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Sepsis is one of the costliest medical conditions in the world – new research clarifies how it can lead to cell death

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Les bactéries (grappes de rose clair, entourées de plus grosses cellules sanguines magenta) peuvent provoquer des infections mortelles, mais des réponses immunitaires trop réactives peuvent porter le coup fatal.  <a href=” src=”https://s.yimg.com/ny/api/res/1.2/tMshXoju3Y1Ha3ZGLeOxhg–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTQzMA–/https://media.zenfs.com/en/the_conversation_us_articles_815/98b59037ceb928631c49scebc7=data” “https://s.yimg.com/ny/api/res/1.2/tMshXoju3Y1Ha3ZGLeOxhg–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTQzMA–/https://media.zenfs.com/en/the_conversation_us_articles_815/98b59037ceb9285bc1c4696e376/”>
Bacteria (clusters of light pink, surrounded by larger magenta blood cells) can cause deadly infections, but over-reactive immune responses can deliver the killing blow. Scharvik/iStock via Getty Images Plus

Sepsis is a life-threatening condition resulting from the body’s overreaction to an infection, causing it to injure its own tissues and organs. The first known reference to “sepsis” dates back to over 2,700 yearswhen the Greek poet Homer used it as a derivative of the word “sepo”, which means “I rot”.

Despite dramatic improvements in the understanding of the immunological mechanisms underlying sepsis, it remains a major medical concern 750,000 people in the United States and nearly 50 million people worldwide every year. Sepsis accounted for 11 million dead worldwide in 2017, and is the most expensive medical condition in the United States, which costs more than tens of billions of dollars annually.

We are researchers who studied how certain types of bacteria interact with cells during infections. We wanted to understand exactly how an overactive immune response can lead to harmful and even deadly effects like sepsis. In our recently published researchwe have discovered the cells and molecules that can trigger death from sepsis.

TNF in autoimmunity and sepsis

The body’s response to infection begins when immune cells recognize the components of the invading pathogen. These cells then release molecules like cytokines that help eliminate the infection. Cytokines are a large group of small proteins that recruit other immune cells to the site of infection or injury.

While cytokines play an essential role in the immune response, excessive and uncontrolled production of cytokines can lead to dangerous disease. cytokine storm associated with sepsis. Cytokine storms were first observed in the context of graft versus host diseasegraft-related complications. They can also occur during viral infectionsincluding COVID-19[feminine]. This uncontrolled immune response can lead to Multi-organ failure and death.

among the hundreds of cytokines that exist, tumor necrosis factor or TNFstands as the most powerful and studied for almost 50 years.

Tumor necrosis factor gets its name from its ability to induce tumor cell death when the immune system is stimulated by a bacterial extract called Coley’s toxin, named after the researcher who identified it more than a century ago. This toxin was later recognized as being lipopolysaccharide or LPS, a component of the outer membrane of some types of bacteria. LPS is the most potent known trigger of TNF, which when alert helps recruit immune cells to the site of infection to eliminate invading bacteria.

Under normal conditions, TNF promotes beneficial processes such as cell survival and tissue regeneration. However, TNF production must be tightly regulated to avoid sustained inflammation and continued immune cell proliferation. Uncontrolled production of TNF can lead to this development of rheumatoid arthritis and similar inflammatory conditions.

Under conditions of infection, TNF must also be tightly regulated to prevent excessive damage to tissues and organs due to inflammation and an overactive immune response. When TNF is not controlled during infections, it can lead to sepsis. For several decades, studies of septic shock have been modeled by studying responses to bacterial LPS. In this model, LPS activates certain immune cells that trigger the production of inflammatory cytokines, including TNF. This then leads to excessive proliferation, recruitment, and death of immune cells, ultimately leading to damage to tissues and organs. Too strong an immune response is not a good thing.

Researchers have shown that blocking TNF activity can effectively treat various autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. The use of anti-TNFs has increased dramatically over the past few decades, reaching a market size of about 40 billion dollars.

However, Anti-TNFs have failed In preventing the cytokine storm that can result from COVID-19 infections and sepsis. That’s partly because exactly how TNF triggers its toxic effects on the body is still poorly understood despite years of research.

How TNF can be deadly

Studying sepsis could provide clues as to how TNF mediates the immune system’s response to infection. In acute inflammatory conditions such as sepsis, TNF blockers are less able to treat overproduction of TNF. However, studies in mice show that neutralizing TNF can prevent animal death due to bacterial LPS. Although researchers do not yet understand the reason for this discrepancy, it underscores the need to better understand how TNF contributes to sepsis.

Blood cells made in the bone marrow, or myeloid cells, are known to be the major producers of TNF. We therefore wondered whether myeloid cells also mediate TNF-induced death.

Le TNF (bleu) est impliqué dans un certain nombre de maladies inflammatoires.  <a href=selvanegra/iStock via Getty Images Plus“data-src=”https://s.yimg.com/ny/api/res/1.2/z3L7tZv7D3jXMJ.EEIgsqw–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTUyOQ–/https://media.zenfs.com/en/the_conversation_us_articles_815/f2112c6e4b80f37e5f” />

First, we identified which particular molecules might offer protection against TNF-induced death. When we injected mice with a lethal dose of TNF, we found that the mice lacked either TRIF or CD14, two proteins generally associated with immune responses to bacterial LPS but not to TNF, improved survival. This finding parallels our Previous work identify these factors as regulators of a protein complex that controls cell death and inflammation in response to LPS.

Next, we wanted to determine which cells are involved in TNF-induced death. When we injected a lethal dose of TNF into mice lacking both proteins into two specific types of myeloid cells, neutrophils and macrophages, the mice showed reduced symptoms of sepsis and improved survival. This finding positions macrophages and neutrophils as major triggers of TNF-mediated death in mice.

Our results also suggest TRIF and CD14 as potential therapeutic targets for sepsis, with the ability to reduce both cell death and inflammation.

This article is republished from Conversation, an independent non-profit news site dedicated to sharing ideas from academic experts. It was written by: Alexander (Sacha) Poltorak, TuftsUniversity and Hayley Muendlein, TuftsUniversity. Like this article ? Subscribe to our weekly newsletter.

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The authors do not work for, consult, own stock, or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.

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