Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
In 1959, an American bacteriologist named Elizabeth King was studying bacteria isolated from children with meningitis. She eventually isolated a previously un-classified microbe and named it Flavobacterium meningosepticum. “Flavo” means “yellow,” an appropriate name for the pale yellow colonies that grew on Dr. King’s agar plates. “Meningosepticum,” as you can probably guess, means “associated with meningitis and sepsis,” the pathologies that led to the isolation of this microbe. Genetic analysis of the bacteria did not place it in any existing genus. As a result, a new genus was named after the Flavobacterium’s discoverer: Elizabethkingia. Now, Flavobacterium meningosepticum’s official name is Elizabethkingia meningoseptica, colloquially referred to as just “Elizabethkingia.”
Chances are you have never heard of Elizabethkingia; and if you have, it probably entered your radar only a couple of weeks ago. After all, Elizabethkingia is rarely implicated in disease: officially, it is classified as a non-fastidious bacterium. Two different species of Elizabethkingia are abundant on Malaysian trees, and the bacteria are also occasionally found in soil and water. Nonetheless, it rarely causes disease. When it does, E. meningoseptica causes fever, shortness of breath, chills, and other flu-like symptoms. It is usually associated with outbreaks of meningitis in infants and newborns in neonatal intensive care units of underdeveloped nations. Sources for these infections have included contaminated medical devices, food, or water. In immunocompromised adults, those whose internal ability to fight infections is hindered by underlying medical conditions, Elizabethkingia is a rare cause of nosocomial infections.
Elizabethkingia is naturally resistant to many typical antibiotics, such as beta-lactams, aminoglycosides, tetracycline, and chloramphenicol. Certain drugs like vancomycin can treat the bacterium, but large quantities of it are required, which calls for alternative treatments due to concerns about side effects and antibiotic overuse. Right now, there are 5 antibiotics that can be used to treat Elizabethkingia: ciprofloxacin, minocycline, rifampin, trimethoprim-sulfamethoxazole, and novobiocin. Rifampin might sound familiar, as it is a go-to drug for people with tuberculosis. Interestingly, Mycobacterium tuberculosis is physiologically quite different from Elizabethkingia.
As you are reading this article, the largest outbreak of Elizabethkingia in public health history is taking place. Usually, the state of Wisconsin records around 5 or 6 Elizabethkingia infections every year. As of March 10, however, an alarming 54-plus people scattered over a dozen counties in Wisconsin have fallen ill with Elizabethkingia. 15 have died, most likely as a result of the infection though this has not been confirmed. There is no obvious connection between these patients other than the fact that most are over the age of 65 and they all have serious underlying health problems. Besides that, some come from hospitals while others haven’t been to one at all. The latter patients became ill at home or in a nursing home.
The outbreak started over four months ago, and authorities are still puzzled about the infection’s source. This is because, so far, none of the usual culprits involved in outbreaks – contaminated food, water, or medical devices – have been isolated. The CDC has dispatched multiple epidemiologists to Wisconsin to interview surviving patients and their families in a collaboration with local health officials. Back in the Atlanta labs, microbiologists are analyzing the genetic makeup of the Elizabethkingia isolated from the Wisconsin patients to search for more clues.
To make matters worse, on March 18 the Michigan Department of Health and Human Services announced that the state saw its first case of Elizabethkingia infection in an older man who eventually succumbed to the illness. If this turns out genetically to be the same strain as the one in Wisconsin, the outbreak has officially crossed its first state border. The CDC has indeed confirmed a common genetic fingerprint between the different samples, which strongly suggests they came from the same source.
To most of us, Elizabethkingia will never pose a threat. However, to immunocompromised patients – old and young – infection could mean a serious illness. As a result, it is of utmost importance to isolate the cause of this current outbreak before it might spread anywhere else, particularly to nursing homes, NICUs, and other vulnerable healthcare settings. The Wisconsin and Michigan public health departments are working closely with the CDC to solve the mysteries of this outbreak.
Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
Last week, the CDC published a perspective on the recent Ebola outbreak that ravaged parts of West Africa over the past 3 years. The exposé discusses different factors responsible for the delayed detection of the outbreak and the staccato responses that made it difficult to control the epidemic.
Among the many risk factors associated with poor outbreak responses, the authors of the article focus on three specific categories: social factors, educational factors, and medical factors.
Socially, West Africa was facing regional instability from recent civil wars. Furthermore, traveling populations and extensive urban spread of the virus contributed to the scale of the Ebola outbreak. In terms of educational factors, a lack of community knowledge of the disease resulted in exacerbation of the outbreak: improper containment practices and unfamiliarity with Ebola allowed the virus to persist rather than burning out. Lastly, medical factors contributing to the breadth of the epidemic include inadequate disease surveillance, unsatisfactory case detection, and insufficient resources for patient care.
Ebola: A History
Ebola virus disease (EVD) was discovered during two separate outbreaks of hemorrhagic fever in 1976. The first occurred in Nzara, Sudan, which is now part of South Sudan. The second occurred in a small village called Yambuku, Zaire, which is now part of the Democratic Republic of Congo.
Hemorrhagic fever was by no means a new pathology; at the time, it was already known to be caused by 3 different virus families (Lassa, Marburg, and yellow fever). Ebolavirus, which is most similar to Marburg, was added as a fourth family upon its discovery by CDC and Belgian scientists. Hemorrhagic fever is characterized by damaged blood vessels spanning multiple organs that ultimately impair the body’s ability to regulate itself. This is the most serious – and dramatic – possible symptom of Lassa, Marburg, Yellow Fever, and Ebola.
During the outbreak in Sudan, 284 people were infected and 151 succumbed to the disease. A few months later, in Zaire, there were 318 cases and 280 deaths. Upon epidemiological and microbiological analyses, it turned out that there were two different strains circulating in Zaire – one was the same as the one in Sudan, and was named Sudan virus. The other was unique to Yambuku, and named Zaire Ebolavirus (now simply Ebola Virus Disease). Ebola’s namesake is the Ebola River, located in Zaire near where the latter outbreak occurred. The first known patient in the Zaire outbreak, a local school headmaster, had recently returned from a trip there. Sudan virus and the Zaire strain are 2 of five different Ebolaviruses isolated to this date.
The next recorded Ebola outbreak took place once again in Zaire, but this time it flared up in 1995. Out of 315 infected individuals who developed the disease, 254 died. Five years later, in Uganda, an outbreak affected 425 people and killed 224. The strain in Uganda was found to be the Sudan virus that caused an outbreak in Sudan in 1976. In 2003, another Republic of the Congo outbreak killed 128 infected individuals out of 143. This is the highest death rate of an Ebola virus to date. For the next decade, a handful of small outbreaks affecting under 200 people each would flare up in Uganda and Democratic Republic of the Congo.
In March 2014, the WHO reported a new major Ebola outbreak unfolding. This time, however, the disease was in Guinea, a nation in West Africa, a region that had not previously seen the virus before. South Sudan, Democratic Republic of the Congo, and Uganda are located in Central/East Africa. Epidemiologists traced the outbreak to an infant who died in December 2013. Within a few months, the disease spread to Liberia and Sierra Leone, which border Guinea and each other. In August, the WHO declared the epidemic an international public health emergency and called for international aid in the affected regions.
"The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times,” read a statement by the WHO media center. “Never before in recorded history has a biosafety [level] four pathogen infected so many people so quickly, over such a broad geographical area, for so long."
For the first time, Ebola was on the global radar as forces were mobilized to the front lines of the epidemic. According to the WHO, about ten percent of the individuals who died from Ebola were health care workers, both local and international. This should not come as surprising, since the disease is spread via bodily fluids.
Which strain was in West Africa?
As you can see, the case counts for previous Ebola outbreaks pale in comparison to the West African epidemic that erupted almost 40 years after Ebola first emerged. The recent Ebola outbreak spread through three countries – Guinea, Liberia, and Sierra Leone – where there were at least 28,603 cases and 11,301 deaths. The fatality rate of this outbreak comes to about 39%, which is lower than the 52% and 88% fatality rates in 1976 then-Sudan and then-Zaire, respectively.
The strain that tore through Guinea, Liberia, and Sierra Leone and trickled into a couple of other nations is called the Makona strain, and it is part of the Zaire ebolavirus species. In animal studies, Makona showed a decreased ability to cause disease compared to the 1976 Zaire strain, which is underscored by the starkly different fatality rates. Another contributing factor to the lower fatality rate, of course, is the level of supportive care available for patients infected in 2014 versus 1976. Though there is currently no antiviral treatment for Ebola, supportive care including fluid replenishment, rest, and fever reduction can go a long way in treating someone with Ebola, especially a milder form of the disease.
An Ebola of Epidemic Proportions
When the outbreak in Guinea spread so rapidly, many hypothesized that the culprit strain was rapidly mutating into an epically virulent pathogen. However, anecdotal evidence mentioned above and genetic analysis of viral isolates show that this was not the case: viral mutation rates were no greater than those observed in previous Ebola outbreaks, and the virus was still only spread through fluid contact as opposed to even more contagious routes like airborne transmission. As a result, the scale of this Ebola outbreak had to be due to factors extrinsic to the virus itself.
The 2013-2016 Ebola outbreak is the first Ebola outbreak to reach epidemic proportions: the aforementioned outbreaks over the last few decades were all quelled within a couple of weeks. Several factors contributed to the size and scale of West Africa’s Ebola epidemic. Extreme poverty in the regions coupled with a dysfunctional healthcare system made it impossible to provide adequate surveillance, case detection, and proper containment practices every time somebody became ill. Furthermore, the outbreak came at the heels of civil war; distrust of government officials halted the already delayed official local response to news of the outbreak.
Local burial customs consist of washing a body after death. Ebola is spread by bodily fluids, and a deceased patient is particularly hot (teeming with virus). As a result, cases climbed up even more. As the outbreak spread, the few existing hospitals in affected regions became overwhelmed. Already short on staff and medical supplies, they were soon forced to close. Thus, in addition to Ebola-related fatalities, an additional death toll was tacked on to the epidemic from people who needed urgent care for other medical needs.
So why here? Why now? As the CDC report says, we do not have exact answers to these questions. Many outbreaks tend to occur as the result of a spillover, an event wherein an animal harboring a pathogen comes into contact with another species (in this case, humans). In the right conditions, the infection is transmitted from the animal reservoir to the new host. In addition to Ebola, other popular spillover microbes include the related Marburg virus, Hendra virus, Nipah virus, malaria, Q fever, HIV, and Legionnaire’s disease.
“In the right conditions” is the operative phrase here. Spillover events are exceedingly rare, and require highly specific environmental and genetic factors that allow a pathogen to survive and eventually propagate within a new host. Nonetheless, due to the massive quantities of microbes and increased human-wild animal interactions, such a one in a million-type event should not come to complete surprise.
Sure enough, genetic analysis of Ebola viruses has put forth nonhuman primates (such chimpanzees, gorillas, and monkeys) and bats as potential primary reservoirs of Ebola. Humans who hunt and eat nonhuman primates, especially when dealing with raw meat, are at risk of hosting a spillover. Contact with bats either directly or indirectly (such as by fecal contact) can also lead to such an event. We will never know the specific interaction that led to a one-year-old baby contracting the first case of Ebola virus in West Africa that led to this epidemic, but the widespread consensus is that it was some sort of spillover.
Organizations from all over the world have helped put a stop to the Ebola epidemic. When the WHO declared the outbreak an international emergency in August 2014, it published a roadmap to help guide and coordinate international response. The goal was to stop Ebola transmission within 6 to 9 months. In September 2014, the UN Security Council declared the epidemic a threat to international peace and security: it quickly resolved that United Nations member states ought to bring forth resources in efforts to raise at least $1 billion to fight the outbreak.
TIME magazine named the healthcare workers on the front lines against Ebola its “Person of the Year” in 2014. Local doctors and nurses, and healthcare workers from many different organizations such as Doctors Without Borders and Samaritan’s Purse were commended heavily for their early response efforts and dedicated workers who put their lives on the line to put a stop to this terrible disease.
The large-scale Ebola epidemic was finally over by the end of 2015. On January 14, 2016, the WHO declared that all known chains of transmission were stopped in West Africa. They cautioned, however, that small outbreaks were still possible in the future and that steadfast attention is essential. On January 15, Sierra Leone confirmed its first new case in 4 months. Sporadic cases have been trickling in, but so far they have been contained and no new outbreak has flared up.
Lessons learned during the outbreak and lessons still to be learned over the next several years will be pivotal in honing future outbreak responses. This is especially important now as the Zika pandemic unfolds in North and South America. While Ebola and Zika are massively different diseases (a point I cannot emphasize more), the broad themes of global infection control from one outbreak can always be applied to another. After all, emerging and re-emerging infectious diseases have been and always will be a perpetual challenge to human survival.
Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
In 2009, researchers at UC Davis published a study reporting an unlikely connection between two very different things: amyloid plaques and bacterial biofilms. Amyloid plaques are a hallmark of Alzheimer’s disease. They are sticky buildups found over neurons that are caused by proteins that no longer fold properly. Biofilms, on the other hand, are slimy conglomerates of microbes that often stick to surfaces thanks to polymers produced by the participant bacteria. Biofilms have been implicated in increased bacterial pathogenicity such as in infections associated with contaminated medical devices – slimy bacterial communities are a lot harder to kill than individual microbes. Non-pathogenic bacteria also form biofilms, such as certain gut bacteria, in order to stick to host tissue and form colonies that help us digest food.
The specific connection researchers found at UC Davis nearly seven years ago is that amyloid plaques and bacterial biofilms actually look very similar in our immune systems’ eyes. Andreas Bäumler and colleagues showed this first by using mice models and then by using human cells. They injected mice with E. coli and salmonella and identified that curli fibrils, coiled fiber-like structures made by these bacteria, triggered the mice’s immune responses against these bugs. When they knocked out the microbes’ ability to aggregate, the same immune response was no longer triggered. Curli fibrils help bacteria adhere to host tissue and to each other in order to form biofilms.
Curli fibrils do in fact look just like amyloid fibers. And when Bäumler’s group presented human cells with both types of fibers, they observed identical immune responses, a finding that implicates morphological specificity rather than protein sequence specificity in inflammation. That is, the structures of these protein aggregates – both neuronal and bacterial – look the same to our immune systems and are thus treated the same way. Both trigger a type of immune response known as inflammation. When we have an infection, this response fights the infection and (hopefully) clears it. And when people get Alzheimer’s, doctors see a characteristic chronic inflammation in the brain that damages their neurons.
In mice, the immune response to curli fibrils is mediated by a protein called Toll-like receptor 2, abbreviated TLR-2. This protein is found on some cell surfaces and recognizes foreign material such as pathogens. When this happens, TLR-2 signals the immune system. Bäumler and colleagues used human immune cells called macrophages to test whether synthetic curli fibril proteins and amyloid plaque-causing proteins would trigger TLR-2 in vitro (in a lab setting). The group found that TLR-2 was triggered by both of these proteins, but only when they were allowed to aggregate.
Through the twentieth and beginning of the twenty-first centuries, scientists tried to figure out what was causing chronic inflammation in Alzheimer’s patients. When microbiology met neuroscience, a possible cause was finally identified. Curli fibrils and amyloid plaques are genetically two completely different things, but they seem to form nearly identical aggregate structures. Thus, some feature of these structures triggers the same innate immune response to elicit inflammation in affected parts of the body.
These findings have been key in the search for amyloid-related disease treatments (such as Alzheimer’s, Huntington’s, type 2 diabetes, and mad cow disease). If scientists can inhibit TLR-2-dependent cascades, the progression of these devastating illnesses could potentially be slowed, if not halted. We are still some ways away from completely understanding Alzheimer’s and related diseases, and we need a full picture of the disease and its specific causes before marketing treatments. Furthermore, potential implications of inhibiting TLR-2 responses (a form of immunosuppression) will need to be investigated before approaching this type of treatment method.
Despite the UC Davis and related studies almost a decade ago, additional potential connections between microbes and Alzheimer's disease remained under-studied and under the radar until recently. Earlier this month, however, a team of scientists and clinicians from around the world co-authored an editorial in the Journal of Alzheimer's Disease. Their article stresses the need for further research on specific microbes and their potential roles in Alzheimer's disease. The group draws from multiple published studies that have implicated microbes in the brain disorder.
The editorial points a finger at three microorganisms: the cold sore-causing Herpes Simplex 1 virus (HSV1), Chlamydia pneumonia bacteria, and various spirochete bacteria such as syphilis, all of which are reportedly present in the brains of many elderly people. For instance, they cite studies that have noted amplification of HSV1 DNA in the brains of immunosuppressed individuals. Furthermore, they write that pathogen hallmarks (such as microbial DNA) tend to co-localize with amyloid plaques in Alzheimer’s patients. Correlations have been deduced between testing positive for HSV1 infection and developing Alzheimer’s disease. More recently, Alzheimer’s has been shown to have a “communicable” feature – features of Alzheimer’s pathology have been found to be transmissible by inoculation of Alzheimer’s-afflicted cells to animal models. Similarities between syphilitic dementia (dementia caused by the bacteria that cause syphilis) and Alzheimer’s disease further underscore a potential connection, and some antivirals such as the drug acyclovir have been shown in vitro to block HSV1-induced amyloid pathology.
The editorial has received mixed reactions. Many have called the referenced studies insufficient; and while there might be a relationship between microbes and Alzheimer’s disease, causation and correlation have not been distinguished. For example, while it is known that many viruses and bacteria tend to be more prevalent in Alzheimer’s afflicted brains compared to healthy brains, this could be a consequence of the disease rather than a cause. Furthermore, what about all the evidence that some types of Alzheimer’s are hereditary? There are, after all, specific genes that have been implicated with increased risk of developing the disease. And while we know that certain aspects of our microbiomes are inherited during birth from our mothers, infection with HSV1, chlamydia, or syphilis is not hereditary.
In 1981, Barry Marshall proved that the bacterium Helicobacter pylori can cause stomach ulcers. Throughout the 1950s and 1960s, studies showed that some viruses can cause cancer (these are now known as oncoviruses). Whether or not the Microbe-Alzheimer’s hypothesis will join these pivotal medical discoveries will be determined if relevant studies end up being funded and undertaken.