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How many bacteria/viruses are actually removed by the body’s natural defenses while we are sick?

March 10, 2015 Leave a comment

The answer to this question is completely dependent on the context of infection. For instance, when you brush your teeth, you introduce bacteria from your mouth into your blood stream and become temporarily bacteremic. Fortunately, the immune system clears these bacteria quickly. In this daily event, thousands of bacteria enter the bloodstream. After brushing, bacteria in the blood were below 104 cfu/ml, as estimated by PCR, and exact numbers are nearly impossible to quantify (Lockhart et al. 2008).

In contrast,  Ebolavirus replicates to ~107 – 108 virions/ml in the blood of non-human primates (Bente et al. 2009). The average person has ~5 liters of blood. Very conservatively, an Ebola survivor will have cleared ~5 x 1010 virions from just the blood. That’s 50 billion virions.

Keep in mind that this is also just a snapshot of a moment during infection. Viruses are constantly propagating, and a single virally infected cell can produce thousands of viral particles in a single day. It’s possible that over the course of a 2 week infection, 1011 – 1012 virions may be produced and cleared (it’s probably much higher). While this number is staggering, it somehow pales in comparison to the magnitude of the U.S. debt, which currently stands at ~$18 trillion, or $1.8 x 1013.

Geisbert et al. 2004 Nat. Med.

Geisbert et al. 2004 Nat. Med.

I also estimated the rough number of virions from the liver and spleen, two organs with significant ebola titer, and the total is nowhere near the magnitude of virions in the blood.* Additionally, ebola virus is being shed through mucosa and other bodily fluids. People generate ~ 4 liters of mucus daily in the gastrointestinal tract. I could not find an accurate estimate of Ebola viral titers in the mucus, but it’s unlikely to be near the levels of that in the blood. Granted, mucus could still contribute significantly to viral titer. There’s also the possibility that other organs harbor high titers of ebola virus, especially the gut.

*Approximately 104 – 105 virions/gram were detected in the liver and spleen using a mouse model for Ebola (Bray et al. 1996). Given that the average mass of a human liver is 1.5kg and a spleen is 140g (Molina et al. 2012), and using conservative estimates, about 1.6 x 107 virions from the spleen and liver alone, over 1000 times less than that from the blood.

Your odds of contracting Ebola vs. Chikungunya

August 12, 2014 1 comment

Sure, Ebola is scary. However, the issue with Ebola is primarily a social one where misinformation, a lack of infrastructure, and general government mistrust have thrown the epidemic out of control (I suggest reading a historical perspective on Ebola response and prevention). Unless you’ve recently traveled to west Africa to eat bushmeat or treat Ebola patients, there is little cause for concern. You are very unlikely to contract Ebola, but recently your odds of getting Chikungunya have significantly increased.

On June 17, 2014, the CDC announced the first case of Chikungunya acquired in the continental US. Previously, Chikungunya in the US had only been identified in travelers coming from the Caribbean where over half a million people have contracted Chikungunya (Caribbean Chikungunya Cases Climb 8%, top 500,000). In late 2013, Chikungunya was introduced to the Caribbean from Africa or Asia, where the disease has been endemic since its discovery in the 1950s. This rapid spread of Chikungunya is particularly alarming, and has been heavily influenced by the increase in international travel.

They're gonna have to change this map.

They’re gonna have to update this map.

What’s Chikungunya?
Chikungunya is a disease caused by chikungunya virus, which is transmitted by Aedes mosquitos. Infection by Chikungunya may result in a fever, rash, insomnia, headache, and joint pain. While Chikungunya is rarely fatal, it is incredibly debilitating, causing symptoms for weeks to months. Chikungunya also presents with other symptoms such as leg swelling and ocular inflammation. Chikungunya pathology is not well understood, and as a result antivirals and vaccines have not been developed.

800px-Aedes_aegypti_feeding

Avoid Aedes mosquitos.

Ebola is not likely to cause a pandemic.
Ebola is one of the deadliest diseases on the planet, but with the proper infrastructure can be controlled. Additionally, the likely reservoir of Ebola is in bats, which are often eaten as bushmeat in villages in Africa (Africans still eating bushmeat despite Ebola). 1. Here in the US we rarely come in contact with or eat bats. 2. Even if we were more bat oriented, the Ebola reservoir is likely specific to animals in Africa. 3. Education plays a major role in the spread of the disease. African tribes are notorious for rejecting help from Doctors without Borders and the like (Superstitions play a role). 4. Ebola transmission requires contact with bodily fluid such as blood, vomit, or diarrhea. It is not a respiratory infection and close contact with a patient is unlikely to cause transmission.

In contrast, Chikungunya transmission is nearly impossible to avoid. Aedes albopictus and Aedes aegypti, reservoirs of Chikungunya virus, are invasive species of Asian tiger mosquito that are now firmly seated in the US. Importantly, on August 7th, Chikungunya was found in mosquitos in the US. The West African outbreak of Ebola is certainly devastating, but Chikungunya is far more widespread and is transmitted with relative ease. So while it is important to be mindful of the current state of Ebola, overlooking other potential outbreaks may have devastating consequences.

The frightening Filoviridae

July 22, 2013 1 comment

f2_mayor_nrm2216-f1
Ebola hemorrhagic fever is caused by Ebola virus, a filamentous virus that is part of the family Filoviridae. Ebolavirus is of particular concern to global health as a result of killing as many as 90% of its victims. The Hot Zone tells in great detail the discovery and fear driven by Filoviruses, I highly suggest it.* This high mortality can be attributed to its ability to avoid detection by the immune system. Normally the human adaptive and innate immune system are capable of recognizing specific markers, or antigens, from pathogens. These antigens trigger an immune response that can clear the infection. The adaptability and complexity of the immune system is astounding, and can be better understood with the above wikipedia links.** While the immune system plays a large role in infectious disease, the star of the game is Ebolavirus.

Viruses are characterized by their parasitism, and the inability to metabolize and replicate in the absence of a host. Because of this, viruses hijack host cell machinery in order to reproduce. But first, the virus must gain entry into a cell. Viruses have found various ways to enter their host cells. For example, HIV entry is characterized by fusion of the viral envelope to the membrane of the cell, without any endocytosis. In contrast, most viruses utilize a process of endocytosis, where fusion of the virus to the cell membrane triggers a response by the cell to engulf the virus. How Viruses Hijack Endocytic Machinery.

After entering a cell, Ebolavirus uses host proteins, along with a few of its own, to make copies of itself. These new viral copies leave the cell in search of another host to infect. However, after leaving the cell, the viral particles are exposed to the dangers of the human immune system. The mechanism by which Ebolavirus evades the immune system has been dubbed antigenic subversion. The paper by Mohan et al. at Emory University is here, and open access: Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus.

Viruses are subject to natural selection and evolution, similar to all organisms. Many pathogens undergo antigenic variationwhere the antigens of the microbe change such that the immune system no longer recognizes it as a pathogen, allowing it to reside in its host undetected. Alternatively, antigenic subversion is a mechanism by which Ebolavirus actively “hides” from the immune system by telling the infected cell to secrete an antigen (secreted GlycoProtein, sGP) that effectively undermines the ability of the immune system to recognize the capsid of the virus. The excreted antigens sequester the antibodies directed toward finding and clearing viral particles coated in GP1,2, the capsid glycoprotein responsible for attachment of the virus to the host cell. Without an appropriate antibody response, clearance of the virus is virtually impossible and free viral particles roam the body destroying cell after cell. This is where it gets heavy.

The translated products that contribute to antigenic subversion are a result of transcriptional editing. The viral polymerase carried by Ebolavirus is prone to slippage, and 20% of the time, the viral RNA polymerase creates a mRNA transcript that allows for the translation of open reading frames as a single protein, the fusion GP1,2 protein. 80% of the time, the polymerase creates a transcript that carries a stop codon before the second open reading frame, creating the secreted sGP protein. (PNAS Sanchez 1996)

Furthermore, antibodies against sGP harbor low reactivity with GP1,2. However, antibodies against GP1,2 react strongly with sGP. Because sGP is simply a truncated version of GP1,2, this suggests that the conformations of sGP create epitopes that differ from those on GP1,2. These conformational changes alter the immune response, leading to the production of antibodies that can strongly opsonize sGP, but weakly bind GP1,2.

Many pathogens employ a decoy mechanism, where they create an antigen that absorbs the effects of the antagonizing antibodies. However, this differs in that the “decoy” antigen is not only sequestering antibodies, but also altering the immune response to create ineffective and poorly protective antibodies against sGP when the immune system would be better off producing anti-GP1,2 antibodies.

A 3 minute discussion about the entry of Ebolavirus:

*A crappily formatted, but readable, PDF version of the book is here.

**I tried to keep it concise, but introduction to viruses is no brief task. I should do a pathogen 101, in addition to an immune system 101. I would like to delve into specific molecular mechanisms, but it’s easier to think about than it is to write about. Next time.

An introduction to emerging infectious diseases

July 17, 2013 Leave a comment

Viral_infections_and_involved_speciesWhile most of my research is directed toward antibiotic resistance in bacteria, the vast majority of the news in the popular media suggests that the most prevalent diseases are caused by cancer and viral agents. While concerns of bacterial drug resistance are on the rise, the fear of an influenza pandemic or an ebola outbreak creates excellent headlines.

Additionally, bacteria are relatively slow killers and infections are generally treatable (although some are not). A virus may have an incubation period of about two or three weeks with mild flu-like symptoms. During this time you may believe you have acquired the seasonal flu, and that it will pass. You hug your kids, and walk around the office touching doorhandles, shaking hands, and using the company copier. By the time you’re hemmorhaging and you realize it’s not just the flu, it’s too late, and you may have infected others.

The first thing you learn in microbiology is that bacteria are ubiquitous, but these single celled organisms are not alone in their pervasiveness. There’s a saying that for each bacterial species, there exists at least one virus that is capable of infection. Viruses are extremely prevalent. In a single milliliter of sea water, there are roughly 10 million viral particles, and about 15 times as many viruses as bacteria (a fun read). Despite the prevalence of viruses, most are incapable of infecting humans. Many bacterial infections are closely associated with immunocompromised individuals, and immunosuppression is often caused by a virus, such as HIV (opportunistic infections and AIDS).

Viral research has lead to incredible advances in medicine. Because general hygiene has decreased the incidences of bacterial caused diseases such as plague and tularemia, scientific efforts have been directed toward understanding viruses. Vaccines for smallpox and polio have saved an immeasurable number of lives. Viruses may even be key to a future cure for cancer or other genetic diseases, as viruses have been engineered as tools to deliver gene therapies (an easy to read microbe wiki link on viral based gene therapies). Hopefully I can shed light on some interesting aspects of emerging infectious diseases.

*I began writing this as a brief introduction to highlight some of the research in the field of microbiology, virology and immunology. I had too much to say, and hopefully my next post will cover this paper about how ebola evades the immune response.

Luckily it’s not all up to luck

June 30, 2013 Leave a comment

SuccessResearch requires a special kind of patience, the kind that will tolerate heavy doses of frustration.

The best thing about science is that it does not lie. If your hypothesis is wrong, it has the balls to tell you that you’re wrong without any of the “A+ for effort” fluff. On the other hand, if you are correct, science will very subtly hint to you that you are somewhat clever in finding a solution to your question. In rare situations, the answer will be right in front of your face. Most of the time, science will tease you with hints of the next step. And always, an answer to your question will pave the way for a hundred new questions. In the end, real answers require not only a lot of work, but also a lot of luck.

Chances are that you will die of heart disease, cancer, or a stroke. But that’s just probability. After all, it was by a marvelous stroke of luck that the monkeys shipped to the US carried Reston ebolavirus rather than any of the agents that cause Ebola hemmorhagic fever. Life is a lot about luck. Science is a lot about luck.

Science is a lot like sports in a way; talent can only take you so far. The thing that separates the good from the excellent is practice. Good baseball players hit the ball well. To be a good hitter, you have to hit, and you have to hit a lot. The same goes with science. If you want to be a scientist it takes a lot of practice and repetition. If you swing the bat enough times, you’ll eventually learn the best way to hit the ball.

In sports, you hear a lot of “I do it because I love the game.” Remember, these athletes are not out there playing the game because they fell into it. They practice and play because they genuinely love the game. Sure it’s nice to make millions of dollars a year to do the thing you love doing, but is money really the driving force here? We could argue about incentives and how they’ve driven society to where it is today. We would go back and forth, and I would agree that incentives are an excellent motivator, however there is one thing I find more motivational than any incentive you can give me. And that one motivator is dopamine.

KfQstXFCocaine is one helluva drug. Kidding. The cliche is as follows: “Do what you love and you won’t have to work a day in your life.”  If you love getting paid to sit in a dugout for half of your salary and bake in the sun for the other half, then baseball might be for you. Of course I’m joking. Who doesn’t love a game where 11 minutes of action are injected 5 seconds at a time throughout a 3 hour period?

The takeaway is this: it’s a lot about luck. frustration is common and failure should be a giddyup. if you enjoy being wrong a lot, science and graduate school are for you.