A letter to the public in regards to specific health and awareness:

by NS

Image 1 from Ref 5

Within the central river valleys of Midwest US, the belt of the Southern Central US, and the upper regions of Central US, there is a microbe that poses an issue for 500,000 individuals per year. Histoplasma capsulatum is a virulent and airborne fungus associated with mild to severe respiratory infections among individuals (3). With 5 – 20% of lifetime residents in these areas showing exposure, as well as a very high mortality rate upon untreated systemic infections, H. capsulatum is a microbe of necessary awareness for public health (2).

Image 2 from Ref 5

H. capsulatum primarily resides in moist rich soil within the regions of infection. Soil that of which is infected by bird and bat fecal matter are of primary risk for contamination. Notably soil near livestock populations, such as chickens, are also at a higher risk (5). Within the soil, the fungus begins its transition to infectious stages at temperatures of 77 degrees Fahrenheit. Upon the surrounding environment reaching this temperature and fungal formation of short stalks completed, disturbance of the fungi through any means, such as walking, will release its infectious agents, spores, for potential infection of individuals(2) (4) (6). Construction sites are at high risk of outbreak due to them containing wind-blown dust that carries the infectious agents. H. capsulatum is not infectious from person to person, which remains an advantage for dealing with outbreaks (5).

Image 3 from Ref 5

The environment H. capsulatum is encountered in determines it’s primary growth stage, of 3 total stages. While residing in soil, H. capsulatum is in its first stage of growth. Formation of infectious agents such as macro and microconidia, both a form of spores, are key to this stage, with the latter hypothesized to be the more infectious form (2). Upon the release of spores from its short stalk formation which lead to subsequent infection, H. capsulatum is able to transition to its next stage from within the human body due to the temperature shift from an environment of 77 degrees to human body temperature of 98.6 degrees Fahrenheit (3) (4). Spores inhaled from the environment of stage one are lodged in the mucus membrane of the lungs where they’re devoured by host immune cells. Contrarily, chronic but mostly harmless infections occur when they stay within the pulmonary calcifications, healed lung tissue, and are not detected by immune cells. After host immune cells engulf H. capsulatum, it begins to transition to an oval budding yeast from within its own safe bubble in the immune cell. After 4 – 6 days of being in stage two, which can be accelerated in abundance of cysteine and iron, the microbe transitions to stage three of growth. Within this stage, the newly formed yeast keeps a constant safe environment of homeostasis around it to perform cellular process (4) (6). H. capsulatum will require cysteine and iron to be successful, which it has counter mechanisms for due to low free iron levels within hosts. Cysteine is vital for yeast stage transition and growth, this is due to yeast requiring a high demand of cysteine and iron for nutrition (2).

Image 4 from Ref 3

Detection is tricky but varies depending on severity. As with stated that some chronic but mostly harmless infections do occur, these types do not show symptoms. These are dangerous due to the potentiality of eventual immune compromisation, meaning the random chance your immune system becomes weakened; the infection will flare up and cause major issues. When it flares back up, symptoms will include ones mirroring pneumonia (1) (6). These would be troubled breathing, light-headedness, dizziness, chronic sweating, and cold chills. Within worsening systemic, whole body, infections symptoms to be aware of include those linked to Superior vena cava syndrome such as shortness of breath as well as facial and arm swelling. Inflammation and chronic pain from within the chest cavity is also a symptom linked to systemic infections due to its association with peripheral tissue inflammations such as Mediastinitis. Contrary to asymptomatic chronic infections, symptomatic infections will arise 3 to 17 days post infection. The symptoms will range from fever, dry cough, chest pains, and a general sick feeling (3) (5).  As with any detection of symptomatic infections, subsequent contact of a doctor is highly advised for overall wellness of patient.

Post detection treatment varies on the stage and type of infection. With chronic infections that flare up after secondary immune compromise events, prolonged treatments with antifungals will occur for about a year (1) (5). Chronic infections have different styles, however treatment will stay the same for all chronic infections with any variance being on medication dosage levels (3) (6). The worse stage of chronic infection is when the yeast becomes disseminated and spreads through the blood to other organs and tissues, which is known as a systemic infection. This stage is very lethal if left untreated due to potential systemic organ failure, however treatment in patients that do not suffer irreversible damage to their tissue is extremely successful (5) (6). Subsequent medications of balancers might be utilized for later stages of this, however antifungals of the same style will be utilized. Due to the reclusive nature of the microbe in undetected stages, it remains hard to detect and subsequently treat it (6). A good reference is that in cases of greater infection, symptoms from H. capsulatum will occur which allows for detection and subsequent treatment.

A key reminder is that the elderly and adolescents pose a higher risk of acute infections due to structurally weaker immune systems. Awareness of the microbe and its symptoms can lead to proper detection and subsequent treatment of such individuals at higher risk.

Prevention of infections is a seemingly coordinated effort for H. capsulatum. Prevention of accumulated bird or bat droppings near opportune soil environments is a combined effort. Within working environments with higher risk, utilization of greater personal protective equipment (PPE) is vital to preventing potential infections. Awareness of areas containing high concentrations of bats and birds is a great advantage in the field of prevention. Contrary to land birds, aquatic birds such as gulls, provide no threat to infection. As with most infections that spike in immune-compromisation, keeping a healthy immune system is vital in preventing more harmful and serious infections (5) (7). Proper diet, sleep patterns, and proper actions within the state of being sick are crucial for preventing a weakening of the immune system. A key thing to note in this is that infections leading to sickness can weaken an immune system to the point where different subsequent microbes, such as H. capsulatum, are allowed to have a more opportune impact on a host. Proper health measures during illness, such as sleeping enough and eating well are crucial for preventing subsequent infections from other microbes (5). With acquired immune deficiency syndrome (AIDS) at pandemic levels, and fungal vaccines still in developmental stages, proper preventative measures prove highly effective for preventing such a microbe from having a high impact on the population. (1)

To summarize, H. capsulatum resides in the central US with 5 – 20% of lifetime residents obtaining chronic infections. Soil frequented by birds, bats, and livestock pose a higher risk, so be aware with frequenting these areas in the ideal temperature range (77 degrees), since any walking can release spores. Infection will occur in the lungs and can eventually progress to a systemic infection. Asymptomatic chronic infections are frequent and these are problematic if your immune system is weakened by future infections. Symptomatic infections will result fairly recent after infection and seeking of a physician is important to prevent a systemic infection. The key factor with infection of H. capsulatum is prevention of a systemic infection, which can be avoided by being aware of symptoms and seeking of medical assistance.  Be aware that elderly, adolescent, and immune-compromised individuals (AIDS) are at a higher risk of infection, and observe symptoms in those individuals if they arise while encouraging seeking medical treatment. Keeping a healthy immune system through sleeping, eating, and exercising properly is a key factor in managing infections and should be done regardless.

References:

(1)      Medici, Natasha P., and Maurizio Del Poeta. "New Insights on the Development of Fungal Vaccines: From Immunity to Recent Challenges." Mem. Inst. Oswaldo Cruz Memórias Do Instituto Oswaldo Cruz 110.8 (2015): 966-73. Web.

(2)      Bossche, Hugo, Frank Odds, and David Kerridge. Dimorphic Fungi in Biology and Medicine. 1st ed. New York and London: Plenum Press, 1993

(3)       Chang, Ryan. "Histoplasmosis." 19 Sep 2005. emedicine. 25 Aug 2007 <http://www.emedicine.com/MED/topic1021.htm>.

(4)      Heitman, Joseph, Scott G. Filler, Aaron P. Mitchell, and John E. Edwards, Jr.Molecular Principles of Fungal Pathogenesis. 1st ed. New York: ASM Press, 2006. (Heitman et al. 611-626)

(5)       "Histoplasmosis." Centers for Disease Control and Prevention. 12 Oct 2005. Centers for Disease Control and Prevention. 25 Aug 2007 <http://www.cdc.gov/ncidod/dbmd/diseaseinfo/histoplasmosis_g.htm>.

(6)      Kobayashi, George S.. "Molecular Basis of Adaptation in Histoplasma capsulatum ." Washington University School of Medicine. 25 Aug 2007 <http://research.medicine.wustl.edu/OCFR/Research.nsf/Abstracts/64ABA9996B650C50862567ED00029E69?OpenDocument&VW=Infectious+Diseases>.

(7)      Lai, Chung-Hsu, Chun-Kai Huang, Chuen Chin, Ya-Ting Yang, and Hsiu-Fang Lin. "Indigenous Case of Disseminated Histoplasmosis, Taiwan." Emerging Infectious Diseases Jan 2007 127-129.

A tale of Histomonas meleagridis

Today in Poultrytopia is just like any other day in this lovely country. There are many states that make Poultrytopia with the two largest being Chickensota and Turkeyia. For many years these were safe states. Both states have a central infrastructure that includes important buildings one of those being called the cecum that is involved in processing much of the plant material in the state and the liver which has many important roles. If the cecum is at all compromised, many of its workers will spill out into the rest of the state. These workers are very dumb and all they know how to do is break down all sorts of material. Many of these workers are different species of bacteria. If they get out of the cecum they will seek to break down other buildings that are important to the infrastructure and ultimately lead to the downfall of the state. If the liver shuts down, the entire state will quickly die because many essential roles are no longer being carried out. Luckily this is very hard to do since the cecum and liver it is made up of very special bricks called cells that very few intruders can breach.

The police force in Poultrytopia is very effective and has many lines of defense. Unfortunately one branch of the police force called the Federal Bureau of Innate Immunity or FBI for short will generically target suspected intruders. They have been known to make mistakes and this causes much displeasure on many different Poultrytopia social media platforms. Anyway, my point is Poultrytopia is generally a very safe place even if the occasional bad seed gets past the border.

So on this bright and sunny day in Chickensota, a seemingly innocent tourist was admitted entry to the state. This tourist’s name is Heterakis gallinarum but he likes to go by the nickname Nematode. For as long as he can remember he has always wanted to visit the different cecums in the different states of Poultrytopia. He had visited the cecum in smaller states such as Grousefornia and Pheasantington. On these visits he was overly excited and didn’t know the rules of the cecum and got lost during the guided tour. He ended up causing some minor issues but luckily didn’t cause any serious damage to either of the smaller states. It’s when nematode enters the cecum with He was determined to redeem himself by behaving on a tour of the cecum in Chickensota and maybe someday visit Turkeyia once he saved up enough money and nothing goes wrong on this trip. Unfortunately for Nematode he wouldn’t be so lucky.

Figure 1: Nematode after taking up the trophozoites. Credit: BNU China    

While he was traveling he had noticed a few Histomonas meleagridis babies that were scared on the side of the highway. The Histomonas meleagridis babies are also known as trophozoites and are very delicate when they are in this state and can’t survive long in the outside world. Nematode has always been a bit of a softy so he decided to wrap the trophozoites in his own Nematode eggs so they will be able to live for up to two years. Nematode was going to leave the eggs behind because he knows it’s against the law to bring baby trophozoites into any state in Poultrytopia. This is due to the fact that the babies can reproduce very quickly through a process called binary fission. Many years ago there was an outbreak that caused many of the states to die. Nematode decided that he would put the eggs with the trophozoites in his backpack and once he reaches the border he’d give the eggs to border patrol and they would be able to find them a place to live. So Nematode gets to the border and see that the FBI is profiling everyone and taking out anything that looks like a threat. Nematode is very scared for the eggs and for himself. He decides to hide the eggs in his backpack and hope the FBI doesn’t notice. Nema isn’t the smartest guy and accidentally gets taken up by the mouth of the state while it is harvesting nutrients from the outside environment. Now that he’s past most of the danger he decides to head to the cecum, the place he is most excited to see. But he must still be careful because the FBI has many different modes of action that help protect various parts of the state.

In the cecum he decides he loves it so much he’s going to hang out awhile and make some more eggs. Many of these eggs leave the cecum and are eventually deposited outside of the state. Many of the eggs that are deposited have the potential to be taken up by other states. While Nematode was hanging out and having the time of his life in the cecum, he forget he left the eggs with the trophozoites alone in the cecum! The trophozoites made their way out of the eggs and much like a puppy, wanted to eat everything.

They started my chewing on all of the cells the make up the lining of the cecum. They were eating so much the they had to divide into more trophozoites so they wouldn’t get too full. As they kept eating they kept dividing. Eventually there got to be so many that they made it out of the cecum and decided that the liver looks especially delicious and decided to continue their feast there. As they left the cecum some of the bacterial workers of the cecum found their way out as well and they too started to damage many of the internal organs. As they munch away on the liver a few of the trophozoites still in the cecum find their way into some of the eggs that Nematode made since they wanted to take a nap after eating. As they’re napping the eggs get sent out of the cecum and out of Chickensota. Before Turkeyia has time to hear about the disaster in Chickensota, the eggs with the sleeping trophozoites are taken up by Turkeyia. Pretty soon trophozoites are in both states and causing all sorts of damage! As the trophozoites spread through the states and they cause lesions in the different vital buildings. These lesions cause many of the buildings to fail. Back in Chickensota, Nematode is freaking out because he has, once again, messed up the cecum but this time in a very big way. He’s also very sad because he will never be able to see the Turkeyia cecum because the trophozoites spread from Chickensota and killed the state. He decided to flee the country and find a cecum in some distant land that he won’t mess up so badly it causes the downfall of every state. Hopefully our pal Nematode will be able to live his life happily ever after in a cozy cecum for the rest of his days.

Sources:

1.    Mcdougald, L. R. (2005). Blackhead Disease (Histomoniasis) in Poultry: A Critical Review. Avian Diseases, 49(4), 462-476.

2.    Mcdougald, L. R. (1998). Intestinal protozoa important to poultry. Poultry Science, 77(8), 1156-1158.

3. Beckstead, R. B. (2014, July). Overview of Histomoniasis in Poultry. http://www.merckvetmanual.com/mvm/poultry/histomoniasis/overview_of_histomonias_in_poultry.html

Microbe Makes the Shortest Path Problem Easy (But Not Really)

by Meghan Maltby

Physarum polycephalum

So, obviously all of us understand the shortest path problem common to computer science.  And obviously, we all know about the acelluar slime mold, Physarum polycephalum. And that these two things, an algorithmic solution living in the binary world and an organism living in the physical world, are incredibly and surprisingly connected.

But just in case you forgot about these two topics, I’ll refresh your memory.

Researchers claimed in 2000 that that an acellular slime mold, a yellow, sticky, tubular growth shown in the picture above, solved the shortest path problem, which asks the question, what is the quickest way to get from one point to another (1)? In the article published in Nature, P. polycephalum determined the shortest path between two food sources.  The importance of that feat lies in the background of the algorithmic solution to the shortest path problem, which I will explain first.  The cellular machinery behind the biological solution is incredible, and will be discussed after.

The shortest path problem lives within the realm of Graph Theory, which is the study of graphs. I know you’re thinking:

But in this case, you’d be wrong.  Graph theory, as it relates to computer science, is a little different than your standard algebra class where you use a set of axes to depict functions. In computer science, graphs look like this:

Where the numbered circles are called nodes and the lines are called edges.  The nodes are destinations and the edges are paths to travel between those destinations.  These graphs are not normally drawn to scale, so weights, represented by the letters, are added and associate a cost with moving along any given single or multiple edges.  This is similar to deciding to take the highway or side streets in rush hour.  The highway may be more direct, having a smaller number of edges to traverse, but taking side streets probably saves time even though the distance is longer.

The shortest path problem asks a simple question, if weights are additive, what is the shortest path between two nodes? There are different variations of this question, depending on what type of problem is being solved.  But for this example, let’s say we are trying to find the quickest path between nodes 1 and 6.

The first famous algorithm that tackled this problem was published by Edsger W. Dijkstra in 1959 (2). The solution is based on two factors; one, the weights of the edges, and two, which nodes are connected. The algorithm moves systematically through the graph, starting at node 1, and determines the placement of nodes and edges (2).  If the algorithm started at node 1, it would find two edges emanating from it; edge a to node 5 and edge b to node 2.  The algorithm will pick a newly found node, say node 2, then determine what edges and nodes it has.  This continues until the entire graph has been discovered.

From discovering node 1 and node 2   

It keeps track of which nodes it has visited and which nodes it hasn’t in a matrix by saving the weight of the edge that connects two nodes. If two nodes do not have a connection, the matrix saves a value of infinity (2). After inputting information gathered from nodes one and two, the matrix would look like this:

There is also another matrix that keeps the minimum weight of a path from one node to another.  This matrix is a bit more complicated. A truncated version is shown with possible pathways between node 1 and any other node.  What is shown in the result from the completion of the program, after the entire graph has been discovered. In reality, the matrix would compare values for different paths, and only save the one that was the shortest:

As you can see, the algorithm gets complicated quickly.  The bigger the graph, the bigger the matrices, and if you’re looking for the shortest distance between any two given nodes…phew.

Now the question is, did this slime mold actually solve the shortest path problem?

The answer is yes. Researchers created a maze and placed small pieces of P. polycephalum throughout and let it grow until the organism filled it entirely (1).  The figure below shows the maze after this point. Blue lines depict the possible ways the organism could grow to create a path between the two food sources (which are shown in the figure after this one, labeled AG), and are labeled by a1, a2, b1, and b2.

There are four possible paths through the maze between the food sources. The slime mold needed to decide which path to take at two different points; between a1 and a2, and between b1 and b2.  a2 was 22% shorter than a1, and b1 and b2 only had a 2% difference (1). Four hours after the food sources were placed, the maze looked like this, which shows that only the connections between the two food sources were kept by leaving growth in all possible pathway solutions, and any growth leading to dead ends was moved.

Noticing this, the researches left the organism for another four hours.  By maximizing the solution the organism chose pathway a2b1, after eight hours which was the best solution to the maze (1).

Researchers were thrilled, and called this incredible show of “foraging efficiency” a primitive form of intelligence. Foraging means obtaining food and nutrients, and completing it efficiently means the organisms fitness increases. Intuitively, taking the shortest path from the cave to the watering hole is the most efficient because it saves both time and energy.

So how does this slimy mold solve a complicated problem in a matter of hours?

It has to do with its physiology.  Because P. polycephalum is acellular, its body consists of one giant cell, so there are no walls separating one side of the organism from another.  That means that its contents, including water, nutrients, and proteins, move without being inhibited. But that does not mean that the movement is not controlled.  The slime mold pulsates, like the beating of a heart, by alternating the direction of water current (3).  The water carries with it Calcium ions, which cause the contraction of the plasma membrane. This is analogous to squeezing a water balloon or stress ball, where the force that you exert with your hand causes the object to bulge out.  This contraction and relaxation cycle moves the front edge of the plasmodium forward.

Here is a gif, adapted from “This Pulsating Slime Mold Comes in Peace (ft. It's Okay to Be Smart) | Deep Look” YouTube  video, of the cellular contents of the plasmodium sloshing back and forth:

make action GIFs like this at MakeaGif

The current within the cell can move in any direction, and changes based on the environment (3).  There are two stages to P. polycephalum movement.  The first is the searching phase, where the majority of the body mass is radiating outward in a fan shape in search of food (4). After the fan gets big enough, there is not enough body mass to cover the surface where the fan has been, so the organism creates veins.  Here is a snapshot from a video that shows four separate droplets of food where P. polycephalum is consuming the first and searching for more:

The veins create a network, which aids in movement and nutrient absorption. The network serves as communication channels between the body mass consuming the food drop and the body mass in search of new food.  Because there is limited protoplasm, most of the mass stays and consumes food, making absorption more efficient.  As the protoplasm searches, the network thins out, thickening veins that lead to new food sources by removing “legs” that lead to dead ends (3). The following snapshots from the same video show this in detail:

https://www.youtube.com/watch?v=mvBSkt6LhJE    

Once the protoplasm finds food, the organism enters the second stage of movement, called the feeding stage (4). Here, almost the entire body mass is moved to the location of the new food source, seen by it being covered completely with yellow slime.

https://www.youtube.com/watch?v=mvBSkt6LhJE   

When the food source runs out, the organism moves back to the searching stage, and fans out, creating veins until it finds its next meal:

https://www.youtube.com/watch?v=mvBSkt6LhJE   

The solution to the shortest path problem lies in the efficiency of the movement style.  As we saw, the protoplasm only leaves a few thick tubes between food sources. From hydrostatic theory, thicker tubes are more efficient than thin tubes at passing nutrients (3).  Think of it like this, if you needed to put out a house fire, you wouldn’t try to push water from a fire hydrant through a straw.  And along the same analogy, if you were putting out a house fire, you would use the fire hydrant that was closest, rather than running the fire hose down another block.  By having thick and short pipes, the organism solves the seemingly complex shortest path problem, simply by maximizing its efficiency.

So, now what?

We’ve learned about the algorithm that answers the question, what is the shortest distance between two places given a bunch of different paths?  And we’ve learned that life, compact in a slime mold, solves the exact same problem without storing tables of numbers.  Though the shortest path problem is an interesting intellectual endeavor for humans, the shortest path problem is life or death for this organism, and it seems to understand intuitively that the shortest path between two points maximizes its likelihood of surviving.  Because of this amazing feat, researchers study Physarum polycephalum to understand the fundamentals of what makes life, alive.

References

1.        Nakagaki T, Yamada H. 2000. Maze-solving by an amoeboid organism. Nature 407:470.

2.        Dijkstra EW. 1959. A note on two problems in connexion with graphs. Numerische Mathematik 1:269–271.

3.        Nakagaki T, Kobayashi R, Nishiura Y, Ueda T. 2004. Obtaining multiple separate food sources: behavioural intelligence in the Physarum plasmodium. Proceedings of the Royal Society B: Biological Sciences 271:2305–2310.

4.        Halvorsrud R, Giaever I, Feder J. 1997. Growth and Synchronization of Physarum Plasmodia on a Lattice of Disconnected Nutrient Drops. Biological Rhythm Research 28:358–364.