(
Xenopsylla cheopis) infected with the
Y. pestis bacterium, which appears as a dark mass in the gut: The foregut (
proventriculus) of this flea is blocked by a
Y. pestis biofilm; when the flea attempts to feed on an uninfected
host,
Y. pestis is regurgitated into the wound, causing infection. In the urban and sylvatic (forest) cycles of
Y. pestis, most of the spreading occurs between
rodents and fleas. In the sylvatic cycle, the rodent is wild, but in the urban cycle, the rodent is primarily the
brown rat (
Rattus norvegicus). In addition,
Y. pestis can spread from the urban environment and back. Transmission to humans is usually through the bite of infected fleas. If the disease has progressed to the pneumonic form, humans can spread the bacterium to others through airborne respiratory droplets; others who catch plague this way will mostly contract the pneumonic form themselves.
Mammals as hosts Several species of rodents serve as the main reservoir for
Y. pestis in the environment. In the
steppes, the
natural reservoir is believed to be principally the
marmot. In the western United States, several species of rodents are thought to maintain
Y. pestis. Several species of rodents are known to have a variable resistance, which could lead to an
asymptomatic carrier status. Evidence indicates fleas from other mammals have a role in human plague outbreaks. The lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog (
Cynomys ludovicianus), in which plague can cause colony collapse, resulting in a massive effect on prairie food webs. However, the transmission dynamics within prairie dogs do not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important, instead. The CO92 strain was isolated from a patient who died from pneumonia and who contracted the infection from an infected cat.
Fleas as vector The transmission of
Y. pestis by fleas is well characterized, with over 125 species of flea capable of transmitting
Y. pestis. While in the insect vector, proteins encoded by hemin storage system genetic loci induce
biofilm formation in the
proventriculus, a valve connecting the
midgut to the
esophagus. The presence of this biofilm seems likely to be required for stable infection of the flea. Aggregation in the biofilm inhibits feeding, as a mass of clotted blood and bacteria forms (referred to as "Bacot's block" after entomologist
A.W. Bacot, the first to describe this phenomenon).
In humans and other susceptible hosts Pathogenesis due to
Y. pestis infection of mammalian hosts is due to several factors, including the ability of these bacteria to suppress and avoid normal
immune system responses such as
phagocytosis and
antibody production. Flea bites allow for the bacteria to pass the skin barrier.
Y. pestis expresses a
plasmin activator that is an important virulence factor for pneumonic plague and that might degrade blood clots to facilitate systemic invasion. Many of the bacteria's
virulence factors are antiphagocytic. Two important antiphagocytic
antigens, named F1 (fraction 1) and V or
LcrV, are both important for
virulence. In addition, the type-III secretion system (T3SS) allows
Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins, called
Yersinia outer proteins (Yops), 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 by T3SS into the pore created in part by YopB and YopD. The injected Yops limit phagocytosis and cell signaling pathways important in the
innate immune system, as discussed below. In addition, some
Y. pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some
cytokines).
Y. pestis proliferates inside
lymph nodes, where it can avoid destruction by cells of the immune system such as
macrophages. The ability of
Y. pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause
lymphadenopathy. YopH is a
protein tyrosine phosphatase that contributes to the ability of
Y. pestis to evade immune system cells. In macrophages, YopH has been shown to
dephosphorylate 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 is a
cysteine protease that inhibits
RhoA by removing the
isoprenyl group, which is important for localizing the protein to the
cell membrane. YopE and YopT have been proposed to 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 and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses. YopJ is an
acetyltransferase that binds to a conserved
α-helix of
MAPK kinases. YopJ acetylates MAPK kinases at
serines and
threonines that 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, and this is proposed to be important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as
Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis. It has also been suggested that a
bacteriophage – Ypφ – may have been responsible for increasing the virulence of this organism. Depending on which form of the plague infects the individual, the plague develops a different illness; however, the plague overall affects the host cell's ability to communicate with the immune system, hindering the body's ability to bring phagocytic cells to the area of infection.
Y. pestis is a versatile killer. In addition to rodents and humans, it is known to have killed camels, chickens, and pigs. Domestic dogs and cats are susceptible to plague, as well, but cats are more likely to develop illness when infected. In either case, the symptoms are similar to those experienced by humans and can be deadly to the animal. People can be exposed by coming into contact with an infected animal (dead or alive), or inhaling infectious droplets that a sick dog or cat has coughed into the air.
Immunity A
formalin-inactivated
vaccine was available in the United States in 1993 for adults at high risk of contracting the plague until removal from the market by the
Food and Drug Administration. It was of limited effectiveness and could cause severe
inflammation. Experiments with
genetic engineering of a vaccine based on F1 and V antigens are underway and show promise. However, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable such that vaccines composed of these antigens may not be fully protective. The
United States Army Medical Research Institute of Infectious Diseases has found that an experimental F1/V antigen-based vaccine protects
crab-eating macaques but fails to protect
African green monkey species. A systematic review by the
Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine. ==Isolation and identification==