PLAGUE! 

 

Emily Berger and Michelle Krasny

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 An Introduction to our Article:

 

    Throughout history, several plagues have had a terrible impact on various populations in the world. In our article, we would like to address what it is about the specific pathogens of these plagues, including modes of infection, structural differences, and responses to the human immune system, that have made them so much more virulent than other pathogens in history. We plan on focusing on three different epidemics, starting with Yersinia pestis, the infectious agent that caused the Black Death starting in 1346 and lasting into the 19^th century (Achtman, Morelli, Zhu, Wirth, Diehl, Kusecek, Vogeler, Wagner, Allender, Easterday, Chenal-Francisque, Worsham, Thomson, Parkhill, Lindler, Carniel, and Kein, 2004). We would also like to investigate the epidemic of Spanish flu that affected a large population in 1918. If anyone has any other plagues they would be interested in reading about, such as the modern epidemic of tuberculosis, particularly drug-resistant strains. It has also been suggested that we look into other diseases like cholera, Spanish flue and Avian flu. We intend to research into other diseases for our next update.

 

Quick Profile of Y. pestis:

 

    Infection usually starts with an incubation period of 3-7 days followed “flu-like” symptoms  (sudden fever, chills, head and body aches, wekness, vomiting and nausea). There are 3 modes of infections, each which carries its own course of infection.

 

    Bubonic

• Most common

• Results from and infected flea’s bite

• Infection enters through the skin at the bite site and travels through the lymphatic system to the nearest lymph node.

• Lymph nodes become inflamed creating bubos – highly painful sores which can become suppurated as an open sore in the advanced stages of infection

 

    Septicemic

• Occurs when infection spreads through the blood stream without bubos

• May result from flea bite or direct contact with the pathogen through cracks in the skin

 

    Pneumonic

• Most virulent

• Least common

• Very high case-fatality ratio

• Sometimes due to a secondary spread from an advanced infection which started in the bubonic form

• Other times due to direct inhalation of aerosolized infective droplets (can be passed from person to person)

 

    Plague can be prevented by avoiding areas where plague is active, taking precautions against flea bites and be careful when handling carcass while in plague-endemic areas. Avoiding direct contact with infective tissues or exposure to patients with pneumonic plague also helps prevent infection. Plague is endemic to many countries in Africa, the former Soviet Union, the Americas and Asia. In 2003 9 countries reported 2118 cases resulting in 182 deaths. 98.7% of those cases were in Africa. Plague, if diagnosed rapidly and treated appropriately, isn’t necessarily fatal. In fact, through a combination of antibiotics and supportive therapy, most cases can be cured if diagnosed in time (http://www.who.int/mediacentre/factsheets/fs267/en/).

 

History for Y. pestis:

 

    The pathogen Yersinia pestis was responsable for both the Justinian Plague of the 6^th-8^th centuries and the more widely known Black Death of the 14^th-19^th centuries (Oyston, 2001). It was commonly thought that Y. pestis evolved just before the outbreak of the Justinian Plague, but due to more recent genomic evidence, it is now believed to have spread long before this time, originating in Asia (Achtman, et al, 2004). Even though the Bubonic Plague is generally thought to be a disease of the Middle Ages, anually 2,000 cases of plague are still reported(Cornelis, 2000).

 

Pathogenicity of Y. pestis:

 

    There are several aspects of the bacteria Yersinia pestis that make it so virulent in mammalian hosts. It has an impressive ability to overcome the natural defenses of the host’s immune system, the most fundamental of which is the ability to multiply at a rate faster than the defense system can handle. The pathogen is capable of much more intricate and varying methods of attack, however, each of which is enabled by Yop virulons. The Yop virulons first allow the extraceullar Y. pestis pathogens to dock at the surface of the host cell and inject the specialized yop proteins across the plasma membrane. These yops carry out a series of processes including disruption of cytoskelular dynamics and prevention of the production of pro-inflammatory cytokines. 29 Yop secretion genes (ysc) are known and 10 of these appear to be involved in the virulence mechanism (known as a type III secretion - a group of outer membrane proteins which is involved in the transport of various macromolecules and filamentous phages across the outer membrane). This type III secretion system is encoded on a pCD1 which in addition to 2 other virulence-associated plasmids, pPst and pFra, is what makes Y. pestis such a virulent and deadly form of Yersinia when compared with other more benign strains (Oyston, 2001).

    The Ysc's include YscC, YscJ, YscN, YscO, YscQ, YscR, YscS, YscT, YscU and YscV.  YscN is absolutely essential for Yop secretion, has ATP-binding motifs. As an interesting side note all these proteins are also involved in the assembly of the bacterial flagellum with the several of the proteins forming the most internal part of the basal body (the Ms ring, C ring and ATPase). So each Ysc secretes a yop, each of which has very specific functions.

    Yops E, H and T target the cytoskeleton. This damage to the host cell's cytoskeletons is what gives Y. pestis its strong resistance to phagocytosis by macrophages. Yop E targets the actin filaments, Yop H targets focal complexes (affects the anti-invasion effect) and Yop T exerts a dramatic depolymerizing effect on actin.

Yops P and J down-regulate the inflammatory response. Injection of Yops P and J have been shown to reduce the release of TNF-alpha by macrophages and to reduce the recruitment of neutrophils to the site of infection. There is also evidence that Yop P and J cause apoptosis in macrophages, although the mechanism by which they do this is not yet clear.

    In addition to inhibiting macrophage activity and down-regulating the inflammatory response, Yops also allow Y. pestis to damage the T and B-lymphocytes directly. T and B cells that have come in contact with the pathogen are impaired in their ability to be activated by means of their antigen receptors. T cells can't produce cytokines and B cell s can't up-regulate surface expression of the co-stimulatory molecule in response to antigenic stimulation. YopH appears to be the Yop which is most involved in the lymphocyte inhibition (Cornelis, 2000).

 

Vector for Y. pestis:

 

    In order for a disease to be considered a plague, it must be highly virulent and carry a high rate of mortality. There are several characteristics of pathogens that may contribute to their categorization as plagues. One important factor is the pathogen’s mode of infection. Yersinia pestis, commonly thought to be the causative agent of the Black Death, can typically be transmitted through two different pathways. The less common of these is what is referred to as pneumonic plague, which is transmitted when a person is exposed to the bacteria suspended in the respiratory droplets of an infected individual, e.g.,  the cough of an infected person. This form of the plague is also the most plausible bioterrorist threat, as aerosolized bacteria, if inhaled, would result in the pneumonic manifestation of the disease. The most common mode of transmission of Y. pestis is the bubonic form. This is characterized by swollen lymph nodes, referred as buboes, and is transmitted by infected materials entering a break in one’s skin. This most commonly occurs via the bite of an infected flea. Bubonic plague is not transmissible from person to person, however if left untreated the bacteria may spread to the lungs, resulting in pneumonic plague, which is contagious in the manner previously described (www.bt.cdc.gov/agent/plague/factsheet.asp, and Oyston, 2001).

 

    There are two possible explanations, not mutually exclusive, as to why an infected flea is such an efficient mode of transmission for Y. pestis. The more widely accepted theory involves the phenomenon of the blocked flea. After a flea bites an infected rodent and ingests contaminated blood, the bacteria quickly multiply until a block is formed in the flea’s proventriculus. This results in several changes that increase the flea’s efficiency of transmission. Due to the block, the blood ingested by the flea does not successfully reach the midgut. This causes the flea to feed more often than it normally would, in an attempt to keep from starving. With each feeding, the blood that was ingested previously, as well as part of the block containing the bacteria, is regurgitated, infecting the host. A single bit can transmit approximately 24,000 bacteria (Lewis, 2001).

 

    The other theory regarding flea transmission of plague bacilli is that of the unblocked flea. Some studies (Eisen, Bearden, Wilder, Montenieri, Antolin, and Gage, 2006) suggest that the blocked flea alone may not be sufficient to explain the transmission of Y. pestis. There is a relatively long period between pathogen acquisition and ability to transmit in fleas, as well as the issue of the flea’s death very soon after infection. This results in a relatively small window of infection. This secondary theory proposes that certain species of fleas may also transmit the pathogen successfully ether before a block is formed, or in species in which blocks do not form.

 

    After the bacteria enter the body, there is an incubation period of two to six days, after which they multiply extremely rapidly. Approximately eight hours after the onset of symptoms, including headache and fever, the buboes begin to form. When the bacteria release a toxin that causes a collapse of the circulatory system, the infected individual goes into shock, and if left untreated, will die shortly of organ failure.

 

Quick profile of Influenza:

 

    Influenza, or the flu, is a viral infection of the family Orthomyxoviridae. Most of us know what flu feels like, but just in case, it affects the nose, throat, bronchi and occasionally the lungs. First you get a sudden high fever  and aching muscles followed by headache, severe malaise, non-productive cough, sore throat and rhinitis. The virus is transmitted easily between people through droplets and small particles produced from coughs or sneezes. Symptoms last about a week or two, and persons usually recover without medical intervention. As with most illnesses, the very young and the elderly are at more risk for complications such as pneumonia, which can be fatal (http://www.who.int/topics/influenza/en/).

 

History and Origins of the Spanish Flu:

 

    The influenza pandemic of 1918-1919, known as the “Spanish flu”, was the most severe and catastrophic infectious disease outbreak in recorded history (Kobasa, et al, 2004). Approximately 50 million people worldwide died, including 20 million American– more than in all the wars of the 20th century combined (“Influenza 1918”). Because the disease was particularly fatal to those with the strongest immune systems, the mortality rate of the 20- to 40-yr-old age group peaked during these years, to approximately twenty times what it had been before (Taubenberger and Morens, 2006). Although there has been much research done, and there are many theories about the causes of the severity of this particular flu pandemic, much is still unknown about the virus.

    Attempts to pinpoint the geographic origin of the Spanish flu are made nearly impossible by the timeline of its occurrence. The first wave of disease was recorded in March of 1918, and spread nearly simultaneously, yet distinctly, in Europe, Asia, and North America over the next six months. The mortality rates in this first wave were low. The second wave occurred in the fall of 1918, and led to extremely increased mortality. The third wave occurred in many places in early 1919. Also difficult to determine is the animal origin of the virus. The 1918-1919 strain of the flu virus demonstrates similarities to avian-like flus, but records show the virus infected humans and swine nearly simultaneously. This makes difficult the determination that the avian form of the virus altered in swine hosts, and subsequently infected humans. It is generally accepted, however, that this highly virulent and fatal strain of flu was the result of antigenic drift. Because of this drift, the human immune system had not been previously exposed to this exact viral strain, and was therefore unprepared to combat it.

    Several factors may have contributed to the extremely elevated numbers of people infected with the 1918 virus. These include environmental conditions, such as temperature and humidity, as well as human conditions. Populations living in very close and crowded conditions, with imperfect sanitation and limited ventilation, as many millions of people were in this time period, are highly susceptible to flu epidemics.

 

Pathogenicity of Influenza:

 

Unlike the Y. pestis, Influenza becomes so virulent so quickly not because of some inherent structural ability of the pathogen to neutralize the host cell, but rather because of the inherent flexibility which allows the virus to annually trick our immune system. As we discussed in class, our immune system searches for the hemaglutinin (HA) and neuraminidase (NA) antigens which are part of the membrane of the Influenza virus. Antigenic drift and shift allow these two antigens to change drastically enough to defy identification by the antibodies our immune system has created.  RNA viruses, such as the flu, are extremely prone to random mutation, allowing for genetic drift (genetic drift explain annual epidemics). Influenza’s ability to infect multiple hosts, coupled with the 8-segmented genome, allow antigenic shift to occur (and create pandemics).

 

Treating or preventing the flu:

 

    Some may say that flu is a minor issue. Yearly epidemics only effect up to 20% of the population and the majority of sufferers can feel completely better after a few weeks of rest. On the other hand, influenza epidemics are responsible, on average, for 20,000 deaths per year in the U.S. and as many as 300,000 hospitalizations in a single flu season (Palese and Gacia-Sastre, 2002). Flu is currently treated with a yearly vaccine, containing a strain of inactivated influenza with an HA/NA combination that is predicted to be the most likely strain for that year. The success of these vaccines is largely dependent on the accuracy of that prediction. Vaccines prevent illness in approximately 70-80% of people under the age of 65. Antiviral agents, such as amantadine, rimantadine, zanamivir and oseltamivir (2 ion-channel M2 protein inhibitors and 2 NA inhibitors, respectively), can prevent the proper release of the flu virus particles from their cytoplasmic membranes. Widespread use of these drugs is limited by concern for possible side effects and trepidation about the possible emergence of drug-resistant strains. Should a new pandemic strain emerge, however, these drugs may come in handy (Palese and Gacia-Sastre, 2002).

 

    Future attempts at preventing flu may include cold-adapted influenza virus vaccines, where the strain is designed to be less virulent at body temperature. These vaccines have been tested effectively in Russia, but have yet to receive the necessary permits for testing in the U.S. Interestingly, because of newly developed abilities to engineer site-specific changes in the genomes of negative-strand RNA viruses, it is now possible to tailor-make strains with special properties that lead to attenuation. We could also design flu virus vaccines that undergo only a single cycle of replication, thus inducing a protective antibody response without allowing the replication of infectious virus. Pretty much the coolest futuristic possibility is DNA vaccination, in which plasmid DNA which encodes one or more of the influenza virus proteins can be injected or topically applied (Palese and Gacia-Sastre, 2002).

 

Conclusions:

 

    Sadly, we did not have the opportunity to explore more epidemic, pandemic and plague causing pathogens, as was our initial goal. However, what we have learned from the 2 pathogens we did focus on, Y. pestis and Influenza, is that there really is no one way to be an extremely virulent virus or bacteria. The necessary components seem to be flexibility, back-up systems and the ability to dodge or trick or manipulate the immune system. We would love to spend some more time examining different pathogens, and are particularly interested in whether there are differences in modes of virulence between bacterial and viral infectious microbes. However, due to time limitations, those questions will have to wait for another semester.

 

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References

1. Achtman, M.; Morelli, G.; Zhu, P.; Wirth, T.; Diehl, I.; Kusecek, B.; Vogler, A. J.; Wagner, D. M.; Allender, C. J.; Easterday, W. R.; Chenal-Francisque, V.; Worsham, P.; Thomson, N. R.; Parkhill, J.; Undler, L. E.; Carniel, E.; and Keim, P. "Microevolution and History of the Placue Bacillus, Yersinia Pestis." Microbiology 101.51 (2004): 17837.  

2. Cornelis, G. R. "Molecular and Cell Biology Aspects of Plague." Colloquium 97.16 (2000): 8778.

3. Darwyn Kobasa, Ayato Takada, Kyoko Shinya, Masato Hatta, Peter Halfmann, Steven Theriault, Hiroshi Suzuki, Hidekazu Nishimura, Keiko Mitamura, Norio Sugaya, Taichi Usui, Takeomi Murata, Yasuko Maeda, Shinji Watanabe, M. Suresh, Takashi Suzuki, Yasuo Suzuki, Heinz Feldmann and Yoshihiro Kawaoka. “Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus." Nature 431, 703-707(7 October 2004)

4. Jones, Esyllt W. “Co-operation in All Human Endeavour: Quarantine and Immigrant Disease Vectors in the 1918-1919 Influenza Pandemic in Winnipeg.” CBMH/BCHM. Volume 22:1 2005 / p. 57-82.

5. Kenner, Robert. “Influenza 1918.” PBS http://www.pbs.org/wgbh/amex/influenza/index.html

6. Lewis, Ricki. "Plague genome: the evolution of a pathogen: flexibility makes yersinia pestis adaptable to new pathways of transmission to humans." The Scientist 15.21 (Oct 29, 2001): p1(2) 

7. Oyston, P. "Plague Virulence." J. Med. Microbiol 50 (2001): 1015.

8. Palese, P., and A. Garcia-Sastre. "Influenza Vaccines: Present and Future." J. Clin. Invest. 110: 9.

9. “Plague: Prevention – CDC Division of Vector-Borne Infectious Diseases http://www.cdc.gov/ncidod/dvbid/plague/prevent.htm

10. Taubenberger, Jeffery K., and David M. Morens. "1918 influenza: the mother of all pandemics." Emerging Infectious Diseases 12.1 (Jan 2006): 15(8).

11. “WHO: Ten things you need to know about pandemic influenza”http://www.who.int/csr/disease/influenza/pandemic10things/en/

12. World Health Organization. <http://www.who.int/en/>.

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Comments & Questions

 

The following is a list of questions we've recieved since our last post, that we intend to answer shortly (for questioners names, please see the appropriate section).

 

General Plage Questions: 

    How does cholera function as a plague pathogen?

    What particular pathogenic traits make some diseases plagues and others not?

    When do plagues "end?"

 

Y. pestis specific Questions

    What's the course of treatment?

    Why is it less virulent now then in the past?

    Do people who get it now get it the same way as people in the past?

    Where does it still occur?

 

Yop specific Questions:

    Molecularly speaking, what are yops?

    How do they hamper the immune system? (How do they affect B and T cells?)

    Are Yops encoded on plasmids or chromosomally?

 

Flu Questions:

    How does Spanish flu funciton as a plague pathogen and is it at all like avian flue?

    How do plagues effect societies?

    Is there a bird Flu vaccine? Is their ENOUGH bird flu vaccine?