Yersinia pestis infection pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editors-In-Chief: Esther Lee, M.A.; Rim Halaby, M.D. [2]; João André Alves Silva, M.D. [3]

Overview

Plague can be transmitted from flea bites or the inhalation of aerosol from an individual who has plague pneumonia. Pathogenesis due to the Yersinia pestis infection of mammalian hosts, results from several factors including the bacteria's avoidance of normal immune system responses, such as phagocytosis and antibody production.

Pathogenesis

According to the way of infection, the plague may be divided in:

Bubonic plague

• The most frequent type of plague.
• Commonly occurs within 2 to 6 days, after a fleabite.
• On the inoculation site there may be aa ulcer, papule, vesicle or eschar.
• Local cutaneous proliferation, not usually clinically evident, ensues following inoculation . The infection spreads via the lymphatics to the regional lymph nodes causing inflammation and swelling in one or several nodes (buboes). Buboes may occur in any regional lymph node sites including inguinal, axillary, supraclavicular, cervical, post-auricular, epitrochlear, popliteal or pharyngeal. Deeper nodes (such as intrabdominal or intrathoracic nodes) may also be involved through lymphatic or hematogenous extension. Yersinia pestis proliferates inside lymph nodes where it is able to avoid destruction by cells of the immune system such as macrophages.

Septicemic plague

• Presence of rapidly replicating gram-negative bacilli in the bloodstream initiates a self-perpetuating immunological cascade typically linked to host response to severe injury, in this case the agent inciting injury is bacterial endotoxin. The host response may result in a wide spectrum of pathological events including disseminated intravascular coagulopathy (DIC), multiple organ failure, and adult respiratory distress syndrome (ARDS).

Pulmonic Plague

• Yersinia pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots in order to facilitate systematic invasion.

• Plague pharyngitis results from contamination of the oropharynx with Y. pestis-infected material from respiratory droplets expelled during coughing by a patient (or animal) with a respiratory plague infection, or ingestion of undercooked or raw tissues of an infected animal.

Meningeal plague

• A complication, often associated with delayed or inappropriate bacteriostatic antibiotic therapy.
• More common in patients with axillary (as opposed to inguinal) buboes.

Infection by Yersinia pestis occurs after the inoculation of the organism into the skin, usually by a fleabite. The fleabite allows for the bacteria to pass the skin barrier.

Once in the body, the bacteria migrates to the regional lymph nodes, migrating through the lymphatics. This will cause regional lymphadenopathy and abscesses. These are often called "buboes".

Due to some of its virulence factors, Y. pestis will be able to avoid phagocytosis by the host's immune system.

In the lymph nodes, Yersinia will replicate and form aggregates of bacteria in necrotic lesions. This will lead to the destruction of the lymph node, which will lead to the spread of bacteria through the bloodstream, causing endotoxemia, bacteremia and septicemia.

Virulence Factors

Yersinia pestis produces several risk factors that allow it to evade the host's immune system and cause infection. These virulence factors include:

Phospholipase D

• Survival inside the flea

V antigen and W antigen

• Phagocytosis resistance

Low-calcium-response plasmid

• Activation of Yersinia pestis outer proteins
• Activation of the V-antigen (low calcium environments)

Hemin storage system

• Pigmentation marker in laboratory
• Survival inside phagocytes
• Stimulates uptake of bacteria by eukaryotic cells

Plasminogen activator

• Degradation of extracellular proteins, such as fibrin, thereby facilitating bacterial spread

Lipopolysaccharide endotoxin

• Responsible for endotoxic shock

Yersinia outer proteins (Yops)

• Inhibitor of:

• Platelet aggregation
• Phagocytosis
• Inflammatory response

F1 antigen

• Antiphagocytic factor
• Target of immunologic] tests for diagnosis
• Initiates humoral response

Adherence and Invasion of Epithelial Cells

Yersinia pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.

Evasion of the Immune System

Anti-phagocytic Antigens

Many of the bacteria's virulence factors are anti-phagocytic in nature. Two important antiphagocytic antigens, named F1 (Fraction 1) and V or LcrV, are both important for virulence. These antigens are produced by the bacterium at normal human body temperature. Furthermore, Yersinia pestis survives and produces F1 and V antigens while it is residing within white blood cells such as monocytes, but not in neutrophils. Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.

Type III Secretion System (T3SS)

The Type III secretion system (T3SS) allows Yersinia pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins are called Yops (Yersinia Outer Proteins) and include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis.

The YopO, YopH, YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells via T3SS, into the pore created in part by YopB and YopD.

The injected Yop proteins limit phagocytosis and [[cell signaling] pathways]] important in the innate immune system. In addition, some Yersinia pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines).

Yersinia Outer Proteins

• YopH - Protein tyrosine phosphatase that contributes to the ability of Yersinia pestis to evade the immune system. In macrophages, YopH dephosphorylates p130Cas, Fyb (Fyn binding protein) SKAP-HOM and Pyk, a tyrosine kinase homologous to FAK.

YopH also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.

• YopE - Functions as a GTPase activating protein for members of the Rho family of GTPases such as RAC1.

• YopT - Cysteine protease that inhibits RhoA by removing the isoprenyl group. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis. This might limit the function of YopB/D to create the pores used for Yop insertion into host cells. It may also prevent YopB/D-induced rupture of host cells, and the release of cell contents that would attract and stimulate immune system responses.

• YopJ - Acetyltransferase that binds to a conserved α-helix of MAPK kinases.

Responsible for acetylation of MAPK at serines and threonine groups, which are normally phosphorylated during activation of the MAP kinase cascade. YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid (IP6). This disruption of host cell protein kinase activity causes apoptosis of macrophages.

This mechanism has been proposed to play a role in the establishment of infection, and evasion of the host immune response, by the bacteria.

• YopO - Protein kinase, also known as Yersinia protein kinase A (YpkA), is a potent inducer of human macrophage apoptosis.

Transmission

Transmission of Y. pestis to an uninfected individual is possible by any of the following means.

• Droplet contact – coughing or sneezing on another person
• Direct physical contact – touching an infected person, including sexual contact
• Indirect contact – usually by touching soil contamination or a contaminated surface
• Airborne transmission – if the microorganism can remain in the air for long periods
• Fecal-oral transmission – usually from contaminated food or water sources
• Vector borne transmission – carried by insects or other animals

Pneumonic plague can be transmitted from person to person; bubonic plague cannot. Pneumonic plague affects the lungs and is transmitted when a person breathes in Y. pestis particles in the air. Bubonic plague is transmitted through the bite of an infected flea or exposure to infected material through a break in the skin.

Flea Bites

Plague bacteria are most often transmitted by the bite of an infected flea. During plague epizootics, many rodents die, causing hungry fleas to seek other sources of blood. People and animals that visit places where rodents have recently died from plague are at risk of being infected from flea bites. Dogs and cats may also bring plague-infected fleas into the home. Flea bite exposure may result in primary bubonic plague or septicemic plague.

This way of transmission distinguishes Yersinia pestis from other enterobacteriaceae such as Yersinia pseudotuberculosis.

Contact with Contaminated Fluid or Tissue

Humans can become infected when handling tissue or body fluids of a plague-infected animal. For example, a hunter skinning a rabbit or other infected animal without using proper precautions could become infected with plague bacteria. This form of exposure most commonly results in bubonic plague or septicemic plague.

Infectious Droplets

When a person has plague pneumonia, they may cough droplets containing the plague bacteria into air. If these bacteria-containing droplets are breathed in by another person they can cause pneumonic plague. Typically this requires direct and close contact with the person with pneumonic plague. Transmission of these droplets is the only way that plague can spread between people. This type of spread has not been documented in the United States since 1924, but still occurs with some frequency in developing countries. Cats are particularly susceptible to plague, and can be infected by eating infected rodents. Sick cats pose a risk of transmitting infectious plague droplets to their owners or to veterinarians. Several cases of human plague have occurred in the United States in recent decades as a result of contact with infected cats.

Gallery

Gross Pathology

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  Necropsy of a rock squirrel, Spermophilus variegatus, formerly known as Citellus variegatus, which was afflicted with the pneumonic hemorrhagic plague. Note the presence of hemorrhagic blood that had been expelled from the animal’s nares, which had been the result of pulmonic hemorrhage. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, which was due to a Yersinia pestis infection, the bacteria responsible for causing plague Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

Microscopic Pathology

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  Photomicrograph depicts a blood smear that revealed the presence of Gram-negative Yersinia pestis plague bacteria Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 500X, this hematoxylin and eosin-stained (H&E) lung tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low magnification of 125X, this hematoxylin and eosin-stained lung tissue sample revealed the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  High magnification of 1200X, this Brown and Brenn-stained lung tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 500X, this hematoxylin and eosin-stained splenic tissue sample revealing the histopathologic changes indicative of what was diagnosed as a case of fatal human plague from the country of Nepal Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Photomicrograph depicting the histopathologic changes in lung tissue in a case of fatal human plague pneumonia; Mag. 160X Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Photomicrograph depicting the histopathologic changes in splenic tissue in a case of fatal human plague; Mag. 400X Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Micrograph of a blood smear containing Yersinia pestis plague bacteria.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Photomicrograph of lung tissue revealing Yersinia pestis organisms Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Yersinia pestis, Gram-negative bacillus, 1000x Magnification Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Yersinia pestis, Gram-negative bacillus Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Yersinia pestis, Gram-negative bacillus, 1000x Magnification Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of lymph node in fatal human plague Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of pancreas in fatal human plague Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of lung in fatal human plagueAdapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of lung in a case of fatal human plague pneumonia.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low magnification of 96X, this hematoxylin-eosin stained (H&E) photomicrograph revealing some of the histopathologic changes seen in a lymph node tissue sample in a case of fatal human plague. Note the medullary necrosis accompanied by fluid due to the presence of Yersinia pestis bacteria Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of lymph node in fatal human plague. Focal cortical necrosis. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of liver in fatal human plague. Focal hepatocellular necrosis adjacent to thrombosis. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of liver in fatal human plague. Necrosis and thrombosis of portal vein. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of lung in fatal human plague. Area of marked fibrinopurulent pneumonia Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of spleen in fatal human plague. Necrosis and Yersinia pestis Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  At a relatively-low magnification of 160X, this hematoxylin and eosin-stained splenic tissue sample revealed the histopathologic changes indicative of vasculitis and thrombosis associated with what was diagnosed as a case of fatal human plague Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

References

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