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

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).

Pathogenesis

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

Bubonic plague

The most frequent type of plague.
Commonly occurs within 2 to 6 days, after a fleabite. The fleabite allows for the bacteria to pass the skin barrier.
On the inoculation site there may be an ulcer, papule, vesicle or eschar.
Local cutaneous proliferation, usually not clinically evident, occurs after inoculation.
Y. pestis can reproduce inside cells, so even if phagocytosed, they can still survive.Plague bacteria secrete several toxins, one of which is known to cause dangerous beta-adrenergic blockade.
The infection spreads via the lymphatics to the regional lymph nodes causing inflammation and swelling in one or several nodes. This will cause regional lymphadenopathy and abscesses., often called buboes. Buboes may occur in any regional lymph node sites including:^[2]

Inguinal
Axillary
Supraclavicular
Cervical
Post-auricular
Epitrochlear
Popliteal
Pharyngeal

Deeper nodes (intra-abdominal or intrathoracic) may be involved by lymphatic or hematogenous extension.^[2]
Some virulence factors, allow Y. pestis to avoid phagocytosis by the host's immune system.^[1]

In the lymph nodes, Yersinia replicates and forms aggregates of bacteria in necrotic lesions. This leads to the destruction of the lymph node, and consequently to the spread of bacteria through the bloodstream, causing endotoxemia, bacteremia and septicemia.^[1]

Pulmonic Plague

Results from the inhalation of droplets infected with Y. pestis. The bacteria initially infect the oropharynx through respiratory droplets, expelled during coughing or sneezing by a patient (or animal) with pulmonic plague, or by ingestion of undercooked or raw tissues of an infected animal.^[1]
The incubation period is usually 1-3 days.^[1]
Yersinia pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague, and that might degrade on blood clots to facilitate systematic invasion.^[3]
Most severe type of plague, commonly leading to death with 24 hours of illness onset.^[1]^[4]^[5]^[6]

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

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

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

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:

F1 antigen

Antiphagocytic factor
Target of immunologic tests for diagnosis
Initiates humoral response

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 - Protein tyrosine phosphatase that contributes to the ability of Yersinia pestis to evade the immune system.^[9] 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.^[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.

YopJ - Acetyltransferase that binds to a conserved α-helix of MAPK kinases.^[11]

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.

YopO - Protein kinase, also known as Yersinia protein kinase A (YpkA), is a potent inducer of human macrophage apoptosis.^[15]

Genetics

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

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.

File:Scanning Electron Micrograph of a Flea.jpg

Xenopsylla cheopis primary vector of Bubonic plague

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]

Aggregations of bacteria in lymphoid tissues, and lungs (cases of pneumonic plague).
Lymph node necrosupporative inflammation.
Identification of the bacteria in infected sites.
Individuals infected orally have more lesions on head and neck lymph nodes.

Gallery

Diagram depicts the modalities of transfer between various hosts of Yersinia pestis bacteria. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[19]

Gross Pathology

Necropsy of a rock squirrel, Spermophilus variegatus afflicted with the pneumonic hemorrhagic plague. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[19]
Necropsy of a rock squirrel, Spermophilus variegatus, exposure of the animal’s abdominal viscera revealed the presence of a massive hemorrhagic reaction, due to a Yersinia pestis infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[19]
Necropsy of a rock squirrel revealed presence of a massive hemorrhagic reaction, due to a Yersinia pestis infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[19]
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.^[19]
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.^[19]