Bugs transmit antiviral immunity to offspring

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Insects do not make the cells and antibodies characteristic of the adaptive immune response of vertebrates. As a result, scientists assumed for years that insects depend on innate immune defenses that are neither inheritable nor directed against a specific pathogen. However, over the last 20 years invertebrates have been shown to inherit some types of immunity from their parents, but it is still not clear how or how often this happens. In a study published December 15 in Cell Reports, researchers show that fruit flies (Drosophila melanogaster) and mosquitoes (Aedes aegypti) confer immunity to viruses in their offspring over several generations.

“The authors present a very thorough set of experiments detailing the existence of this transfer of immunological memory to the offspring from generation to generation,” says Barbara Milutinović, postdoc at the Institute for Science and Technology Austria, who did not participate in Auf der Arbeit . Some scientists are still debating immunity in Drosophila as if it were only innate and not tailored to specific pathogens, she adds, but “this study shows us. . . that there is something really specific going on. “

Maria Carla Saleh, an immunologist at the Pasteur Institute in Paris, and her colleagues wanted to understand immunity to insects because mosquitoes are the carriers of so many viruses that make people sick, but are not injured by these infections themselves. “The same virus will cause fatal disease in humans, but the mosquito will be very happy,” she says. They focused on so-called persistent viral infections: those with high virus titers but without fitness costs for their insect hosts. Understanding the basics of persistent infections could make it possible to drive the mosquito out of this persistent state – either to succumb to the pathogen or to get rid of it, she explains.

In any case, the information seems to be transmitted as DNA.

– Maria Carla Saleh, Pasteur Institute

In Saleh’s laboratory, researchers often work with fruit flies because they have an immune system similar to mosquitoes and fruit flies are much easier to work with. In 2018, the team showed that D. melanogaster exposed to a virus as larvae successfully controlled it as adults, while naive adults did not. The next question was whether or not this type of immune expression can also be passed on from the parent to the offspring.

In the new study, Saleh and colleagues injected female fruit flies with either the recombinant Sindbis virus or a sham injection of the same volume that did not contain the virus. The Sindbis virus is transmitted by mosquitoes in Europe, Asia, Africa and Australia. Infections are usually mild in people and can include arthritis, fever, and rash. In contrast, Sindbis produces high virus titers in fruit flies, but does not make them sick and does not pass from the mother to the offspring. After receiving the injection, the females mated and laid eggs. Once the next generation reached adulthood, the researchers injected the new generation with the same recombinant Sindbis virus. The flies whose mothers were infected with the virus had lower virus titers and a lower activity of the reporter gene incorporated into the virus than the offspring of mothers who were sham infected before mating.

The researchers found that the protective effect of a virus infection lasted for at least five generations in the founding generation. They saw a similar level of antiviral protection between generations when they repeated the experiments with three other single-stranded RNA viruses with positive sense, but not with one double-stranded RNA virus or one single-stranded RNA virus with negative sense.

To determine whether or not an intact virus was necessary for the antiviral immunity of the offspring, the researchers constructed double-stranded RNA that corresponds to two different parts of Sindbis virus and mimics intermediate forms of the virus that were produced during virus replication. When injected into female flies, this piece of double-stranded RNA also protected their offspring from subsequent viral challenges. “That was mind blowing because it means the system is sort of recognizing this double-stranded RNA. . . is exogenous, or that’s something you should immunize against, ”says Saleh.

Next, the authors injected female Aedes aegypti mosquitoes with Chikungunya virus – a positive-meaning single-stranded RNA virus that can cause headaches, muscle pain, and joint swelling in humans – or fed them an infected blood meal. When the researchers then exposed the mosquito’s offspring to the virus, the insects had lower virus titers than those whose mothers were sham infected.

In their 2018 study, Saleh and colleagues showed that viral DNA, which corresponds to part of a viral RNA sequence, was present in adult flies after being exposed to a virus as larvae. On the assumption that viral DNA plays a role in the transgenerational immunity they had observed in the new study, the authors examined both viral DNA and RNA concentrations in flies that were positive with one of two single-stranded positives RNA viruses and their descendants were infected. They found both viral RNA, as expected for a current infection, and viral DNA in the mothers, but the offspring had no viral RNA, only viral DNA.

“In any case, the information seems to be transmitted as DNA,” says Saleh. But “the paper raises many questions. For example, we could only observe this protection or transfer of antiviral immunity for positive single-stranded RNA viruses. Why?”

Previous work has shown that “these types of memory-conferring mechanisms exist in invertebrates – or at least some invertebrates – and may look very different from what we are used to in vertebrate immune systems,” says Matt Ballinger, a Mississippi State University biologist who did not participate in the study. “Probably for the next five or ten years, [the field] will work to find out exactly how that happens. In this article alone, you have introduced some new steps that are worth pursuing. “

In addition to the targeted questions about viral DNA and how the positive sense single-stranded RNA viruses do it, there are human health implications for this work, according to Bryony Bonning, an insect biologist at the University of Florida who did not participate Education.

“There are several viruses with single-stranded RNA genomes that are transmitted from mosquitoes to humans,” said Bonning, including dengue, chikungunya, Zika, yellow fever and West Nile viruses. “To understand how the mosquito might have an immune mechanism to suppress the replication of these human viruses. . . You could imagine that if you get this under control, there could be something downstream that could be tried to try and suppress the transmission of the virus to humans. “

JA Mondotte et al., “Evidence of long-lasting antiviral immunity between generations in Insects ” cell Reports, doi: 10.1016 / j.celrep.2020.108506, 2020.

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