Suppose you are recovering from the COVID-19 virus when you mistakenly eat an inadequately cooked piece of chicken that has been infected with harmful salmonella bacteria. How does your immune system decide which pathogen to attack first? When a second infection follows on the heels of a first, the two arms of the immune system may clash. 

Even after overcoming a viral infection, our immune system stays active, protecting us from any lingering viruses or recurring disease. A new study at the Weizmann Institute of Science just published in the journal Immunity shows that in such cases, the immune system has a clever way of setting priorities, one that might be exploited for the development of future therapies against autoimmune diseases. 

This prioritizing involves the two arms of immunity – innate and adaptive. Innate immunity, the body’s first line of defense, springs into action as soon as the immune system senses an invasion by viruses, bacteria or other pathogens, deploying its cells and biochemicals in a broad offensive to neutralize the invaders. 

Adaptive immunity, on the other hand, could take several days to prepare its weapons – dedicated cells and antibodies that are tailored to bind to different invaders with amazing precision. The antibodies remain on guard for months or even years, offering long-lasting security. 

This means that innate and adaptive immunity generally come to the fore at different stages of an infection. But when one infection is followed by another – for example, when a person overcoming a flu virus comes down with a bacterial infection such as salmonella – the two arms are forced to go into high gear at the same time: Innate immunity starts fighting the bacteria, while adaptive immunity is still busy making antibodies against the flu virus. 

A team headed by Prof. Ziv Shulman of Weizmann’s immunology department wanted to know how the two arms of immunity interact during such an overlap. In a study using mice, led by doctoral student Adi Biram, they found that the interaction ends in a clash. Infection with salmonella interferes with the manufacture of antibodies against the flu. In other words, when faced with a lethal threat, the immune system shuts down mechanisms needed for long-term protection, dealing instead with the more urgent danger. 

The researchers discovered that salmonella doesn’t produce this effect directly. Rather, when it infects lymph nodes, it sets off an alarm that reaches as far as the bone marrow, priming innate immunity cells called monocytes to rapidly leave the marrow in order to fight the bacteria. These monocytes flood the lymph nodes en masse, from there launching an attack on the salmonella. But in the process, as a result of their antimicrobial activity, these cells alter the environment within the lymph nodes, releasing various chemicals and causing a local shortage of oxygen. 

Most immune cells adapt to this shortage by changing their metabolism, shifting to burning glucose for energy instead of oxygen. But for a subset of B cells that live in the lymph nodes in microscopic structures called germinal centers, an oxygen shortage proves fatal. Unable to adapt their metabolism, these B cells choke and die. This is exactly the subset of cells that plays a key role in adaptive immunity, generating antibodies having the best possible fit against the invading pathogen. The death of these cells puts an end to the production of antibodies required for long-lasting protection against the viral infection.

“It’s an either/or situation – when you are fighting life-threatening bacteria, you can’t be bothered with long-lasting immunity,” Shulman explained. “Destroying the salmonella gets priority because it’s a matter of survival.”

The study’s findings may have applications in various areas of immunology. Currently, certain bacterial proteins are sometimes added to vaccines to enhance their effectiveness, but the study suggests that such additions might backfire, harming antibody production. In addition, if confirmed in humans, the new findings might lead to a new type of therapy for autoimmune diseases caused by the mistaken production of antibodies, for example, rheumatoid arthritis and lupus erythematosus. Such a therapy would harness bone marrow monocytes to stop the production of disease-causing antibodies.