150 research primates got diarrhea, flooding lab with priceless vaccine data

The outbreak began in December 2022 at the Wisconsin National Primate Research Center in Madison. Non-human primates are natural hosts for Shigella, like humans, and it’s not uncommon for outbreaks to flare at such facilities now and then. But it is unusual for an outbreak to be so big and last so long. Even some of the people who worked at the facility fell ill. In all, there were 169 microbiologically confirmed shigellosis cases among the non-human primates. Researchers collected 151 Shigella isolates for serotyping and did whole genome sequencing on 95 representative isolates. The outbreak was caused by two related clusters of Shigella flexneri, a species that commonly strikes captive non-human primates. (Human outbreaks are more often driven by Shigella sonnei, but both species can infect either type of primate.) Of the 90 isolates tested for antimicrobial resistance, more than half (63 percent) were multidrug resistant. Most of the cases caused only mild diarrheal symptoms, but there were some asymptomatic cases and some cases that led to severe symptoms. Infants were the hardest hit, similar to what’s seen in humans. The researchers found various antibodies that bound to the Shigella’s O-antigen. But some seemed to have been honed from repeated exposures to the bacteria. And most interestingly, they seemed to develop the ability to attack O-antigen from many different Shigella serotypes—a feat that would be critical for the success of a vaccine. Moreover, they found that the antibodies that bound tightly to the O-antigen could trigger cascading reactions of plasma proteins that end with the bacterial cells being disintegrated—another useful feature. Next, they looked at antibodies that attacked part of a type 3 secretion system, or T3SS for short. This is a common apparatus that bacteria assemble to attack their victims. When the components come together, a T3SS forms a syringe-like structure, complete with a needle that pokes out from the bacterial cell into a cell it’s trying to attack. The bacteria then pumps in a suite of proteins, called effectors. These can have a variety of specific functions but generally work to dampen the host cell’s defenses and promote a comfy environment for the invading bacteria. At the very tip of Shigella’s T3SS, there are two proteins, IpaB and IpaD, that antibodies from the non-human primates attacked. These, the scientists found, were generally able to spur protective responses from immune cells, including T cells. Sorting through the antibodies, the scientists found some of them seemed to backfire, sparking reactions that helped Shigella burst blood cells. Others, however, prevented blood cell bursting. They found that these two types of antibodies bound to the tip proteins at different niches within the proteins. The researchers were able to identify the exact spot where the helpful antibodies bound, giving vaccine developers a precise mark to attack. Together, the findings provide new insight and directions to develop an effective vaccine against Shigella. Though we’re still far from having one, the researchers are hopeful that the data from the outbreak can help overcome existing challenges and that their strategy of using such structural and immunological data will help researchers better design bacterial vaccines generally.