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Wolbachia Turns 100: The Journey of a Triumphant Endosymbiont

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In the mid-Twenties, entomologist Marshall Hertig and pathologist Simeon Burt Wolbach determined to step out of their laboratories at Harvard College and gather bugs within the environment of Boston and Minneapolis. The duo studied the Rickettsiales order—a gaggle of obligate intracellular micro organism that depend on host cells for replication. Within the early 1900s, researchers undertook the duty of characterizing bacterial members of this order in arthropods and finding out the ailments they trigger in people, resembling Rocky Mountain noticed fever and typhus. Hertig and Wolbach needed to find out the frequency of those Rickettsia-like organisms in bugs and establish traits that may allow their distinction from cell granules and artifacts. Among the many specimens they introduced again to the lab had been over 20 Culex pipiens mosquitoes. By fastidiously dissecting the insect’s tissues and inspecting them underneath the microscope, the researchers recognized for the primary time tiny Rickettsia-like microorganisms within the mosquito’s ovaries, testes, and eggs.1 

Wolbachia is endlessly fascinating.

 —William Sullivan, College of California, Santa Cruz

A couple of years after their discovery, Hertig named these intracellular microorganisms Wolbachia pipientis. Since Hertig’s and Wolbach’s preliminary description in 1924, researchers all over the world have delved into the biology of Wolbachia. They not solely found the wide selection of arthropods and nematodes that harbor the micro organism inside their cells, but additionally a stunning constellation of parasitic and mutualistic variations that make this bacterial endosymbiont an unmistakable instance of evolutionary success.2,3

How Wolbachia Propagates: An Endosymbiont’s Dance for Vertical Transmission

Hertig’s and Wolbach’s early observations of Wolbachia within the eggs of C. pipiens strongly instructed that the micro organism had been maternally transmitted. William Sullivan, a cell biologist on the College of California, Santa Cruz, was intrigued by how the endosymbiont propagates to the subsequent era. “Wolbachia is endlessly fascinating,” he stated.

Sullivan discovered from the analysis of Michael Turelli, an evolutionary biologist on the College of California, Davis, that the micro organism had been spreading in fruit flies in California. So, he took his college students on a discipline journey to analyze whether or not Wolbachia had reached the wineries in Santa Cruz County. In accordance with Sullivan, it was by way of this exercise and the scholars’ shows and studies that he immersed himself on the planet of the endosymbiont. 

As Wolbachia are effectively transmitted from the feminine host to her offspring, Sullivan puzzled how the endosymbiont does that. Earlier proof instructed that some intracellular microbes use elements of the cell cytoskeleton to have the ability to transfer inside and between cells. This was the case of Listeria monocytogenes, a pathogenic micro organism recognized for inflicting listeriosis.4 Within the early Nineteen Nineties, researchers confirmed that L. monocytogenes hijacks the host’s cytoskeleton to type actin-rich constructions referred to as rocket tails, which allow the micro organism to zip across the cell cytoplasm.5 

A group of people outside near a beach.

William Sullivan (second from left) and his crew research the molecular and mobile interactions between Wolbachia and its insect hosts.

William Sullivan

To discover if Wolbachia would additionally snatch elements of the cytoskeleton to make sure its excessive transmission charges, Sullivan and his crew first centered on the early phases of oogenesis. Within the ovaries of Wolbachia-infected Drosophila melanogaster fruit flies, they discovered that the micro organism clearly localized on the anterior finish of the oocyte and used the host’s microtubule community and the related motor protein dynein to achieve that subcellular localization.6 

Throughout late phases of egg improvement, Wolbachia focus on the posterior finish of the mature oocyte, the place germline precursor cells are positioned.7 To analyze whether or not microtubules performed a job within the micro organism’s anterior to posterior reallocation, Sullivan’s crew appeared on the ovaries of Wolbachia-contaminated fruit flies within the late phases of oogenesis. Microtubules bear a significant rearrangement contained in the oocyte in the course of the mid-stages of oogenesis, shifting their polarity in order that the microtubules plus ends focus on the posterior pole of the oocyte.8 Due to this fact, Sullivan and his crew centered on the motor protein kinesin, which is understood for transferring in direction of microtubules plus ends. Utilizing mutant flies that lacked kinesin, they discovered that Wolbachia hijacked this motor protein to reallocate to the posterior finish and place themselves on the web site of germline cell formation, seemingly making certain the bacterial vertical transmission.9 “Which means Wolbachia needs to be actually subtle,” Sullivan defined. “There have to be some floor proteins early in oogenesis to have interaction the motor [protein] dynein after which [Wolbachia] should flip off these floor proteins and activate a floor protein that engages kinesin.”

The image shows a fruit fly oocyte infected with Wolbachia bacteria.

Wolbachia (pink) are recognized to contaminate the oocytes (blue and inexperienced) of bugs resembling Drosophila melanogaster.

Yonah Radousky

As a result of reaching the posterior pole of the mature oocyte is a milestone for the vertical transmission of Wolbachia, Sullivan investigated the bacteria-kinesin affiliation extra carefully. Kinesins are tetramers composed of two heavy chains (KHC), liable for motor exercise, and two mild chains (KLC), which may bind cargo and act as a linker protein.10 By pulling down KLC, Sullivan’s crew discovered that the micro organism weren’t solely capable of attain the posterior pole however their numbers additionally elevated drastically.11 “This was simply a kind of loopy outcomes,” he recalled. Overexpression of KHC induced an identical improve in Wolbachia ranges at that oocyte subcellular location, suggesting that KHC availability limits the micro organism transport. For the reason that oocyte has a restricted variety of kinesins to maneuver important elements to the posterior pole, Wolbachia have to be cautious to not disrupt this course of, Sullivan defined. “It wants that germline to be intact for itself. So, it has developed to be this actually weak competitor,” he added.

Whereas the endosymbiont dynamic choreography contained in the oocyte was fascinating to Sullivan, it was not the one Wolbachia-related phenomenon that piqued his curiosity. “I acquired actually enthusiastic about cytoplasmic incompatibility,” he stated.  

Wolbachia Micro organism and the Artwork of Reproductive Manipulation

Among the many reproductive manipulations related to Wolbachia, cytoplasmic incompatibility (CI) might be probably the most enigmatic. First recognized by biologist Hannes Laven within the Nineteen Fifties, CI designates a phenomenon wherein breeding between bugs of the identical species fails to provide a viable offspring. Laven noticed this peculiar mating incompatibility whereas finding out C. pipiens populations from totally different geographical areas. Based mostly on his experiments, he proposed that an incompatibility issue current within the cytoplasm was handed from the dad and mom to the progeny.12 Laven was additionally one of many first to acknowledge that CI may contribute to speciation and mosquito inhabitants management.13,14 

It was solely within the early Nineteen Seventies that researchers established the hyperlink between CI and Wolbachia once they noticed important numbers of the microorganism within the eggs and embryos of incompatible crosses of C. pipiens.15

In accordance with Sullivan, CI stands out as Wolbachia’s cleverest reproductive manipulation as a result of it requires a collaboration between men and women. “If a male is contaminated however not a feminine, the eggs don’t hatch. But when a male is contaminated in addition to the feminine, the eggs hatch. So, if you happen to’re an uninfected feminine in an contaminated inhabitants, you’re at a drawback,” he defined.

Seth Bordenstein, a biologist at Pennsylvania State University, has been studying Wolbachia for more than 25 years. He wears a gray jacket and black shirt.

Biologist Seth Bordenstein explores how bacteriophages form the endosymbiotic relationship between Wolbachia and its hosts.

Pennsylvania State College

Sullivan and others had been intrigued by how Wolbachia tinkered with the reproductive cells of bugs to induce CI, and he approached this reproductive puzzle from a chromosome perspective. Early research from the Nineteen Nineties instructed that Wolbachia disrupted paternal chromosome dynamics throughout fertilization and early embryonic improvement, and scientists hypothesized that the micro organism brought on a mismatch between the timing of occasions happening in the beginning of embryogenesis.16,17 

To check this concept, Sullivan and his crew developed a cytological method to review the fertilization and first mitotic division in dwelling embryos of the wasp Nasonia vitripennis. They noticed that the male pronuclei in CI embryos confirmed delayed nuclear envelope breakdown—a sign of entry into mitosis—inflicting asynchrony between the female and male pronuclei in the course of the early phases of embryonic improvement.18 In a subsequent research, the crew discovered that CI affected chromatin condensation and correct DNA replication within the male pronucleus by delaying the deposition of key histones and prolonging the retention of the proliferating cell nuclear antigen, each of which may contribute to mitotic defects and embryo lethality.19   

A Phage’s Present

Whereas Sullivan and different researchers had been exploring Wolbachia’s reproductive manipulations on the mobile degree, Seth Bordenstein, a biologist at Pennsylvania State College, needed to know the genetic secrets and techniques that enabled this endosymbiont to command its host. “After I discovered about [Wolbachia], I stated, ‘how is it potential {that a} easy microorganism with a small genome can dwell inside an animal host and do these wonderful reproductive modifications with the intention to profit itself?’ It felt like Wolbachia was a puppeteer of a really advanced host,” Bordenstein stated. 

Phage WO holds a whole lot of the powers that Wolbachia is so well-known for.

 —Seth Bordenstein, Pennsylvania State College

Endosymbionts had been thought to lose a big quantity of their genomes once they entered an obligate symbiotic relationship with their hosts—a course of termed genome discount.20 Researchers thought of that cell genetic components, resembling bacteriophages and transposons, had been the primary to be eradicated on this course of; but, the sequencing of Wolbachia’s genome revealed in any other case, indicating that the bacteriophage-like particles first recognized within the endosymbiont within the late Nineteen Seventies included their genetic supplies into the streamlined microbes.21-23  

Phages had been recognized to grant adaptive traits to free-living micro organism, so Bordenstein puzzled if the bacteriophage present in Wolbachia, phage WO, would do the identical for the endosymbiont and have an effect on its skill to trigger CI.

Bordenstein’s crew in contrast the genome of Wolbachia strains recognized to trigger CI with one which didn’t trigger the mating incompatibility and located that solely two genes had been shared between CI-causing strains.24 “No one finds two genes in a multiomics evaluation, they often discover a whole lot of genes. So, we thought we had been both lifeless flawed or lifeless proper,” Bordenstein recalled. 

Since Wolbachia don’t replicate exterior of the cells of their hosts, and scientists can not tradition them within the lab, Bordenstein and his crew created transgenic fruit flies that expressed the 2 genes the crew named CI components A (cifA) and B (cifB). The person expression of the genes didn’t recreate the CI phenotype. That’s once they determined to precise cifA and cifB collectively. “It was our last-ditch effort, and we had been capable of finding that the 2 genes expressed collectively from a fly genome recapitulated the cytoplasmic incompatibility sperm trait,” Bordenstein stated. In the identical yr that these findings had been made public, researchers led by Yale College biologist Mark Hochstrasser reported related outcomes in a distinct Wolbachia pressure, collectively offering the primary proof for the genetic foundation of Wolbachia’s CI.25     

Scott O’Neill, founder and chief executive officer of the World Mosquito Program, aims to fight mosquito-borne pathogens using Wolbachia. In the photo, he wears glasses and a black t-shirt.

Scott O’Neill has pioneered Wolbachia-based methods to manage mosquito-borne ailments for over a decade.

World Mosquito Program

Bordenstein and his crew went on to discover the results of cifA and cifB by assessing whether or not the genes may contribute to CI rescue seen when contaminated males mate with contaminated females. Utilizing transgenic fruit flies expressing these genes, they discovered that feminine expression of cifA rescued CI and repealed the Wolbachia-induced embryonic loss of life.26   

The power to trigger, and in females rescue, CI was not the one secret saved within the phage WO genome. Bordenstein knew that Wolbachia may shift the intercourse ratios in a inhabitants by way of a phenomenon termed male killing, and researchers thought of this crafty technique as one other instance of the endosymbiont’s talents to make sure its presence in a big proportion of females in a number inhabitants.27 To analyze whether or not the phage WO genes had been additionally linked to this phenotype, Bordenstein’s crew used a comparative genomic method and located a candidate gene they named WO-mediated killing (wmk).28 When the researchers transgenically expressed wmk in fruit flies, they discovered that wmk induced cytological defects and male embryonic loss of life. “Phage WO holds a whole lot of the powers that Wolbachia is so well-known for,” Bordenstein stated. 

Wolbachia Flip right into a Microbial Ally within the Struggle Towards Ailments 

Biologist Scott O’Neill has additionally been fascinated by Wolbachia’s organic methods. The founder and chief govt officer of the World Mosquito Program first discovered in regards to the endosymbiont throughout his graduate research. The wide selection of phenotypic outcomes that the micro organism induced in arthropods, together with CI and male killing, impressed O’Neill to discover Wolbachia as an agent for illness management.

Most mosquito-borne pathogens expertise a big interval of improvement inside their vectors earlier than they’re transmitted to a brand new host, suggesting that the survival of the mosquitoes is of utmost significance for pathogen transmission. Within the late Nineteen Nineties, scientists recognized a Wolbachia pressure that shortened the lifespan of its pure D. melanogaster host.29 O’Neill noticed this as a possible technique to skew the age distribution of mosquito populations, thus impacting the vector’s skill to unfold the pathogens they carry.  

To discover Wolbachia’s potential mosquito-killing expertise, O’Neill and his crew first needed to decide whether or not the life-shortening pressure would adapt to a brand new host. They transferred the fruit fly’s native micro organism to a cell line derived from the mosquito Aedes albopictus and maintained this cell line for greater than 200 serial passages earlier than infecting different mosquito cell traces.30 When the crew reintroduced the Wolbachia pressure into the unique host, they noticed diminished life-shortening and CI capabilities in comparison with the native fruit fly micro organism, suggesting that the pressure had tailored to its new mosquito host. The researchers then microinjected the mosquito-adapted life-shortening Wolbachia in uninfected embryos to generate mosquito traces carrying the endosymbiont. “These switch experiments had been very troublesome to do, and we spent a very long time doing that work till we had been profitable,” O’Neill recalled. Then, the crew zoomed in on Aedes aegypti, a significant vector of epidemiologically related viruses, paying specific consideration to the feminine mosquitoes, that are blood feeders that may transmit disease-causing pathogens as they seek for their subsequent blood meal.31 The life-shortening Wolbachia pressure not solely lowered the longevity of feminine A. aegypti mosquitoes by roughly 50 %, however it additionally induced a powerful CI phenotype and was maternally transmitted to the offspring.32 

A man is releasing Wolbachia-infected mosquitoes.

By releasing Wolbachia-infected mosquitoes, the World Mosquito Program initiative goals to fight mosquito-borne ailments and scale back their burden in many alternative elements of the world.

World Mosquito Program

Whereas disrupting mosquito biology appeared a promising technique for controlling mosquito-borne pathogens, Wolbachia nonetheless had one other trick up its sleeves. Within the mid-2000s, O’Neill collaborated with Karyn Johnson, a molecular virologist on the College of Queensland, who was considering finding out the results of the endosymbiont on the viruses carried by D. melanogaster. The researchers examined the survival charges of flies contaminated or not with viral pathogens and located that Wolbachia-carrying fruit flies had a delayed mortality that corresponded to a delayed accumulation of the viruses within the bugs.33 “That consequence was very hanging and really highly effective,” O’Neill stated. 

O’Neill realized that this was one more skill of Wolbachia that could possibly be leveraged to manage insect-borne ailments, significantly these transmitted by mosquitoes. Utilizing the Wolbachia-infected A. aegypti mosquitoes that they beforehand generated, O’Neill and his crew confirmed that Wolbachia-carrying mosquitoes had lowered masses of dengue and chikungunya viruses, suggesting that the endosymbiont blocked these viruses from replicating inside their pure vector.34 

Over the previous 15 years, O’Neill and others have translated these early laboratory findings into discipline methods to manage mosquito-borne ailments and proven encouraging ends in decreasing dengue transmission in lots of areas of the world.35    

“It’s typically undervalued by politicians and by skeptics of science that our investments in basic fundamental analysis can transition into one thing grand,” stated Bordenstein. “A whole lot of Wolbachia biology was fundamental science initially. And now, it’s used to curb ailments transmitted by mosquitoes and ailments attributable to filarial nematodes,” he famous. “We’re speaking about tens of millions of people who could possibly be having their burden of illness or danger of illness lowered from this fundamental science.” 

A Vibrant Future for a Centenarian Microbe

Whereas researchers have uncovered lots of Wolbachia’s organic enigmas over the previous 100 years, puzzles stay to be solved. In accordance with Bordenstein and Sullivan, one such puzzle is the mechanism that mediates CI rescue. Bordenstein plans to sort out this phenomenon to higher perceive how Wolbachia-infected females de-encrypt the modifications the endosymbiont induces in males, permitting embryonic improvement to happen.

Understanding how Wolbachia impacts somatic cells is one other attention-grabbing space, in line with Sullivan. “Wolbachia has this big somatic life,” he stated. His crew is investigating this side of the endosymbiont’s life by exploring how Wolbachia can affect its host’s conduct. “That’s a complete wonderful story of Wolbachia concentrating on totally different areas of the mind to have an effect on conduct,” Sullivan stated.

How microorganisms, together with Wolbachia, may contribute to species formation is one other space of curiosity for Bordenstein. “Microbes had been basically ignored from the final 100 years of speciation biology, which had largely been dominated for the reason that fashionable synthesis by genetics and discovering the quantity and varieties of genes,” he defined. Over time, researchers have discovered proof of how microbial symbionts can affect the origin of species.36 “As soon as we are able to open this Pandora’s field just a little [more], we’ll actually begin to know whether or not symbiont microbes are simply as necessary as nuclear genes are for speciation,” Bordenstein stated. “That’s an enormous query.” 

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