Madangchanok Imchen and Seth R. Bordenstein from the One Health Microbiome Center - winner of Applied Microbiology International’s WH Pierce Global Impact in Microbiology Prize 2024 - explore the potential of the reproductive microbiome, particularly the fascinating Wolbachia, to counter global disease threats.

Microbiome science has for the past two decades focused extensively on animal guts and plant roots in experiments on host-associated bacterial communities. These studies, enabled by advances in sequencing technology, ushered in a deep recognition of the intimate effects that microorganisms have on visible life.

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Yet the largest impacts of the microbiome on host fitness (e.g., reproduction) will arguably stem from the less studied reproductive microbiome, e.g., microbes that inhabit the reproductive organs. Growing attention indicates that the female reproductive microbiome plays a crucial role in pH regulation in the vagina and upper genital tract, defense against pathogens, colonization of the newborn’s microbiome, and fertility.

Similarly, in male semen, the microbiome is positively associated with semen volume and sperm concentration, motility, and fertility. In mice, dysbiosis in the testicular and seminal vesicle microbiome also reduces sperm motility. In insects, the influence of the reproductive microbiome affects sexual selection, mating behavior, gamete modification, embryonic lethality, sex determination, and many other reproductive processes.

Wolbachia are the most prevalent reproductive bacteria

Wolbachia are an archetype for reproductive microorganisms and were first discovered in 1924. These intracellular bacteria occur in the gonads of approximately half of all arthropod species, making it the most prevalent intracellular microbe in the animal kingdom.

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Wolbachia mainly reside in the reproductive organs of the host and cause reproductive manipulations such as cytoplasmic incompatibility (CI), male killing, feminization of genetic males into functional females, and asexual reproduction.

During CI, an incompatible cross between a Wolbachia-infected male and an uninfected female results in a fertilized embryo that fails to develop due to abnormal DNA divisions conferred by the sperm. However, crosses with infected females rescue this paternal effect lethality during embryogenesis and spread the maternally-transmitted Wolbachia to the next generation.

Wolbachia target developing sperm cells in the testes

During the sperm maturation process in the male reproductive organ (testes), histone proteins are replaced by protamine proteins to facilitate sperm DNA compaction for proper packaging and ensuring genetic stability during fertilization. Wolbachia hijack this process in a catastrophic cascade of events.

First, an enzyme from a prophage of Wolbachia depletes a specific long non-coding RNA from the host in early sperm cells. During the later stages of sperm development, DNA damage of the sperm genome ensues, and there is an increase in histone retention, which ultimately leads to protamine deficiency in the mature sperm.

Thus, prophage enzymes from Wolbachia hijack the evolutionary-conserved, histone-to-protamine transition in developing sperm to cause their selfish CI adaptation.

Wolbachia are an ally in the war against mosquito-borne diseases

Mosquito-borne diseases such as dengue, Zika, and chikungunya are a global health challenge, but Wolbachia offer a natural solution with transformative potential. Wolbachia block the growth of these viruses within mosquitoes, likely by enhancing the insect’s immune system and/or regulating resources essential for viruses.

This capability has led to innovative vector control strategies that are both sustainable and environmentally friendly. One approach, population replacement, involves releasing mosquitoes with CI Wolbachia that spread the virus-blocking trait to their offspring, gradually replacing virus-carrying populations and impeding the transmission of viruses.

READ MORE: One Health Microbiome Center named as winner of WH Pierce Global Impact in Microbiology Prize 2024

READ MORE: Study reveals how virus hijacks insect sperm to control disease vectors and pests

Another method, population suppression, releases Wolbachia-infected males that cause embryonic death via CI, reducing mosquito numbers overall.

Notably, the World Mosquito Program has released Wolbachia mosquitoes in 14 countries with an estimated prevention of 725,000 dengue cases and 50,000 hospitalizations. These methods offer a promising, eco-conscious alternative to chemical insecticides, significantly curbing the spread of deadly diseases with members of the reproductive microbiome.

Conclusion

Beyond Wolbachia, the reproductive microbiome in different hosts includes other bacteria, viruses, archaea, protists – forging a portfolio of host-microbial interactions that may significantly alter reproduction and host fitness, with downstream impacts on sexual selection and even speciation. Indeed, CI-inducing bacteria can prevent interbreeding between arthropod populations or incipient species.

Understanding these diverse microorganisms in the reproductive organs holds great promise for developing sustainable and eco-friendly solutions to control disease transmission, enhance reproductive success, manage pest populations, and contribute to conservation and public health efforts.

Written by Madangchanok Imchen and Seth R. Bordenstein from the Departments of Biology and Entomology, One Health Microbiome Center, Huck Institutes of the Life Sciences, The Pennsylvania State University, USA.

 Lab website: bordensteinlab.com.

Lab Researcher Open Position: https://psu.wd1.myworkdayjobs.com/en-US/PSU_Staff/job/Research-Technologist—Life-Sciences-Advanced-Professional_REQ_0000062556-1