Sepsis is one of the most expensive medical conditions in the world – new research sheds light on how it can lead to cell death

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Bactérias (aglomerados de rosa claro, cercados por células sanguíneas magenta maiores) podem causar infecções mortais, mas respostas imunológicas excessivamente reativas podem desferir o golpe letal.  <a href=Scharvik/iStock via Getty Images Plus” src=”–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTQzMA–/” “–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTQzMA–/”
Bacteria (clumps of light pink, surrounded by larger magenta blood cells) can cause deadly infections, but overly reactive immune responses can deal the lethal 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 over 2,700 years, when the Greek poet Homer used it as a derivative of the word “sepo”, meaning “I rot”.

Despite dramatic improvements in understanding the immune mechanisms behind sepsis, it still remains a major medical concern, affecting 750,000 people in the US and nearly 50 million people globally each year. Sepsis was responsible for 11 million deaths worldwide in 2017 and is the most expensive medical condition in the US, costing over tens of billions of dollars annually.

We are researchers studying how certain types of bacteria interact with cells during infections. We wanted to understand exactly how an exaggerated immune response can result in harmful and even lethal effects like sepsis. In our newly published research, we uncovered the cells and molecules that potentially trigger death from sepsis.

TNF in autoimmunity and sepsis

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

Although cytokines play an essential role in the immune response, excessive and uncontrolled cytokine production can lead to a dangerous cytokine storm associated with sepsis. Cytokine storms were first observed in the context of graft-versus-host disease resulting from transplantation complications. They can also occur during viral infections, including COVID-19. This runaway immune response can lead to multiple organ failure and death.

Among the hundreds of existing cytokines, tumor necrosis factor, or TNF, stands out as the most potent and the most studied in the last 50 years.

Tumor necrosis factor owes its name to 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 lipopolysaccharide, or LPS, a component of the outer membrane of certain types of bacteria. LPS is the strongest known trigger of TNF, which, once alerted, assists in the recruitment of 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 prevent sustained inflammation and continued proliferation of immune cells. Uncontrolled TNF production can lead to the development of rheumatoid arthritis and similar inflammatory conditions.

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

Researchers have demonstrated that blocking TNF activity can effectively treat several autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. The use of TNF blockers has increased dramatically over the last few decades, reaching a market size of approximately $40 billion.

However, TNF blockers have not been successful in preventing the cytokine storm that can arise from COVID-19 infections and sepsis. This is in part because exactly how TNF triggers its toxic effects in the body is still poorly understood despite years of research.

How TNF Can Be Lethal

Studying sepsis may provide some clues about how TNF mediates how the immune system responds to infection. In acute inflammatory conditions such as sepsis, TNF blockers are less able to deal with the overproduction of TNF. However, studies in mice show that the neutralization of TNF can prevent the death of the animal by bacterial LPS. While researchers still don’t understand the reason for this discrepancy, it highlights the need to better understand how TNF contributes to sepsis.

Blood cells produced in the bone marrow, or myeloid cells, are known to be the main producers of TNF. So we asked whether myeloid cells also mediate TNF-induced death.

O TNF (azul) está implicado em várias doenças inflamatórias.  <a href=selvanegra/iStock via Getty Images Plus” data-src=”–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTUyOQ–/” />

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

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

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

This article is republished from The Conversation, a non-profit independent news site dedicated to sharing ideas from academic experts. Written by: Alexander (Sasha) Poltorak, tufts university and Hayley Muendlein, tufts university🇧🇷 Did you like this article? subscribe to our weekly newsletter.

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