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]


The route of infection (fleabite or aerosolized particles) classifies plague into: bubonic, pulmonic or septicemic. Yersinia pestis produces several virulence factors which are responsible for: evasion of the immune system, survival of the bacteria inside host cells, and infectious mechanisms, such as: degradation of extracellular proteins, production of endotoxins and inhibition of platelet aggregation. Y. pestis aggregates in different tissues, causing inflammation and necrosis, that are responsible for some of the clinical findings of plague: lymphadenopathy and abscesses (bubonic); bacteremia and sepsis (septicemic) and pneumonia and ARDS (pulmonic).


According to the route of infection, the plague may be divided into:[1]

Bubonic plague

Pulmonic Plague

Septicemic plague

  • May be classified in primary or secondary septicemic plague:[1]
  • Primary Septicemic Plague:
Cutaneous exposure to the bacteria, without lymphadenopathy, followed by systemic bacteremia.
Althought it affects all age groups, elderly are more commonly affected.
  • Secondary Septicemic Plague:
Bacterial spread, from an initial focus of infection, such as the skin (bubonic plague) or the lungs (pulmonic plague).
Simillar clinical presentation to other gram-negative septicemias.
  • Presence of rapidly replicating gram-negative bacilli in the bloodstream typically linked to the host response to the bacterial endotoxin.
  • Bacterial endotoxins cause disseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischaemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/haemoptysis (coughing up or vomiting of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the center.
  • 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).Untreated, septicemic plague is usually fatal.

Meningeal plague

Virulence Factors

Yersinia pestis produces several virulence factors that allow it to evade the host's immune system and cause infection. These virulence factors include:[1]

Phospholipase D

  • Survival inside the flea

V antigen and W antigen

Low-calcium-response plasmid

Hemin storage system

Plasminogen activator

Lipopolysaccharide endotoxin

Yersinia outer proteins (Yops)

  • Inhibitor of:

F1 antigen

Evasion of the Immune System

Anti-phagocytic Antigens

Many of the bacteria's virulence factors are antiphagocytic in nature. Two important antiphagocytic antigens, named F1 (Fraction 1) and V or LcrV, are important for the virulence. These antigens are produced by the bacteria 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.[7]

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.[8]

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 also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.
  • 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.[10] 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.
Responsible for acetylation of MAPK at serines and threonine groups, which are normally phosphorylated during activation of the MAP kinase cascade.[12][13] YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid (IP6).[14] 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.


Yersinia pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.[16]


Transmission of Y. pestis may occur through:[17]

  • 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

Unlike other types of plague, the pneumonic type can be transmitted from person to person. 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.

Bubonic plague is mainly a disease in rodents and fleas (Xenopsylla cheopis). Infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to begin to starve. The flea then voraciously bites a host and continues to feed, even though it cannot quell its hunger, and consequently the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new victim, and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents, or a rise in the rodent population.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.[1]

In 1894, two bacteriologists, Alexandre Yersin of France and Shibasaburo Kitasato of Japan, independently isolated the bacterium in Hong Kong responsible for the Third Pandemic. Though both investigators reported their findings, a series of confusing and contradictory statements by Kitasato eventually led to the acceptance of Yersin as the primary discoverer of the organism. Yersin named it Pasteurella pestis in honor of the Pasteur Institute, where he worked, but in 1967 it was moved to a new genus, renamed Yersinia pestis in honor of Yersin. Yersin also noted that rats were affected by plague not only during plague epidemics but also often preceding such epidemics in humans, and that plague was regarded by many locals as a disease of rats: villagers in China and India asserted that, when large numbers of rats were found dead, plague outbreaks in people soon followed.

In 1898, the French scientist Paul-Louis Simond (who had also come to China to battle the Third Pandemic) established the rat-flea vector that drives the disease. He had noted that persons who became ill did not have to be in close contact with each other to acquire the disease. In Yunnan, China, inhabitants would flee from their homes as soon as they saw dead rats, and on the island of Formosa (Taiwan), residents considered handling dead rats a risk for developing plague. These observations led him to suspect that the flea might be an intermediary factor in the transmission of plague, since people acquired plague only if they were in contact with recently dead rats, but not affected if they touched rats that had been dead for more than 24 hours. In a now classic experiment, Simond demonstrated how a healthy rat died of plague after infected fleas had jumped to it from a plague-dead rat.

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.

Gross Pathology

Bubonic Plague

Common presentation includes a skin lesion that may be a papule, vesicle, ulcer or eschar on the site of the bite, and enlarged regional lymph nodes. The "buboes" may measure from 1 to 10 cm. There may also be deeper enlarged lymph nodes.[1]

Pulmonic Plague

Commonly occurs with pulmonary lobe involvement, progressing into bilateral pneumonia, pleurisy, cavitations, potentially culminating in ARDS.[1]

Septicemic Plague

This type of plague commonly leads to small vessel thrombosis, which is responsible for the necrosis of extremities, such as fingers, toes and tip of the nose. These manifestations may occur in advanced stages of the disease.[1]

Microscopic Pathology

Studies in Y. pestis-infected cats revealed similar histological changes to those verified in humans. Common microscopic findings include:[18]


Gross Pathology

Microscopic Pathology


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