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Why The Plague Is So Deadly, Still

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How the plague uses stealth tactics and friendly fire to kill.

plague, Yersinia pestis, pest, disease, deadly, outbreak, infection, pandemic, black death, inflammatory, immunce cells

Few infections are as notorious or as deadly as the plague. Three widespread pandemics in recorded history have been attributed to the plague, a disease caused by infection with the bacterium Yersinia pestis.

The impact of this single microorganism in shaping our collective past is almost incomprehensible from the safe distance of time – the last pandemic subsided in the early 20th century. The deadliest of the three pandemics – known as the Black Death – reached across Asia, Europe and Africa to wipe out up to a quarter of the World’s population in the 14th century and continued to wreak havoc throughout Europe well into the 17th century. So infamous is the plague that it has become simply the plague, laying claim to a word that once referred to all pandemic disease outbreaks.

It might not have caused a global pandemic in recent times, but the plague is certainly still with us. Small outbreaks in tropical regions where the bacterium is endemic occur on an almost yearly basis, and the threat of its use as a potential biological weapon looms in the minds of public health officials. Antibiotics have provided us with the weapons needed to stop an outbreak in its tracks, but without treatment, Y. pestis still kills close to 100% of people who become infected in as little as a day.

With such a formidable foe, it’s a wonder that we don’t know everything there is to know about how Y. pestis infects and kills its victims. A team of researchers led by William Goldman at the University of North Carolina have been filling in some of the gaps by investigating how the bacterium does its dirty work when it gets into the lungs.

Infections of Y. pestis can take a number of forms. In most cases of the plague during the Black Death, infections were contracted via flea bites and raged in enlarged lymph nodes called buboes – hence the term bubonic plague. But inhalation of the bacteria can lead to an even nastier form of the disease – pneumonic plague – which can be coughed and spluttered out for other hapless individuals to catch.

Goldman’s team used mice infected with Y. pestis through their noses to track the immune response to the infection. The researchers found that the infection occurred in two distinct phases.

During the first phase, the bacterium is in stealth mode. It takes up residence in the lung and starts multiplying without any response from the host’s immune system. This pre-inflammatory phase is followed by a pro-inflammatory phase during which the immune system kicks into overdrive, sending an army of immune cells to the site of infection.

To find out how Y. pestis is able to go undetected in the pre-inflammatory phase, Goldman and his team looked at which immune cells were being targeted during infection. When Y. pestis infects a host cell, it does so by injecting the cell with a protein called a Yersinia effector protein, or Yop. By using a strain of plague containing a hybrid Yop protein that can generate a fluorescent signal when a chemical catalyst is added, the researchers could easily identify which cells were being injected with Yop during infection.

During the pre-inflammatory phase, immune cells known as macrophages were the target. Macrophages are members of what’s known as the innate immune system, an arm of the immune system that responds in a non-specific way to bodily assaults. Macrophages are in the immune system’s first line of defence, engulfing and digesting things like bacterial intruders. By targeting the macrophages, Y. pestis is able to stay under the radar of the immune system as it builds its forces.

Twelve hours after infection, a dramatic switch in targets occurred. Instead of infecting macrophages, Y. pestis starts to infect neutrophils, another of the innate immune system’s foot soldiers.

The team then started modulating the types of immune cells produced by the mice to observe how this affected the progression of the plague infection. When neutrophils were limited, the progression of disease slowed, indicating that the plague’s lethality is primarily due to the action – or re-action – of the neutrophils when they come under attack from Y. pestis. Unfortunately, the defence is the host’s undoing: the storm of immune chemicals unleashed by the neutrophils results in widespread friendly-fire destruction of lung tissue.

Tempering this neutrophil response in combination with antibiotic therapy could improve the chances of surviving infection by expanding the very narrow time window between infection and irreparable tissue damage that leads to death.

Reference

Photo: Flickr, frank_to_artist

Source: Pechous RD, Sivaraman V, Price PA, Stasulli NM, & Goldman WE (2013). Early host cell targets of Yersinia pestis during primary pneumonic plague PLoS Pathogens DOI: 10.1371/journal.ppat.1003679

plague, Yersinia pestis, pest, disease, deadly, outbreak, infection, pandemic, black death, inflammatory, immunce cells

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