Biology concepts – fever, infectious disease, sexually transmitted disease, innate immune system
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Would you be willing to be a human guinea pig, to see if one disease might stop another? The term “human guinea pig” refers to the fact that from the 1890’s to the 1920’s guinea pigs were a major model for medical research. Later replaced by rats and mice that could be bred faster, guinea pigs were used to develop the first diphtheria antitoxins, which subsequently saved millions of lives. |
What if the disease you're to be given as treatment is a form of the infection that kills a million people each year, the second most of any infection? Now you're thinking the disease you already have must be pretty horrible if this is the best idea for a cure. Let’s investigate and see if it might be worth it to save you from.... neurosyphilis.
Syphilis is a sexually transmitted disease that has distinct stages. The primary infection is marked by a lesion on those parts of your body that are most at play in the contracting of a sexually transmitted disease. It is amazing that some scientists believe that sexually transmitted diseases such as syphilis, in their primary stages, actually make sexual relations feel better. The organism (Treponema pallidum) benefits from this because the infected individuals might be more likely to have sex more often and this is an opportunity for the organism to be transmitted to additional hosts. Called “host manipulation” this is an evolutionary process that is just now gaining more attention, and will be something we will talk a lot more about in this blog in the near future.
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The gumma lesions (left side) of secondary syphilis are not meant for polite society. It's no wonder the Elizabethans opted for the ruff collar (right side). |
The tertiary (3rd) stage of syphilis is much more likely to be fatal. Appearing anywhere from 3-15 years after the primary lesion, tertiary syphilis attacks the brain, heart, liver, or bone tissues of the victim. Neurosyphilis can bring dementia, hallucinations, psychosis, as well as unsteady gait and movements (ataxia or paresis). While only a quarter of the patients reach this stage, it is a nasty way to go.
Do you agree that being purposefully infected with one disease to avoid the ravages of neurosyphilis might be worth considering? Even if the doctors were going to give you....... malaria?
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This is the spirochete bacterium Treponema pallidum, the causative organism of syphilis. Recent evidence suggests that the bacterium is flatter and less like a corkscrew than previously thought. They don’t look like they have a flagella to move around, but they do. It is located INSIDE the cell, which makes the whole cell whip back and forth, not just the tail. |
In the modern day, the treatment for syphilis is antibiotics; penicillin G can easily kill T. pallidum in the primary and secondary stages. However, antibiotics do not cross the blood brain barrier very easily (this barrier is made by very tight junctions between the cells and reduced movement of molecules through the cells, in order to protect your brain from toxins and infectious agents). Very high doses of drugs must be used to treat neurosyphilis. They may not work at all and might bring side effects.
But in the days before antibiotics, other treatments had to be sought. In the state of Indiana, USA, just as in all states and countries at the turn of the 20th century, syphilis was rampant in mental hospitals. This was both the cause and effect for some of the incarcerations, and was a source of constant battle in the institutions.
For better or worse, these patients were a stable population for the testing of different therapies for neurosyphilis, and Walter Bruetsch at the Central State Hospital in Indiana was a leading American researcher on the use of malaria to combat neurosyphilis.
Originally developed by Professor Julius Wagner-Jauregg of Vienna, Austria, the “malaria cure” was used to originally to treat paresis (very unsteady) and general paralysis patients; he suggested that fevers were helpful in paresis and tertiary syphilis.
Wagner-Jauregg had noted as early as 1887 that in the tropics, both malaria and syphilis were common, but those with syphilis rarely progressed to the tertiary stage, with the paresis that if often brought. In 1917, he treated nine paretic patients with good results, so other institutions expanded the study of this treatment. In Indiana, several decades of work were summarized in a series of papers in the 1940’s, making Indiana the prime American spot for “malaria cure work.”
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The female Anopheles mosquito can take in quite a bit of blood in just a short time. Take too long and they could get squished.....but take hot blood in too fast and they roast. That drop of fluid at the end of their abdomen evaporates and helps cool their body as they suck up the 37˚C blood, according to a 2011 study. |
There are five species of malaria parasites; P. falciparum is the one that causes the most severe disease. Other species include P. vivax and P. malariae, which are dangerous but do not cause as many deaths. They are also the prevalent species outside of Africa.
The merozoite (meros= portion, and zoo = animal, so like half an animal) stage of the organism invades the RBC’s and reproduces asexually. Periodically the merozoites burst out of the depleted erythrocytes and look for new blood cells to infect. These periodic bursts are timed differently in the different species, from every 48 hours for P. falciparum, or every 36 hours for P. vivax. When they break the RBCs and escape into the bloodstream, an immune reaction is stimulated by the broken cells, including a very high fever, from 103-110˚F!
The fever itself may be lethal, but there other factors, such as the fact that infected cells have parasite proteins on their surface that makes them sticky. The infected RBC's don't pass through the entire circulation and can block circulation in the brain or spleen and cause other problems. So which part of the infection was helpful in tertiary syphilis?
The consensus idea was that the malarial fever killed the T. pallidum of syphilis. Microorganisms like to live inside us because we provide them with something they need, and they have evolved to live best at our temperature. A fever is one way your body tries to make you a bad host for the organism. A high fever, induced by malaria, would make you a very inhospitable host for T. pallidum, and could be lethal to the organism.
Think about this the next time you want to take an Advil or Tylenol for that low grade fever. By medicating yourself, you are preventing your body from using one of its natural defenses against infectious agents. But high fevers cause damage on their own, so declining an anti-febrile (anti-fever) drug when your temperature is 100˚F is much different that counting on your body alone when the fever is 105˚F and you're having convulsions.
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Here is a macrophage (false color image) ingesting bacteria. The macrophage is part of the innate immune system, it can phagocytose (eat) many different foreign invaders. One macrophage can take up and destroy hundreds of bacteria. They stick to tissue culture plates not because they are sticky, but because they're trying to eat the plate! |
In later years, antibiotics took over as the major treatment for syphilis, and only rarely does the infection progress to the tertiary stage. However, proponents of fever therapy have, over the years, suggested that malaria as a treatment could be used for a variety of infections, from lyme disease to HIV.
The primary cheerleader for using malaria to treat HIV infection was none other that Henry Heimlich, inventor of the Heimlich maneuver. In the late 1990’s and early 2000’s Heimlich carried out a series of highly questionablestudies on malaria fever in HIV infection. It is not altogether clear whether proper informed consent was used, and the results of the studies have been universally discounted. But that is not where HIV and malaria part company.
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A schematic cartoon shows how HIV replicates. It first attaches and uncoats. The RNA is reverse transcribed and then transcribed and translated into protein. When the new virus assembles itself, the coat proteins have to be chopped up into usable pieces. This is the job of the HIV protease. Protease inhibitors stop this and prevent virus maturation. |
It turns out that malaria parasites use proteases very similar to those of HIV, and preliminary studies indicate that these drugs can prevent reproduction of the organisms. As hard as it has been to come up with useful malaria drugs, here’s hoping that human studies are successful.
Finally, there is some speculation that malaria and HIV are linked. The dangerous P. falciparum was not used to induce fevers in syphilis patients; doctors used less virulent Plasmodium species, such as P. malariae or P. vivax. Charles Gilks, in a 2001 paper in Philosophical Transactions of the Royal Society, suggests that some primate strains of malaria were also used, wherein infected monkey blood was injected directly into the syphilis patients. Gilks wonders if this is where a simian immunodeficiency virus made the jump to mankind. I think that is an extremely long leap.
Next week let’s work the other side of the street; do some diseases keep you from getting malaria? Yes, and there are more than you might have guessed.
For more information and classroom activities, see:
Syphilis –
Malariotherapy in syphilis and other infectious diseases –
Malariotherapy in HIV –
Protease inhibitors-
http://www.thebody.com/content/art12606.html