Trained Immunity via Saprophytic Leptospira Exposure Confers Protection Against Severe Leptospirosis

Leptospirosis is caused by Leptospira bacteria which is a serious threat to both humans and animals. It can lead to kidney failure, liver problems, severe lung damage, and  meningitis. Every year, over a million people around the world catch leptospirosis, and about 65,000 do not survive. The numbers are staggering, yet it remains one of the most overlooked diseases, especially in tropical areas where warm, wet conditions and poor sanitation make it easy for the bacteria to spread. Efforts to control leptospirosis rely on vaccines that target specific bacterial strains and antibiotic treatments for those at high risk. The problem is, these vaccines are mostly designed for animals and only protect against certain strains for a short time. There is no widely available vaccine for humans that provides broad, long-lasting protection. On top of that, antibiotics only work if the infection is caught early, which is tricky because leptospirosis looks a lot like other illnesses such as dengue fever and malaria. All of this makes finding better solutions more urgent than ever. One of the biggest challenges in fighting leptospirosis is developing a vaccine that protects against multiple strains. Scientists have tried using different bacterial proteins or inactivated forms of the bacteria, but leptospirosis is tricky—it has a diverse set of antigens, and it is excellent at dodging the immune system. Some recent studies, however, suggest an interesting possibility. A harmless type of Leptospira known as L. biflexa has been shown to activate the immune system. But could it do more? Could it actually train the immune system to fight off the dangerous strains?

To this account, scientists at the University of Tennessee Health Science Center led by Professor Maria Gomes-Solecki, with contributions from Dr. Suman Kundu and Dr. Advait Shetty, their study—published in eLife—tested whether exposing animals to L. biflexa before infection with a harmful strain would help protect them and that early exposure might “train” the immune system to be better prepared, offering a new approach to preventing leptospirosis beyond traditional vaccines. To put their hypothesis to the test, the researchers used C3H/HeJ mice, which are commonly used in leptospirosis research. Their goal was to figure out whether being exposed to L. biflexa ahead of time could change how the immune system responds and lessen the severity of the disease when the mice later encountered a dangerous strain of L. interrogans.  In their study, the researchers split the mice into different groups—some got a single dose of L. biflexa, others received two doses, and a control group was either left unchallenged or infected with L. interrogans alone. The team tracked several key factors, including weight loss, survival rates, how well the bacteria spread, kidney health, and immune system activity. The findings were clear. Mice that had been exposed to L. biflexa beforehand had much better survival rates and lost less weight when infected with L. interrogans compared to those that had no prior exposure. The control mice that faced L. interrogans with no preparation developed severe symptoms and had high mortality rates. But those that had been primed with L. biflexa seemed to fight off the disease better, surviving at much higher rates and recovering their body weight more quickly. Interestingly, while exposure to L. biflexa did not stop L. interrogans from settling in the kidneys, it did appear to protect the organs from damage. Mice that had previous exposure to the non-pathogenic strain showed lower levels of immune cell buildup in their kidneys and had reduced markers of fibrosis, like ColA1. This suggests that L. biflexa might help the body achieve a kind of immune balance, preventing the worst effects of infection without completely wiping out the pathogen. Moreover,  the researchers found that mice exposed to L. biflexa had an increase in a specific type of immune cell—CD4+ effector T cells—along with higher levels of IgG2a antibodies which target L. interrogans and this indicates that these immune responses are linked to better control of bacterial infections. One unexpected result was that pre-exposed mice actually shed more bacteria in their urine compared to those that had never encountered L. biflexa. Instead of outright eliminating the bacteria, it seemed their immune systems were keeping things under control while still allowing some bacterial persistence. This raises new questions about how immune tolerance might play a role in chronic infections. To confirm these findings, the team used flow cytometry to analyze immune cells in the spleen. Their data supported the idea that prior exposure to L. biflexa trained the immune system, strengthening protective responses while preventing severe tissue damage.

Wrapping up, the work done by Professor Maria Gomes-Solecki and her team makes a strong case for the hypothesis that early exposure to L. biflexa can help lessen the impact of leptospirosis. Their findings suggest that this harmless strain can steer the immune system toward a protective Th1 response while also helping the kidneys maintain better function during infection. While there is still a lot to uncover about the exact mechanisms behind this protection, these results hint at a promising new approach to immunization—one that does not rely on traditional vaccines but instead uses non-pathogenic Leptospira to prepare the immune system for a real threat. Additionally, the authors’ findings of a link between immune tolerance and bacterial shedding is worthy to investigate further. Normally, the goal of a vaccine  is to prevent disease. But in this case, the mice that were pre-exposed to L. biflexa actually shed more L. interrogans in their urine while still avoiding severe illness. This suggests that the key to protection might not be eradicating the bacteria but rather managing the infection in a way that keeps the host healthy. It is a fresh perspective that challenges the standard thinking about immunity and raises new questions about the balance between immune defenses and allowing certain pathogens to persist without causing harm. Looking beyond leptospirosis, this study has bigger implications for immunology as a whole. It highlights how exposure to a harmless bacterial strain can train the immune system to handle a more dangerous one, a concept that could be applied to other infectious diseases. There is real potential here—if this approach works for Leptospira, it might also work for other bacteria that cause chronic infections. Future studies should explore whether this kind of immune training can offer protection across different Leptospira strains or even against entirely different pathogens. If so, it could open up new ways to develop immunity beyond conventional vaccines, providing broader, longer-lasting protection in a way we have not seen before.