Immunity
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Battling the Bite: Tradeoffs in Immunity
to Insect-Borne Pathogens
David Samuel Schneider1,*
1Stanford Microbiology and Immunology, Stanford, CA 94305-5124, USA
*Correspondence: dschneid@stanford.edu
http://dx.doi.org/10.1016/j.immuni.2016.06.008
Effective pathogens are successful, by definition, because they can defeat our immune response. Pingen
et al. (2016) in this issue of Immunity demonstrate that some mosquito-transmitted viruses depend upon a
strong host immune response triggered by the innate immune response to the bite to promote dissemination
through the body.
Insect bites are complicated; a blood-
feeding arthropod doesn’t simply slice
open our skin and feed on the pooling
blood or dip a proboscis into a capillary
for a drink. If they tried that, they would
surely get slapped or if we failed to notice
the bite, our rapid ability to clot would
prevent the pest from feeding. Mosquito,
sandfly, blackfly, bug, and tick salivas
contain a pharmacopeia of compounds
that manipulate the bite to provide anes-
thesia, modulate inflammation, reduce
clotting, and even physically glue the
blood sucker to the host (Schneider and
Higgs, 2008). Vector-mediated disease
transmission of viruses, bacteria, worms,
and protozoa occurs in the middle of this
battlefield where the host is mounting
a response to a small wound while
the arthropod interferes with the host
response. Pingen et al. (2016) wanted to
understand how these non-viral factors
affect pathogen proliferation.
Diseases transmitted through arthropod
bites are peculiar in that they must initiate
an infection with the tiny inoculum con-
tained in an insect bite, but to be trans-
mitted from a vertebrate host back to an
insect, the virus must reach high titers in
the blood so that it can be picked up in
a miniscule blood meal. Typically, this
means that the pathogens need to spread
systemically and replicate spectacularly;
their growth burst and the accompanying
immune reaction are responsible for the
symptoms we experience. The balance
between how hard the host tries to clear
the pathogen and the intensity of the
resulting symptoms defines our disease
tolerance to the pathogen (Ayres and
Schneider, 2012). In the case of viral trans-
mission from an Aedes mosquito, this
balance seems set too much toward killing
the pathogen, which inadvertently leads to
its spread.
Our immune responses fail to contain
many viral infections spread by mosqui-
toes, as evidenced by the diseases caused
by these infections. Culicine mosquitoes
like Aedes aegypti and Aedes albopictus,
among others, are responsible for trans-
mitting important viruses like yellow fever,
dengue, and Zika. Yellow fever has been
causing human suffering for centuries,
and dengue and Zika are newly emerging
threats. Any step where we can interfere
with the process of disease transmission,
from viral growth in the mosquito, mos-
quito olfaction of a vertebrate host, trans-
mission to a vertebrate host, spread within
the host, or transmission back to a mos-
quito vector will help us limit the damage
caused by these infections. Pingen et al.
(2016) set out to determine how a mosquito
bite contributed to an arbovirus infection to
identify potential restriction points for viral
treatment.
The authors developed a model in
which they introduced the insect-borne
Semliki forest virus (SFV) into the skin of
a mouse via an injection. They injected
mice either in un-manipulated skin or at
the site of a mosquito bite and found
that the virus reached higher systemic
titers when introduced at a bite site.
Though they found that edema occurring
at the site of infection limits initial trans-
mission of the virus from the site of infec-
tion to draining lymph nodes, this effect
was a transitory victory. This neutrophil-
driven bite with a viral response attracts
myeloid cells, which are ultimately res-
ponsible for spreading the disease from
the initial site of infection (Figure 1). The
authors showed that depletion of neutro-
phils with an antibody could prevent this
Immunity 44, June 21, 2016 ª 2016 Published by Elsevier Inc. 1251
dissemination as could suppression of
caspase 1 function with the protease
inhibitor Z-VAD-FMK. If the host limited
its immune response to a bite with a viral
challenge naturally, it would limit the
symptoms of the disease and prevent dis-
ease transmission to another mosquito.
Why would our immune system evolve
to do something so foolish as trafficking
a virus? One answer might be that these
viral pathogens are not co-evolved hu-
man pathogens and thus our immune
systems haven’t had the opportunity to
evolve an effective response. It is hard
to test this idea because it predicts that
our immune response excels at blocking
infections of viruses that have infected
us historically and now don’t make us
sick. Of course we don’t study these in-
fections because they have little impact
on our lives; rather, we study things that
can evade our immune responses and
cause pathology.
If our immune responses have evolved
to be balanced to fend off a variety of
pathogens, what will happen if we manip-
ulate this response? Is there a risk that
in developing treatments to alter our im-
mune response to better defend against
some pathogens, we will expose our-
selves to new ones? There is already an
example that suggests this could happen.
Sandflies transmit leishmaniasis and the
parasite is transmitted more efficiently if
the vertebrate host does not suffer a large
inflammatory response after the bite (Col-
lin et al., 2009; Oliveira et al., 2015). This
finding provides a potential route for a
vaccine based on sandfly saliva, which
would cause hosts to have a local adap-
tive immunity-driven immune response
in response to a bite, which could prevent
pathogen spread. Reducing the immune

Figure 1. Insect Bites Encourage Viral Spread
Virus particles in an unbitten inoculation site do not infect a large number of macrophages, resulting in
minimal viral spread (left). When virus is inoculated into a bite site, a larger number of neutrophils are
attracted to the site by the bite. These neutrophils secrete cytokines, which in turn attract myeloid cells to
the bite site. These myeloid cells become infected with the virus, enter the blood stream, and spread the
pathogen throughout the body.
response against some insect bites could
increase disease transmission from other
insect bites; we will need to pay attention
to the collection of infectious threats
faced by patients before prophylactically
altering generalized immune responses.
Our growing problems with antibiotic
resistance should teach us that we should
always consider the evolutionary pres-
sures our treatments place on pathogens
(Vale et al., 2014). If we reduce the
immune response to limit transmission,
how could this go wrong and affect viral
evolution—in a bad way? For a disease
that is transmitted through humans, the
pathogen must spread through the body
and replicate. Suppose we limited virus
spread by lowering the sensitivity of neu-
1252 Immunity 44, June 21, 2016
trophils so that viruses remained trapped
at the bite site; one evolutionary route
the virus might have to overcome this
problem would be to increase the amount
of pathology caused at the wound site,
to attract the attention of drugged disin-
terested neutrophils. This would be bad
enough for a treated person infected
with this evolved virus, but would be
worse for an untreated person as they
would face a pathogen with increased
virulence. Vaccinations of chickens for
Marek’s disease have driven this type of
virulence evolution (Read et al., 2015).
Use of a leaky vaccine meant to protect
chickens from this devastating disease
selected for viruses with increased viru-
lence because this was required for trans-
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mission. This made the disease worse
and necessitated our development of
new vaccines, which led to the evolution
of yet more virulence.
Our immune system has to defend
against a variety of potential pathogens
and to balance the investment in each
defense. A high rate of local inflammation
might be ideal for limiting some patho-
gens, like leishmania, but would promote
susceptibility to some mosquito-borne
viruses. The result is that we evolve a
balanced response that allows patho-
gens to sneak around the edges of
our defenses. If we understand the dis-
eases faced by patients, we may be
able to develop prophylactic treatments
that prevent dissemination of the disease
through the body with the risk that we
might drive the evolution of more virulent
pathogens. It is therefore essential that
we understand how each pathogen is
spread to carefully develop these new
treatments.
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