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Three years ago the mosquito-disease control world was abuzz with news of a promising new method to prevent mosquitoes from carrying, and passing on, dengue to humans. It involved infecting mosquitoes with Wolbachia, a bacterium commonly carried by a variety of insects around the world, and then releasing them into the wild.
Scientists discovered that when mosquitoes are infected with Wolbachia, their lifespan was halved and their ability to transmit dengue was greatly reduced, although the exact mechanism behind those effects wasn’t understood.
And given that, for mosquitoes – Wolbachia is a sexually transmitted disease – it was expected that wouldn’t take long after releasing a relatively small number of infected mozzies to start a local epidemic. We looked at some of these early trials back in 2011, with A Mosquito STD To Fight Dengue & A Sexually Transmitted Disease Cure).
And the early results were impressive. In early 2011 scientists in Queensland, Australia began releasing thousands of Wolbachia infected mosquitoes each week into the remote communities of Gordonvale and Yorkeys Knob, and within weeks infected mosquitoes overran the uninfected mosquito population in both test environments.
When an infected male mosquito mates with an uninfected female, the resultant fertilized eggs will fail to mature due to an abnormality known as cytoplasmic incompatibility (CI). Only the offspring from the union between already infected parents survive.
Since the Wolbachia infection is passed down from one generation to the next, that was expected to give the Wolbachia infected mosquitoes quite an evolutionary advantage.
And over the past couple of years hopes have even been raised that Wolbachia might be used to control malaria as well, as laboratory studies showed that infected anopheles stephensi mosquitoes developed resistance to malarial infection.
Wolbachia Invades Anopheles stephensi Populations and Induces Refractoriness to Plasmodium Infection
Guowu Bian1,2, Deepak Joshi1, Yuemei Dong3, Peng Lu1, Guoli Zhou1, Xiaoling Pan1, Yao Xu1, George Dimopoulos3, Zhiyong Xi1,4,*
+Wolbachia is a maternally transmitted symbiotic bacterium of insects that has been proposed as a potential agent for the control of insect-transmitted diseases. One of the major limitations preventing the development of Wolbachia for malaria control has been the inability to establish inherited infections of Wolbachia in anopheline mosquitoes. Here, we report the establishment of a stable Wolbachia infection in an important malaria vector, Anopheles stephensi. In A. stephensi, Wolbachia strain wAlbB displays both perfect maternal transmission and the ability to induce high levels of cytoplasmic incompatibility. Seeding of naturally uninfected A. stephensi populations with infected females repeatedly resulted in Wolbachia invasion of laboratory mosquito populations. Furthermore, wAlbB conferred resistance in the mosquito to the human malaria parasite Plasmodium falciparum.
While Wolbachia’s stock is riding high, yesterday a study published in PLoS Neglected Tropical Diseases raises a bit of an unexpected red flag.
Researchers from Penn State, the University of Maryland, New York’s DOH and the State University of New York at Albany infected Culex tarsalis mosquitoes with Wolbachia and then allowed them to dine on West Nile Virus infected blood, fully expecting to see the same reduction in viral carriage as observed with dengue.
Instead, they found quite the opposite:
Wolbachia Enhances West Nile Virus (WNV) Infection in the Mosquito Culex tarsalis
Brittany L. Dodson, Grant L. Hughes, Oluwatobi Paul, Amy C. Matacchiero, Laura D. Kramer, Jason L. Rasgon mail
Published: July 10, 2014 DOI: 10.1371/journal.pntd.0002965
Abstract
Novel strategies are required to control mosquitoes and the pathogens they transmit. One attractive approach involves maternally inherited endosymbiotic Wolbachia bacteria. After artificial infection with Wolbachia, many mosquitoes become refractory to infection and transmission of diverse pathogens. We evaluated the effects of Wolbachia (wAlbB strain) on infection, dissemination and transmission of West Nile virus (WNV) in the naturally uninfected mosquito Culex tarsalis, which is an important WNV vector in North America. After inoculation into adult female mosquitoes, Wolbachia reached high titers and disseminated widely to numerous tissues including the head, thoracic flight muscles, fat body and ovarian follicles.
Contrary to other systems, Wolbachia did not inhibit WNV in this mosquito. Rather, WNV infection rate was significantly higher in Wolbachia-infected mosquitoes compared to controls. Quantitative PCR of selected innate immune genes indicated that REL1 (the activator of the antiviral Toll immune pathway) was down regulated in Wolbachia-infected relative to control mosquitoes. This is the first observation of Wolbachia-induced enhancement of a human pathogen in mosquitoes, suggesting that caution should be applied before releasing Wolbachia-infected insects as part of a vector-borne disease control program.
Author Summary
Current methods to control mosquitoes and the pathogens they transmit are ineffective, partly due to insecticide and drug resistance. One novel control method involves exploiting naturally occurring Wolbachia bacteria in insects. Wolbachia are bacterial symbionts that are attractive candidates for mosquito-borne disease control due to their ability to inhibit pathogens infecting humans. Additionally, Wolbachia affects insect reproduction to facilitate its own transmission to offspring, which has been exploited to establish the bacterium in naturally uninfected field populations. Most Wolbachia pathogen control research has focused on Aedes and Anopheles mosquitoes, but Culex mosquitoes also transmit pathogens that affect human health.
We evaluated impacts of Wolbachia infection on West Nile virus (WNV) in the naturally uninfected mosquito Culex tarsalis. Wolbachia was able to efficiently establish infection in Cx. tarsalis but contrary to other studies, Wolbachia enhanced rather than inhibited WNV infection. Enhancement occurred in conjunction with suppression of mosquito anti-viral immune gene expression. This study indicates that Wolbachia control strategies to disrupt WNV via pathogen interference may not be feasible in Cx. tarsalis, and that caution should be used when releasing Wolbachia infected mosquitoes to control human vector-borne diseases.
Skipping down to the discussion section of the study, the authors write:
To our knowledge this is first study showing Wolbachia can potentially enhance a vector-borne pathogen that causes human disease. Our results, combined with other Wolbachia enhancement studies [17]–[20], [46]–[47], suggest that field deployment of Wolbachia-infected mosquitoes should proceed with caution.
Wolbachia effects on all potential pathogens in the study area should be determined. Additionally, several studies have shown that Wolbachia is capable of horizontal transfer to other insect species which could have unforeseen effects on non-target insects [52]–[54].
A lack of understanding of Wolbachia-pathogen-mosquito interactions could impact efficacy of disease control programs. Cx. tarsalis is a competent vector for many human pathogens, and further studies that assess alternative Wolbachia strains and viruses in Cx. tarsalis may elucidate the importance of host background on pathogen interference phenotypes in this medically important mosquito species.
None of this knocks Wolbachia out of the running as a potential control for dengue or malaria, two of the greatest impact infectious diseases in the world. This is a preliminary study, based on a single strain of Wolbachia in a single species of mosquito, and much more research is needed.
It does, however, remind us that there are a great many more variables in the wild than can be accounted for inside the laboratory.
And that when contemplating `bio-engineering’ - no matter how noble the goal - one must always consider the law of unintended consequences and proceed with caution.
