Is Wolbachia going to solve our Zika,
dengue, chikungunya, and malaria problems? The short answer is maybe, the long
answer is below. I have to be honest; this was a difficult post to write. The
topic is technical and I found myself amassing a ridiculously long citation
list (a tribute to how much foundational research plays into this story). My
usual tack in this blog is to profile one of the citations and highlight how
important that research is to the larger puzzle. I did that with the first Wolbachia installment
but if I did that with everyone in this story we would end up with a book - which
I could be working on. There are many unique and interesting players; I only
skimmed the surface of Wolbach, and didn’t even get to Marshall Hertig or the
countless others. Regardless of the level of difficulty, I did want to address
the potential outcomes we could expect from using Wolbachia-infected mosquitoes to control disease transmission, and
address the important question: How effective will Wolbachia-infected mosquitoes be at limiting the spread of human
diseases? If you haven’t read the previous two posts in this series (I & II),
I recommend you do so.
It is probably clear by now that scientists
are currently relying on decades of Wolbachia
research (covering many different types of insects) to get us to this point. In
order to take the next step it is necessary to develop experiments testing how Wolbachia will spread through an Aedes aegypti mosquito population once
infected individuals are introduced into a disease afflicted area. Interestingly,
one of the very intriguing things about Wolbachia
that has been extensively studied is its mode of transmission. After years of
research, hours of scientific brainpower, and 100+ publications, the true
nature of Wolbachia as a genetic
manipulator has been revealed. Wolbachia
manipulates the reproductive genetics of its host to enable its spread through a population. How does it do
this? The mechanisms of manipulation rely on the premise that Wolbachia is vertically transmitted,
which means it is passed from parent to offspring. Specifically, Wolbachia is transferred from mother to
offspring in the cytoplasm of the egg cell (the cytoplasm is the jelly-like
matrix of a cell); Wolbachia cannot
be passed from father to offspring in sperm cells. These are the four types of
genetic manipulation that can occur in natural populations based on this type
vertical transmission:
1. Cytoplasmic incompatibility: If Wolbachia-infected males mate with
uninfected females, or females infected with a different Wolbachia strain, the sperm will die before they can fertilize the
egg1,2. The outcome of cytoplasmic incompatibility = increased Wolbachia infection in the population
because infected males can only produce infected offspring.
2. Parthenogenesis: Females can produce
offspring without mating with a male3. The outcome of
parthenogenesis = increased number of females in a population spreading Wolbachia.
3. Feminization of male offspring: Wolbachia infection in embryos causes
male offspring to develop into females4,5. The outcome = increased
number of females in a population spreading Wolbachia.
4. Male killing: Infected male embryos are
not viable, leading to populations that are mostly female6. The
outcome = increased number of females in a population spreading Wolbachia.
Notice a trend? Each of these mechanisms is
often specific to a particular type of insect, so it is important to point out
that the fruit fly strains of Wolbachia
that prevent A. aegypti from
spreading disease manipulate the genetics of their host through cytoplasmic incompatibility.
Our first window into the transmission
dynamics of Wolbachia is based on a
study done in 1971 by Janice Harumi Yen and Allan Ralph Barr at the UCLA School
of Public Health2. Decades after S. Burt Wolbach and M. Hertig first
discovered Wolbachia, Yen and Barr (studying
the same species of mosquito, Culex
pipiens) found that Wolbachia infection
reduced the ability of certain C. pipiens
mosquitoes from producing offspring. Through detailed studies, Yen and Barr
found that when sperm were swimming toward the nucleus of the egg, they died
after swimming through a field of Wolbachia
bacterial cells. Yen and Barr called this phenomenon cytoplasmic
incompatibility, a very syllabic phrase that essentially means: the environment
of the egg is lethal to the sperm and the egg does not get fertilized. Because
the sperm died after swimming through the Wolbachia
field, Yen and Barr hypothesized cytoplasmic incompatibility had something to
do with the Wolbachia cells present within
the egg cell of the mosquito.
Yen and Barr saw the implications of
cytoplasmic incompatibility for controlling mosquito populations, but in a
different way than is currently being considered.
What we are thinking about here is not a way to control mosquito populations,
but a way to release infected mosquitoes and then getting the infection to
spread. In this scenario, you want uninfected mosquitoes (that can transmit
human diseases) to die, but you want infected mosquitoes (that do not transmit
human diseases) to reproduce and spread the Wolbachia
infection. The beauty of Wolbachia as
a genetic manipulator, especially when it comes to cytoplasmic incompatibility,
is that it accomplishes both of these goals.
We are building here. This is the foundation
scientists are currently relying on to reduce the spread of Zika and other diseases
transmitted by mosquitoes. There may be a voice in the back of your head
saying, huh, I wonder if a politician at some point in history spoke out about
wasteful spending on insects, their bacteria, or the fruit flies from which the
effective Wolbachia strain came from?
And the answer is yes,
numerous times. Imagine if none of this research had been done.
Now that we know Wolbachia infection has the inherent ability to spread through a
population due to cytoplasmic incompatibility, we can plug this information
into mathematical models (!) and make theoretical predictions. Don’t stop
reading, we don’t have to get into the mathematics to understand what factors will
affect how Wolbachia will spread
through a mosquito population after infected individuals are released. The
first factor to consider is the number of mosquitoes that currently exist in
the target area. Jansen and colleagues7 found that the smaller the
population of mosquitoes, the fewer infected individuals that need to be
released; increasingly larger mosquito populations required the release of more
infected adults and eggs. Thus, when planning a release it is important to consider
the season, as we know that mosquito populations fluctuate throughout the year.
It is also beneficial to have releases coincide with other population control
methods (such as some of the biocontrol options talked about in the last post)
to reduce population sizes before the release occurs.
What are the associated risks? With the
implementation of any control option there are risks to consider. Risk factors
include logistical issues, like not being able to generate enough infected mosquitoes,
and public opposition; there are also ecological and economic consequences to
consider. Groups of individuals with expertise in different aspects of
potential outcomes (biological, economic, and public) were convened to brainstorm
and discuss widespread release of Wolbachia-infected
mosquitoes8. Generally speaking, the risks were calculated as being
very low. One of the biggest concerns was that households would reduce efforts
to control mosquitoes (eliminate sources of standing water, etc.). Another
concern was that dengue would evolve to overcome the resistance of Wolbachia-infected mosquitoes to dengue
infection. This type of concern is persistent when dealing with pathogens that
can evolve very rapidly (we have talked about this before).
There is a reason a new flu vaccine is developed every year – it is called
evolution. However, the panel of experts agreed that this risk was relatively
low due to the efficiency with which Wolbachia-infected
mosquitoes prevent the transmission of dengue.
With all this in mind, release of Wolbachia-infected mosquitoes was
recently done in Australia in dengue-impacted regions with successful results9.
One month before the release of infected mosquitoes standing water sources
(mosquito breeding grounds) were removed from the release sites. Over a period
of 9-10 weeks, approximately 150,000 mosquitoes were released at each of two
sites in Australia. With each subsequent release, the Wolbachia infection rate increased, and continued to increase up to
five weeks after the last release of infected mosquitoes. At this point though,
is too early to say how the release affected the transmission of dengue, and
scientists are currently evaluating the best way to monitor these effects10.
One important thing to note is that much of
the research done on Wolbachia-infected
mosquitoes was implemented with the goal of reducing the spread of dengue
(primarily), not Zika. However, because these two diseases are similar, and
transmitted by the same mosquito vector, this research can be applied to the
recent Zika outbreak. This is important because it highlights the importance of
supporting research during a time of crisis, as well in between crises. Our
ability to respond to disease outbreaks is directly related to the research available
at the time the outbreak occurs. This is especially pertinent as the number of infectious disease outbreaks is predicted to increase, in part due to climate change.
Are you still with me? Have I answered the
question? It may seem like the way my twenty-something self would have
responded to the question of having a boyfriend: it’s complicated. It is
complicated, but I think the bottom line is that Wolbachia-infected mosquitoes will be an important aspect of a
multi-pronged approach to controlling human diseases vectored by mosquitoes. I
think scientists have come a long way with this line of research and it has the
potential to have a significant payoff. If you are still yearning for more I
will steer you to the Eliminate Dengue website. This is an amazing and well-organized resource with an extensive
publication section that provides PDFs of nearly all of the articles associated
with the program (also includes current research on Zika).
6Hurst GDD, Jiggins FM, Hinrich Graf von der
Schulenburg J, Bertrand D, West SA, Goriacheva II, Zakharov IA, Werren JH,
Stouthamer R, Majerus MEN (1999) Male-killing Wolbachia in two insect species.
Proceedings of the Royal Society London B 266:735-740.
9Hoffmann AA, Montgomery BL, Popovici J,
Iturbe-Ormaetxe I, Johnson PH, Muzzi F, Greenfield M, Durkan M, Leong YS, Dong
Y, Cook H, Axford J, Callahan AG, Kenny N, Omodei C, McGraw EA, Ryan PA,
Ritchie SA, Turelli M, O’Neill SL (2011) Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission.
Nature 476:454-457.
10Lambrechts L, Ferguson NM, Harris E, Holmes
EC, McGraw EA, O’Neill SL, Ooi EE, Ritchie SA, Ryan PA, Scott TW, Simmons CP,
Weaver SC (2015) Assessing the epidemiological effect of Wolbachia for dengue control.
The Lancet Infectious Diseases 15:862-866.
