Yearly outbreaks of Lassa fever take center stage

The multimammate rat Mastomys natalensis is a common feature of savannas and forests in many portions of Africa. These pesky rats often infiltrate people’s homes and make themselves comfortable indoors, feasting on any available food stores. While doing so, they leave behind urine and fecal matter. This can be the start of a local Lassa fever epidemic.

Lassa virus is a single-stranded RNA virus that is member of the Arenaviridae family, similar to the Ebola and Marburg viruses. The virus is vectored by the multimammate rats of Africa. Lassa virus, named after the town in Nigeria where the first case arose, is endemic in Sierra Leone, Liberia, Guinea, and Nigeria. However, cases can also be picked up by travelers and brought back to their home countries. So far this year, Lassa has been reported in Nigeria (273 cases, 149 deaths), Liberia (38 cases, 15 deaths), Germany (2 cases, 1 death), Sweden (1 case), Togo (2 cases, 1 death), and Benin (71 cases, 23 deaths). Lassa is frequently transmitted from the original infected person to healthcare workers, as the disease is not easy to diagnose and is easily spread through contact with infected blood, tissue, or secretions.

The symptoms of Lassa fever are non-specific and almost non-existent in many cases. 80% of those infected will have mild symptoms of fever, general malaise, and/or headache. In 20% of cases, however, much more severe symptoms can occur. Hemorrhaging, respiratory distress, swelling, and vomiting are associated with severe disease. Additionally, Lassa fever can often lead to various degrees of deafness, which can be permanent; as many as 25% of people who survive the disease will suffer from some form of deafness, even if they only present with mild symptoms.

Treatments for Lassa include antiviral drugs, such as Ribavirin, which show the highest efficacy when given early. However, Lassa symptoms do not usually manifest until 1-3 weeks after exposure to the virus, and diagnosis requires the use of an enzyme-linked immunosorbent serological assay (ELISA), which is not cheap and often not available in the clinics. The small Seattle biotech company Kineta recently won a $7.2 million award to develop a novel antiviral specifically for treating Lassa fever. This could help overcome the logistic challenges of treatment. In the current outbreak in Nigeria, for example, health officials have said that logistics support and delayed case reporting by the states is severely dampening their ability to combat the threat.

The typical Lassa virus transmission season is beginning to wind down this year, and WHO believes that the number of cases is on the decline and that the epidemic will end soon. Others, however, are concerned that the WHO and local governments have not taken the outbreak seriously enough. The outbreak was not officially announced until January of 2016, while cases had begun to occur last August. The public in Nigeria has also raised questions as to whether or not the government has been down-playing the significance of the outbreak. This year’s outbreak has been far more deadly and widespread than others in the past. The mortality rate has approached 50% in Nigeria this year, a massive increase from the more typical 1%. Additionally, Lassa has spread to more states in Nigeria than have ever seen the disease before.

Officials have cited increased awareness of disease as a major reason for the uptick in mortality and spread. In the wake of the Ebola outbreak, more cases of fever and hemorrhage have been reported to the health system, allowing for increased diagnosis of Lassa. But beyond the public health aspects at play, some researchers fear the virus itself may be undergoing changes that are allowing the increase in spread and making it more deadly than before. Only time will tell whether it is just increased vigilance or viral mutations that are the driving forces here. For now, all we know for sure is that sales of rat poison are on the rise as the countries continue to fight and manage this most recent epidemic.

Yellow fever strikes again

Yellow fever is an age-old disease that has plagued Africa, Latin America, and, sporadically, portions of Asia for centuries. A recent outbreak of yellow fever erupted in Luanda, Angola in late 2015. It is estimated that since the outbreak began, there have been over 1700 cases and 238 deaths from the disease, though many organizations believe these could be underestimated numbers due to poor reporting. While the global response was quick and yellow fever vaccine was immediately deployed in the area, this outbreak has exposed our true weakness against this disease: our meager vaccine production capabilities.

Yellow fever is a disease cause by a virus of the family Flaviviridae, the same family that plays host to Dengue virus, West Nile virus, and the latest superstar, Zika virus. The yellow fever virus is spread between humans through a mosquito vector. Disease spread occurs through three different transmission cycles: the jungle, or sylvatic, cycle, typically spreads disease from a nonhuman primate to other nonhuman primates, with the occasional cross to humans; the urban cycle typically spreads disease from human to human; and the intermediate, or savannah, cycle can involve transmission from both nonhuman primates and humans to other nonhuman primates and humans. Each transmission cycle uses its own mosquito vectors, with Aedes aegypti, also known as the yellow fever mosquito, being responsible for the urban cycle that typically lead to the most severe outbreaks. Once a mosquito takes a blood meal from a human infected with the virus, the virus begins replicating and infecting the cells of the mosquito. Once the infection spreads to the mosquito’s salivary glands, the virus can be passed on to a new human.

Yellow fever virus often leads to mild, or no, disease in humans. Patients may experience fevers, aches, chills, and other flu-like symptoms. However, about 15% of cases can lead to severe disease and bleeding, shock, and organ failure; roughly half of these cases are fatal. We have no cure for yellow fever, so our best defense is a good offense. The yellow fever vaccine is known to be highly efficacious, typically providing lifelong immunity after just one dose. However, there are major problems with yellow fever vaccine production which have led to our current defensive stance against the virus.

The yellow fever vaccine is produced using a very old-fashioned and low-tech procedure introduced 80 years ago that involves passing the virus through chicken embryos to produce attenuated, less-virulent virions. This process can only be done in four facilities throughout the world, two government-run plants in Russia, the vaccine company Sanofi Pasteur’s plant, and the Pasteur Institute. Between these four facilities, it is estimated that 75 million doses of vaccine can be made each year. In the past, this has been enough to deal with the vaccination of children in many areas, but has not been able to cover the catch-up vaccinations of adults who were not vaccinated as children. Since the outbreak in Luanda, nearly 6 million people in that city alone have been vaccinated, but the disease has continued to spread throughout the rest of Angola, depleting the global emergency stockpile of vaccine. With the vaccine in high demand, a United Nations report estimated that they would need 42% more vaccine than was available in the next 3 years. Unfortunately, vaccine production is expected to decline rather than increase in the near future as one of the four plants will be closing for a 5-month renovation.

Many experts worry that the worst case scenario, a spread of yellow fever to Asia, where the disease has not been able to gain a solid foothold in the past, would be catastrophic. With vaccine stores already depleted, we would have no defense against such a spread. There are currently no signs of this being a threat, so we still have time to gain the upper hand. If we can remain on the offensive against this disease and find ways to streamline and increase vaccine production, this global threat could one day become a thing of the past. But such an achievement would require a renewed research effort into yellow fever vaccine production, and increased funding for this endeavor. In a tight funding climate, this can be a difficult feat to achieve, but such an achievement is essential for ensuring the protection of future generations from outbreaks like the one currently happening in Angola.

Welcome

Since I've now decided to begin actively sharing the link to this blog with people, I'd like to extend a warm welcome to anyone who clicked on it and found themselves here. I appreciate your support, even if you never visit my blog again (but I hope you will!). I also apologize for the less-than-stellar piece right below this. I procrastinated writing my March entry, and it didn't turn out too great. But I welcome comments and suggestions on any of the posts! Please help me make my writing better. THANKS!

A new leader in minimalistic genomes is born

Thanks to the work of scientists at the J. Craig Venter Institute in San Diego, CA, a new minimalistic microbe has been brought into the world. Through genome engineering, they have created a synthetic bacterium called Syn 3.0 that requires only 531,000 bases in its genome to grow with a doubling time of 3 hours in the laboratory. The next smallest free-living organism, Mycoplasma genitalium, has a genome of 600,000 bases, but grows with a doubling time of about 2 weeks. For comparison, consider the more well-known bacterium, Escherichia coli, which has a genome of 4,639,221 bases and a replication time of about 30 minutes in the laboratory. But what makes this new organism, which is approximately one-ninth the size of E. coli’s genome, able to survive and grow so readily? This question is especially puzzling in light of the fact that approximately one-third of Syn 3.0's genome codes for genes of unknown function.

Ever since the invention of genome sequencing, scientists have been identifying genes of unknown function. Even in the most well-studied of organisms, like the mouse, almost 96% of the genome remains of unknown function. Many of these segments are considered important for higher organization of the genome, allowing tight regulation of expression of the genes that code for specific RNAs and proteins. Bacteria tend to have the most completely annotated genomes of the model organisms due to their simplicity. In E. coli, 66% of the genes are of known function, and as much as 76% of the genome can be assigned a function by biochemical analysis software. Since approximately 3 million of E. coli’s 4 million bases of genetic material have known functions, it is rather shocking to find another bacterium that contains so many segments with unknown functions. Since Syn 3.0 has the smallest genome the researchers at the Venter Institute could engineer that could successfully sustain life, this suggests that we still do not know the functions of many essential genes.

In order to identify the function of genes of unknown function, many approaches can and have traditionally been used by researchers. The oldest method is to use random mutagenesis. Through this technique, you are able to use chemical mutagens or electromagnetic radiation to induce changes in different bases throughout the genome. After mutagenesis, you can identify what processes the organism can no longer perform. Sequencing can allow you to identify where the mutations you introduced occurred, thus helping link those genes with a molecular process. If you are only interested in one molecular process, you can design a screen to specifically pick out mutants that are deficient in this process for analysis.

More recent advances in genetic engineering have allowed for more sophisticated analyses. You can now delete a specific gene of interest and observe the phenotype. Alternatively, you can tag a gene with a marker, so that the specific protein produced is linked to a fluorophore or tag. This allows you to identify where and when the protein is expressed. The advent of new genetic engineering technologies, which made production of Syn 3.0 possible, will also enable us to discover the functions of those unknown genes.

The invention of this novel minimalistic microbe shines new light on our true lack of understanding of genetic material in organisms. By improving our knowledge of this unique bacterium, we can hope to improve our understanding of our own genome, and that of our many pathogens. Discoveries made from Syn 3.0 may be the key to great steps forward in understanding the genetic basis of disease and finding cures for the future.

A new way to fight the flu?

Coughing, runny nose, fever, achy joints. These are some of the stereotypical symptoms of the flu. Every year during flu season, about 10% of people will come down with the illness. While most people just take a few days off from work, sleep, and drink lots of fluids to recover, the flu can be associated with much more severe disease. I’m sure we all remember the H1N1 outbreak a few years ago, and the severity that came with that. In that outbreak, as well as previous ones, it was shown that young adult women were more likely to experience severe outcomes associated with the disease than men. Interestingly, during the H1N1 outbreak in 2009, women were 2-6 times more likely to die from the infection than men.

This issue of gender differences in disease has long been of interest to Dr. Sabra Klein, Associate Professor in the Johns Hopkins School of Public Health. She has dedicated years of study to the issue, and recently made an exciting breakthrough that may aid in our treatment of women with influenza.

Dr. Klein’s lab published an article in the American Journal of Physiology - Lung Cellular and Molecular Physiology in late December. The study found that estrogen and estrogen-like compounds could reduce the level of flu virus replication in the human nasal epithelial cells of women, but not men. This seemed to be caused through the action of the genomic estrogen receptor 2. Notably, this reduction in virus level was not associated with an increased production of cytokines, but rather a decrease in cellular metabolism. Since cytokine storms are often associated with adverse outcomes for women with the flu, the fact that this antiviral effect was achieved without excess cytokines is very promising.

The flu virus isn’t the first disease that’s been found to be inhibited by estrogen. Replication of Human Immunodeficiency Virus (HIV), Hepatitis C, and even Ebola has been shown to be inhibited by estrogen. This raises the possibility of new treatments for these diseases. Select estrogen receptor modulators (SERMs) such as clomiphene and raloxifene are already approved by the FDA for treatment of osteoporosis and infertility. It is possible that someday, these or other similar drugs could be repurposed to treat the flu in women, along with these other viral infections. That would certainly be one small step for woman, one giant leap for man and womankind.

Zika virus--an emerging infectious disease or an old nuisance?

Zika virus has been peppering the news the last few weeks as cases have begun to emerge in the United States. What the news anchors most likely won’t tell you is that Zika is just the most recent of the “tropical” diseases to make its way into the US. Also, they probably won’t mention that transmission of Zika within the US is unlikely at this point, so efforts for disease control and eradication should be focused at the epicenter of the outbreak, South America. Here are the facts of this disease.

Zika is not a new virus. Outbreaks have occurred throughout Africa, Southeast Asia, and the Pacific Islands since the 1950's, long before the outbreak of 2015 that caught the media buzz. The infections spread to Brazil in May 2015, and have disseminated from there for the past 9 months. Zika virus is transmitted between people by the bite of an infected female Aedes mosquito. The Aedes mosquito is also responsible for the transmission of Dengue virus and the emerging Chicunguña virus, which have also recently popped up on the radar of Americans. These mosquitoes are very common near the equatorial zone of the globe, including the southern US states, but not as common farther north.

They are known to lay eggs in bodies of standing water, which can be as small as a bucket. Once they reach adulthood, a female must take a bloodmeal in order to lay her eggs. This genus of mosquito prefers to feed on humans above other mammals, and they tend to feed during the daytime. Each bloodmeal is an opportunity to pick up or spread the virus.

At this time, the only real way to deal with Zika virus infection is to prevent mosquito bites. There is no vaccine for the virus, and also no cure. Once infected, an individual has about a one in five chance of developing illness. However, it is important to remember that even those who do not develop clinical symptoms can contribute to spread of the disease as the virus replicates in their cells. The most common clinical symptoms include fever, rash, joint pain, and conjunctivitis. In most cases, the disease is mild and resolves itself in a few days. The real danger that has been identified with Zika virus is the risk that it poses to pregnant women. Zika has been linked to microcephaly in the developing fetus, leading to birth defects and lifelong challenges.

Now for my own opinions. Since the same mosquitoes can carry the Zika virus as carry the Dengue and Chicunguña viruses, fighting all three together through mosquito control is a logical step. In the United States, we are fortunate to have the luxury of air conditioned buildings with firm walls and screened windows, keeping us at a lower risk of exposure to mosquito bites. This is not the case in many other countries. If we, in America, want to stop the threat of Zika (and other mosquito-bourne pathogens), we should think about focusing our efforts on expanding mosquito control methods in other countries. Of course, it would be great to develop a vaccine for this disease; but vaccine development takes many years, and that strategy would require a separate vaccine for each of the mosquito-bourne diseases. Vaccination is a great long-term goal, but to have the most impact in the short-term, vector control is an essential component of the strategy. 

The fight against infectious diseases is difficult and often disheartening. As soon as one outbreak is under control, another arises. As a global community, we just wrapped up the Ebola crisis, and now another potential crisis is emerging right in front of use. But it is important to remember our past successes as a global community that works together to save the lives of everyone at risk from these infections. As has been done with smallpox and almost done with polio, diseases can be controlled and even eradicated if we can just work together and find the right way to address them.

Apologies for the absence

So, since my last post was 9 months ago, I guess this blogging thing isn't going as well as I had hoped. Sorry! Of course, since pretty much no one is reading this, I'm really only apologizing to myself. The plan moving forward is to try to get one post up here every month, even if it's just a brief one. Call it a new year's resolution of sorts. Anyway, here's to January and the whole of 2016!