I though we’d shift gears today and cover a disease that has been catastrophic and historic: Yersinia Pestis a.k.a. “The Plague”. This article will explain why the bacteria Y. Pestis is so lethal in humans. It uses our own immune response to multiply and continue the infection, thereby continuing its life. I hope you enjoy this post which is a trimmed down version of a much longer research paper that I have been working on:
This essay’s main topic will be a discussion on how the human immune system functions in a period of active infection. For this paper, Yersinia Pestis will be the highlighted pathogen. Human Y. Pestis can take three main forms: pneumonic, septicemic, and bubonic.Y. Pestis is classified by the CDC as a Category A pathogen with a mortality rate of 50-90% if untreated; 15% when diagnosed and treated. A pathogen is defined as any disease-producing agent, especially a virus or bacterium or other microorganism. Category A Pathogens are high-priority agents that pose a risk to national security, can be easily transmitted and disseminated, result in high mortality, have potential major public health impact, may cause public panic, or require special action for public health preparedness.
Y. Pestis as Plague is transmitted to humans by fleas or by direct exposure to infected tissues or respiratory droplets; the disease is characterized by fever, chills, headache, malaise, prostration, and leukocytosis3. The infected flea bites the human, the bacteria is forced past the mechanical barrier of the skin and enters the tissue and then begins to collect in the lymphatic system without causing a protective immune response upon initial introduction into the system. The chemical barriers such as sweat, lysozymes, defensins, play little or no role in the prevention of infection by Y. Pestis. Y. Pestis annihilates the first line of defense in the human immune system well before a full immuno-response can be generated.
When Y. Pestis is first active in the human body, it produces a protease that clears the capillaries and lymphatic stem of clots and then move into the regional lymphatic system where they are attacked by macrophages.
The first cells to attack Y. Pestis are the macrophages, these cells, as their name suggests, engulf and then digest the pathogen and then present the pieces of the pathogen to the T and B cells for the secondary immune response. Y. Pestiss is unlike most other pathogens that invade humans, Y. Pestiss uses the phagocytes, especially the macrophages to multiply and become more deadly. When the macrophage comes in contact with Y. Pestis uses a type-III secretion pathway to inject “Yops” or Yersina Outer Membrane Proteins” which interfere with normal Macrophage action by directly suppressing T-lymphocyte activation which would eventually kill Y. Pestiss. also this pathway uses a protein that causes the affected cells to release 40 times the normal levels on interleukin 10 which will suppress the immune response.
The temperature inside the mammalian host (37C) signals Yersinia Pestis to produce an F1 antigen that becomes part of the anti-phagocytic capsule, it becomes encapsulated and ready for full pathogen activity; the carrier flea’s body temperature is 26C, which does not trigger encapsulation and therefore is not a pathogen in the flea itself. Yersinia Pestis has the ability to survive inside the macrophage and force that cell to aid in the bacterial reproduction inside the very cell that was sent to kill it. This pathogen multiplies inside the macrophage and then the macrophage dies, releasing more Yersinia Pestis that are now activated and encapsulated, express Yops, pilus adhesin, compliment resistance, and heme storage for energy.
These newly released and activated Y. Pestis then continue moving in the lymphatic system following the lymph flow from distal to proximal or form the infection site inward toward the main lymph system, . Y. Pestis rapidly moves through the afferent lymphatic vessels toward the collecting ducts and the draining lymph nodes. Once in the subscapular sinus of the node, the bacteria rapidly multiply and spread through the node. This is the cause of the painful Buboles in Bubonic Plague. These Buboles contain extensive amounts of extracellular Y. Pestis, hemorrhage and fibrin, and necrotic lymph tissue. “Without early antibiotic treatment, bubonic plague usually progresses rapidly to septicemic plague, a form of the disease characterized by bacteremia, systemic spread, and life-threatening Gram-negative sepsis. Hematogenous spread to the lungs can also result in pneumonic plague.”
At this point he Spleen’s Red Pulp, which is the site of mechanical filtration of red blood cells and the reserve of monocytes, is filtering infected and dead macrophages, neutrophils, and dendridic cells. The B-Cells in the spleen, that reside in the White Pulp, have not been fully activated because the macrophages have not brought back enough material from digested Y. Pestis for a secondary immune response. The T-Cells in the Thymus at this point are not yet mature and ready to attack the pathogen. Yersinia Pestis as Bubonic Plague has a 50-80% mortality rate if left untreated, untreated Pneumonic Plague is always almost fatal. “Early antibiotic therapy is recommended for persons deemed exposed to or infected with plague. Tetracyclines (e.g. doxycycline), fluoroquinolones (e.g., ciprofloxacin), and aminoglycosides (e.g., streptomycin, although not widely available, and gentamicin) are all antibiotics that have been used for treatment of plague.”
Once antibiotics are administered and begin to take effect in disrupting the cell wall protein production or DNA replication, or in the event that the infected person survives the first few days, the immune system can begin to respond to the infection with T and B cells. The antibiotics aid the immune system by destroying the bacteria outright. The immune system in the rare patient that has survived beyond the normal fatal period of a Y. Pestis infection without antibiotic treatment can fight back following a normal infection/immune-response pattern of primary/humoral response: Eventually, one of the bacteria cells will be met by a B-Cell that can effectively act on the bacteria, the bacteria may be weak or effected by the antibiotic, or it is a week into the infections and ht B-Cells are now active, regardless, what needs to occur is that the B-cells , which are matured in the bone marrow, and activated by a Th Cell (which mature in the Thymus), responds to extra cellular antigens/pathogens by proliferating and then differentiating into plasma cells that function as production sites for Y-Shaped proteins known as antibodies. These antibodies then bind to the pathogens at the external protein binding sites of the bacteria. This binding of antigens has the effect of blocking the entrance of the bacteria into a host cell, thereby preventing reproduction and encouraging phagocytosis. In short, the Th Cell checks the antigen as friend or foe, notifies the B-Cell to multiply and that the cell in question is an pathogen, and the B-Cell differentiate into plasma cells and they mark the pathogen for destruction with antibodies.
This above step that creates Humoral Immunity, or immunity and immune action outside of host cells. Innate, or immunity against pathogens that are already inside a host cell also depends on Helper T-Cells. In this case a pathogen is already inside a host cell and have left protein markers on the outside of that cell. A Dendridic cell activates Helper T-cells that then activate macrophages that engulf the specific anitgen that is already recognized as a threat by the dendritic cell. That dendritic cell also activates Cytotoxic T cells that, with the stimulation from Th Cells activate Tc (cytotoxix) cells that induces apoptosis in the infected host cell.
The B-Cells that have manufactured a given antibody now remain in the circulation for life, thereby granting almost life-long immunity in case of a re-occurrence of that pathogen in the system. The B-cells that are descendents of the activated B-Cells that have produced antibodies are then referred to as Memory B-Cells. These cells are very long lived and provide the memory of what antibodies to produce when a similar infectious agent is present again.
Immunity, infection, and exposure to a given pathogen will be often apparent in blood tests where certain types of Immunoglobulin are present in the test. These Immunoglobulin (Ig A/D/G/D/M) gamma globulin protein types are specific to the pathogen and act as markers for past/present infection or immunity depending on the disease and are produced by the plasma cells that come from the Acitvated B-cells. Generally, in the primary response, IgG and IgM are low, then the second time the antigen is present the IgG levels spike rapidly in response from memory to the antigen. Antibodies clearly contribute to defense against Y. Pestis but the mechanisms by which they do so in vivo remain to be established. It is accepted that the determination of efficacy of the humoral phase of immunity is based on the concentration of antibodies. However, the state of immunity against the plague is not determined by the blood concentration of the antibody. What appears to be the determinant factor is the availability of the anti-bodies the the regional lymph nodes. “ It is indeed significant that the immunity afforded by a virulent infection is greater than that conferred by vaccination with different avirulent strains, which in turn is more permanent than that produced by plague prophylactics consisting of antigens. Whether an infection in an immune animal stimulates the physiologic activity of the histiocytes and their related cells to produce antibodies more rapidly and more effectively than the susceptible animal has not as yet been determined. It is not unlikely that the immune state is further conditioned by an increased phagocytic capacity of the microphages and macrophages.”
The main reason Y. Pestis is so deadly is that it takes the human body up to 8-10 days to mobilize the T and B cells to fight the bacteria. By that time the host is most likely dead from septicemic or pneumonic plague. This bacteria shows us how the innate immune system works with macrophages, neutrophils, and dendritic cells, as well as how the adaptive immune system with the B and T cells functions. The adaptive system is much slower but far more powerful and specific.–Coldwarrior24JULY2010.
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