of malaria, bringing us closer to the ultimate goal of wiping out malaria altogether.”

The selected preclinical candidate compound, ELQ-300, has been demonstrated to be very effective at blocking transmission in the mouse models.

There is a further benefit in that the predicted dosage in patients would be very low and it’s expected that ELQ-300, which has a long half-life, would provide significant protection.

The development of a new chemical class of anti-malarial drugs is very timely as the parasite is becoming increasing resistant to currently available treatments.

Eskitis Director Professor Ronald J Quinn AM said “I congratulate Professor Avery on her contribution to the discovery of this new class of anti-malarials. This is an exciting discovery that closely aligns with the Institute’s focus on global health and fighting diseases that burden the developing world. We are continuing to take the fight to malaria along a number of fronts, including targeting its many life cycle stages.”

Journal reference: Science Translational Medicine

A. Nilsen, A. N. LaCrue, K. L. White, I. P. Forquer, R. M. Cross, J. Marfurt, M. W. Mather, M. J. Delves, D. M. Shackleford, F. E. Saenz, J. M. Morrisey, J. Steuten, T. Mutka, Y. Li, G. Wirjanata, E. Ryan, S. Duffy, J. X. Kelly, B. F. Sebayang, A.-M. Zeeman, R. Noviyanti, R. E. Sinden, C. H. Kocken, R. N. Price, V. M. Avery, I. Angulo-Barturen, M. B. Jiménez-Díaz, S. Ferrer, E. Herreros, L. M. Sanz, F.-J. Gamo, I. Bathurst, J. N. Burrows, P. Siegl, R. K. Guy, R. W. Winter, A. B. Vaidya, S. A. Charman, D. E. Kyle, R. Manetsch, M. K. Riscoe, Quinolone-3-Diarylethers: A New Class of Antimalarial Drug. Sci. Transl. Med. 5, 177ra37 (2013).

Provided by: Griffith University

How Herpesvirus Invades Nervous System


Northwestern Medicine scientists have identified a component of the herpesvirus that “hijacks” machinery inside human cells, allowing the virus to rapidly and successfully invade the nervous system upon initial exposure.

Led by Gregory Smith, associate professor in immunology and microbiology at Northwestern University Feinberg School of Medicine, researchers found that viral protein 1-2, or VP1/2, allows the herpesvirus to interact with cellular motors, known as dynein. Once the protein has overtaken this motor, the virus can speed along intercellular highways, or microtubules, to move unobstructed from the tips of nerves in skin to the nuclei of neurons within the nervous system.

This is the first time researchers have shown a viral protein directly engaging and subverting the cellular motor; most other viruses passively hitch a ride into the nervous system.

“This protein not only grabs the wheel, it steps on the gas,” says Smith. “Overtaking the cellular motor to invade the nervous system is a complicated accomplishment that most viruses are incapable of achieving. Yet the herpesvirus uses one protein, no others required, to transport its genetic information over long distances without stopping.”

Herpesvirus is widespread in humans and affects more than 90 percent of adults in the United States. It is associated with several types of recurring diseases, including cold sores, genital herpes, chicken pox, and shingles. The virus can live dormant in humans for a lifetime, and most infected people do not know they are disease carriers. The virus can occasionally turn deadly, resulting in encephalitis in some.

Until now, scientists knew that herpesviruses travel quickly to reach neurons located deep inside the body, but the mechanism by which they advance remained a mystery.

Smith’s team conducted a variety of experiments with VP1/2 to demonstrate its important role in transporting the virus, including artificial activation and genetic mutation of the protein. The team studied the herpesvirus in animals, and also in human and animal cells in culture under high-resolution microscopy. In one experiment, scientists mutated the virus with a slower form of the protein dyed red, and raced it against a healthy virus dyed green. They observed that the healthy virus outran the mutated version down nerves to the neuron body to insert DNA and establish infection.

“Remarkably, this viral protein can be artificially activated, and in these conditions it zips around within cells in the absence of any virus. It is striking to watch,” Smith says.

He says that understanding how the viruses move within people, especially from the skin to the nervous system, can help better prevent the virus from spreading.

Additionally, Smith says, “By learning how the virus infects our nervous system, we can mimic this process to treat unrelated neurologic diseases. Even now, laboratories are working on how to use herpesviruses to deliver genes into the nervous system and kill cancer cells.”

Smith’s team will next work to better understand how the protein functions. He notes that many researchers use viruses to learn how neurons are connected to the brain.

“Some of our mutants will advance brain mapping studies by resolving these connections more clearly than was previously possible,” he says.

Story Source:

The above story is reprinted from materials provided by Northwestern University, via EurekAlert!, a service of AAAS.

Journal Reference:

Sofia V. Zaichick, Kevin P. Bohannon, Ami Hughes, Patricia J. Sollars, Gary E. Pickard, Gregory A. Smith. The Herpesvirus VP1/2 Protein Is an Effector of Dynein-Mediated Capsid Transport and Neuroinvasion. Cell Host & Microbe, 2013; 13 (2): 193 DOI: 10.1016/j.chom.2013.01.009

Source 3: Protein Essential for Ebola Virus Infection Is a Promising Antiviral Target

September 30, 2012 Leave a comment

In separate papers published online in Nature, two research teams report identifying a critical protein that Ebola virus exploits to cause deadly infections. The protein target is an essential element through which the virus enters living cells to cause disease.

The first study was led by four senior scientists: Sean Whelan, associate professor of microbiology and immunobiology at Harvard Medical School; Kartik Chandran, assistant professor at Albert Einstein College of Medicine; John Dye at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) and Thijn Brummelkamp, originally at the Whitehead Institute for Biomedical Research and now at the Netherlands Cancer Institute. The second study was led by James Cunningham, a Harvard Medical School associate professor of medicine at Brigham and Women’s Hospital, and also co-authored by Chandran.

“This research identifies a critical cellular protein that the Ebola virus needs to cause infection and disease,” explained Whelan, who is also co-director of the HMS Program in Virology. “The discovery also improves chances that drugs can be developed that directly combat Ebola infections.”

Both papers are published in the August 24 online issue of Nature.

The African Ebola virus — and its cousin, Marburg virus — are known as the filoviruses. Widely considered one of the most dangerous infections known, Ebola was first identified in 1976 in Africa near the Ebola River, an area in Sudan and the Democratic Republic of the Congo. Infections cause severe hemorrhage, multiple organ failure and death. No one quite knows how the virus is spread, and there are no available vaccines or anti-viral drugs that can fight the infections.

Through conducting a genome-wide genetic screen in human cells aimed at identifying molecules essential for Ebola’s virulence, Whelan and his colleagues homed in on Niemann-Pick C1 (NPC1).

NPC1 has been well known in the biomedical literature. Primarily associated with cholesterol metabolism, this protein, when mutated, causes a rare genetic disorder in children, Niemann-Pick disease.

Using cells derived from these patients, the group found that this mutant form of NPC1 also completely blocks infection by the Ebola virus. They also demonstrated that mice carrying a mutation in the NPC1 gene resisted Ebola infection. Similar resistance was found in cultured cells in which the normal molecular structure of the Niemann-Pick protein has been altered.

In other words, targeting NPC1 has real therapeutic potential. While such a treatment may also block the cholesterol transport pathway, short-term treatment would likely be tolerated.

Indeed in the accompanying paper, Cunningham’s group describes such a potential inhibitor.

Cunningham and his group at Brigham and Women’s Hospital investigated Ebola by using a robotic method developed by their colleagues at the National Small Molecule Screening Laboratory at Harvard Medical School to screen tens of thousands of compounds. The team identified a novel small molecule that inhibits Ebola virus entry into cells by more than 99 percent.

The team then used the inhibitor as a probe to investigate the Ebola infection pathway and found that the inhibitor targeted NPC1.

For Cunningham and Chandran, this finding builds on a 2005 paper of theirs for which Whelan was also a collaborator. In that study, he and his group discovered how Ebola exploits a protein called cathepsin B. This new study completes the puzzle. It now seems that cathepsin B interacts with Ebola in a way that preps it to subsequently bind with NPC1.

“It is interesting that NPC1 is critical for the uptake of cholesterol into cells, which is an indication of how the virus exploits normal cell processes to grow and spread,” said Cunningham. “Small molecules that target NPC1 and inhibit Ebola virus infection have the potential to be developed into anti-viral drugs.”

The paper coauthored by Whelan was funded by the U.S. National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute, the U.S. Army, and the Burroughs Wellcome Foundation. Cunningham’s work was funded by the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases at Harvard Medical School.

Story Source:

The above story is reprinted from materials provided by Harvard Medical School, via ScienceDaily. The original article was written by Robert Cooke and Lori Shanks.

Journal References:

  • 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
  • Marceline Côté, John Misasi, Tao Ren, Anna Bruchez, Kyungae Lee, Claire Marie Filone, Lisa Hensley, Qi Li, Daniel Ory, Kartik Chandran, James Cunningham. Small molecule inhibitors reveal Niemann–Pick C1 is essential for Ebola virus infection. Nature, 2011; DOI: 10.1038/nature10380