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Why can’t the immune system fight plague?


The plague, caused by the bacterium Yersinia pestis, is one of the deadliest infectious diseases in human history. Despite modern antibiotics and improved living conditions, plague still persists in certain parts of the world and causes isolated outbreaks. But why is our immune system so ineffective at clearing Y. pestis infections? In this article, we will examine the virulence factors and immune evasion mechanisms that enable the plague bacterium to overwhelm the immune defenses.

What is plague?

Plague is a zoonotic disease, meaning it originates in animals but can be transmitted to humans, typically by the bite of an infected flea. The bacterium Yersinia pestis is the causative agent of plague. Y. pestis evolved from the related but less virulent Yersinia pseudotuberculosis bacterium some 1500-20,000 years ago. There are three primary forms of plague infection:

  • Bubonic plague – The most common form, accounting for 80-95% of infections. Y. pestis is deposited in the skin from a fleabite, then travels via the lymphatic system to the nearest lymph node where it replicates rapidly. This causes the painful swelling of lymph nodes known as “buboes.” Bubonic plague has a mortality rate of 30-75% if left untreated.
  • Septicemic plague – Y. pestis replicates in the bloodstream directly, without establishing infection in lymph nodes first. Mortality rates approaching 100%.
  • Pneumonic plague – The most deadly form that arises when Y. pestis replicates in the lungs after inhalation of infectious droplets. Direct human-to-human transmission occurs through coughing. Untreated pneumonic plague is invariably fatal.

In the 14th century, the Black Death pandemic killed up to 60% of the European population in just a few years, demonstrating the devastating potential of plague. Modern outbreaks are rare but highlight our continued vulnerability.

How does Yersinia pestis evade and suppress the immune system?

Y. pestis employs an array of virulence factors and immune evasion strategies that enable it to effectively counteract multiple arms of the immune system.

Innate immune evasion

The innate immune system acts as the first line of defense against invading microbes. Key innate responses include:

  • Physical barrier defenses like skin that block entry of pathogens
  • Phagocytic cells (neutrophils, macrophages) that engulf and destroy bacteria
  • Inflammatory signaling molecules like cytokines that recruit immune cells to sites of infection

Y. pestis is able to circumvent many innate immune mechanisms:

  • It uses flea vectors to breach physical barrier defenses – fleas transmit Y. pestis when taking blood meals from mammalian hosts including humans.
  • Y. pestis produces a capsular antigen and biofilm that helps it evade phagocytosis.
  • The plasmid pYV in Y. pestis encodes a Type III secretion system that injects Yersinia outer proteins (Yops) into host immune cells. Yops act to inhibit phagocytosis and downregulate production of inflammatory cytokines.

By crippling these key innate responses, Y. pestis is able to establish infection and delay the recruitment of adaptive immune cells.

Suppression of adaptive immunity

While innate immunity acts immediately, the adaptive immune system takes 4-7 days to mount a tailored response mediated by lymphocytes like B cells and T cells. Yops delivered by the Type III secretion system also disable adaptive immunity:

  • YopH inhibits T cell signaling by blocking phosphorylation steps needed for T cell activation.
  • YopJ inhibits production of protective cytokines like interleukin-6 by macrophages and dendritic cells.

This suppresses the normal lymphocyte activation required to clear Y. pestis infections.

Disabling immune signaling

As infection progresses, Y. pestis also releases factors that directly destroy immune cells:

  • Pla protease degrades complement proteins C3 and C3b that mediate phagocytosis and inflammatory signaling.
  • Y. pestis produces the toxin pesticin that forms pores in neutrophil and macrophage cell membranes.

The combined action of Yops, Pla, and pesticin allows Y. pestis to paralyze most arms of the immune system – both innate and adaptive. This enables rapid proliferation and systemic dissemination.

Y. pestis proliferation and dissemination

Once initial immune defenses have been dampened, Y. pestis is free to replicate unchecked. The massive growth of bacteria leads to widespread tissue destruction and sepsis. Key aspects of Y. pestis proliferation include:

  • Rapid growth to high cell density at infection sites (lymph nodes, blood, lungs). Can exceed 109 bacteria/mL of blood in septicemic plague.
  • Biofilm formation protects clusters of Y. pestis from phagocytosis and antimicrobial peptides.
  • Expression of F1 capsular antigen inhibits phagocytosis.
  • Release of endotoxin (LPS) from lysed bacteria causes damaging inflammatory response.

As the bacterial load increases, Y. pestis spreads through the lymphatic system into the bloodstream and eventually colonizes distant organs. For plague pneumonia, inhalation of just 100-500 bacteria is enough to establish a lethal lung infection.

Septic shock and organ failure

The combined effects of massive bacterial growth, cytokine dysregulation, and tissue damage lead to septic shock and multi-organ failure:

  • Loss of vascular tone causes hypotension and poor circulation.
  • Widespread blood clotting further impairs blood flow, threatening limbs and vital organs.
  • Lung damage fills alveolar air spaces with fluid (ARDS), impairing gas exchange.
  • Kidney dysfunction leads to water/electrolyte imbalances.
  • Liver failure disrupts metabolism, blood clotting, and detoxification.
  • Hyperinflammation from endotoxin release causes tissue damage throughout the body.

Patients ultimately succumb to some combination of shock, hypoxia, and multiorgan dysfunction. Even with aggressive modern support, septic plague carries mortality over 10%.

Why are antibiotics not more effective?

While antibiotics can inactivate extracellular Y. pestis, several key factors limit their efficacy once an infection is established:

  • Rapid growth to high cell density overwhelms the bactericidal activity of antibiotics.
  • Intracellular localization – Y. pestis can survive inside phagocytes where most antibiotics cannot penetrate.
  • Biofilms physically block penetration of antibiotics into aggregated bacterial masses.
  • Antibiotic-tolerant persister cells represent a small subpopulation of bacteria that survive antibiotic exposure by entering a dormant state.

This “fractional killing” by antibiotics allows some Y. pestis to persist even after treatment. Additionally, widespread tissue damage and cytokines induced during infection progress even with antibiotic administration. So while antibiotics can save some patients, they have limited impact once irreversible shock and organ failure develop.

Could plague be treated with antivirulence drugs?

Antibiotics target essential bacterial processes, imposing selective pressure for resistance to emerge. An alternative strategy could be antivirulence drugs that selectively inhibit bacterial virulence factors like Yops without affecting growth. Potential benefits of antivirulence drugs for plague treatment include:

  • Disabling Yops may allow innate immune defenses to initially control infection prior to adaptive immunity activation.
  • Reducing immune system disruption could diminish system-wide inflammation and organ damage.
  • Not bactericidal, so impose less selective pressure for resistance to develop.

While promising in theory, antivirulence approaches face numerous challenges:

  • Difficulty developing drugs that safely inhibit virulence factors.
  • Rapid progression of Y. pestis infections provides a narrow window for treatment.
  • Would still require combination with antibiotics to fully clear bacteria.
  • Redundancy of Y. pestis virulence factors reduces likelihood of clinical success by targeting any single mechanism.

Despite these limitations, antivirulence approaches represent a promising area for continued research. Used alongside antibiotics and supportive care, they could potentially improve clinical outcomes during plague infection.

Vaccine challenges

A highly effective vaccine that induces sterilizing immunity would provide the ultimate solution for controlling plague. Unfortunately, several factors make plague vaccine development problematic:

  • Both antibody and cell-mediated immunity are required for protection, but difficult to optimally stimulate together.
  • Yops and capsular antigen inhibit immune responses to Y. pestis.
  • Extreme virulence makes testing vaccine efficacy in humans unfeasible.
  • Genetic variability between global Y. pestis strains complicates broad-range protection.

The FDA-approved killed whole-cell plague vaccine provides some protection but has significant limitations including short-lived immunity and frequent side effects. Next-generation plague vaccines based on protein subunits or live-attenuated strains may yet improve on this but have not proven superior in trials so far.

Conclusion

Despite our many advances in medicine and public health, plague remains almost as lethal today as in past centuries. The intrinsic virulence and immune evasion mechanisms of Yersinia pestis continue to thwart our immune defenses and treatment efforts. While antibiotics can offer a slim survival advantage if administered promptly, our inability to rapidly control Y. pestis growth before irreparable tissue damage occurs remains a key barrier to improving outcomes. The challenges of vaccine development and antivirulence drugs further highlight the evolutionary prowess of Y. pestis as a formidable foe of the human immune system. Continued research to unravel the elegant pathogenic strategies of this bacterium may one day enable us to finally consign plague to the history books. But for now, it remains among the deadliest of infectious diseases known to humanity.