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Battling the Bite: Tradeoffs in Immunity to Insect-Borne Pathogens
Immunity
Previews Battling the Bite: Tradeoffs in Immunity to Insect-Borne Pathogens David Samuel Schneider1,* 1Stanford Microbiology and Immunology, Stanford, CA 94305-5124, USA *Correspondence: [email protected] 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 bloodfeeding 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 anesthesia, 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 contained in an insect bite, but to be transmitted 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 transmission 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 mosquitoes, as evidenced by the diseases caused by these infections. Culicine mosquitoes like Aedes aegypti and Aedes albopictus, among others, are responsible for transmitting 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, mosquito olfaction of a vertebrate host, transmission to a vertebrate host, spread within the host, or transmission back to a mosquito 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 transmission of the virus from the site of infection to draining lymph nodes, this effect was a transitory victory. This neutrophildriven bite with a viral response attracts myeloid cells, which are ultimately responsible for spreading the disease from the initial site of infection (Figure 1). The authors showed that depletion of neutrophils with an antibody could prevent this
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 disease 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 human 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 infections 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 manipulate this response? Is there a risk that in developing treatments to alter our immune response to better defend against some pathogens, we will expose ourselves 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 (Collin 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 adaptive immunity-driven immune response in response to a bite, which could prevent pathogen spread. Reducing the immune
Immunity 44, June 21, 2016 ª 2016 Published by Elsevier Inc. 1251
Immunity
Previews
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 pathogens, like leishmania, but would promote susceptibility to some mosquito-borne viruses. The result is that we evolve a balanced response that allows pathogens to sneak around the edges of our defenses. If we understand the diseases 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.
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 pressures 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 disinterested 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 virulence because this was required for trans-
REFERENCES Ayres, J.S., and Schneider, D.S. (2012). Annu. Rev. Immunol. 30, 271–294. Collin, N., Gomes, R., Teixeira, C., Cheng, L., Laughinghouse, A., Ward, J.M., Elnaiem, D.E., Fischer, L., Valenzuela, J.G., and Kamhawi, S. (2009). PLoS Pathog. 5, e1000441. Oliveira, F., Rowton, E., Aslan, H., Gomes, R., Castrovinci, P.A., Alvarenga, P.H., Abdeladhim, M., Teixeira, C., Meneses, C., Kleeman, L.T., et al. (2015). Sci. Transl. Med. 7, 290ra90. Pingen, M., Bryden, S.R., Pondeville, E., Schnettler, E., Kohl, A., Merits, A., Fazakerley, J.K., Graham, G.J., and McKimmie, C.S. (2016). Immunity 44, this issue, 1455–1469. Read, A.F., Baigent, S.J., Powers, C., Kgosana, L.B., Blackwell, L., Smith, L.P., Kennedy, D.A., Walkden-Brown, S.W., and Nair, V.K. (2015). PLoS Biol. 13, e1002198. Schneider, B.S., and Higgs, S. (2008). Trans. R. Soc. Trop. Med. Hyg. 102, 400–408. Vale, P.F., Fenton, A., and Brown, S.P. (2014). PLoS Biol. 12, e1001769.
Previews Battling the Bite: Tradeoffs in Immunity to Insect-Borne Pathogens David Samuel Schneider1,* 1Stanford Microbiology and Immunology, Stanford, CA 94305-5124, USA *Correspondence: [email protected] 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 bloodfeeding 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 anesthesia, 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 contained in an insect bite, but to be transmitted 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 transmission 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 mosquitoes, as evidenced by the diseases caused by these infections. Culicine mosquitoes like Aedes aegypti and Aedes albopictus, among others, are responsible for transmitting 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, mosquito olfaction of a vertebrate host, transmission to a vertebrate host, spread within the host, or transmission back to a mosquito 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 transmission of the virus from the site of infection to draining lymph nodes, this effect was a transitory victory. This neutrophildriven bite with a viral response attracts myeloid cells, which are ultimately responsible for spreading the disease from the initial site of infection (Figure 1). The authors showed that depletion of neutrophils with an antibody could prevent this
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 disease 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 human 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 infections 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 manipulate this response? Is there a risk that in developing treatments to alter our immune response to better defend against some pathogens, we will expose ourselves 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 (Collin 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 adaptive immunity-driven immune response in response to a bite, which could prevent pathogen spread. Reducing the immune
Immunity 44, June 21, 2016 ª 2016 Published by Elsevier Inc. 1251
Immunity
Previews
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 pathogens, like leishmania, but would promote susceptibility to some mosquito-borne viruses. The result is that we evolve a balanced response that allows pathogens to sneak around the edges of our defenses. If we understand the diseases 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.
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 pressures 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 disinterested 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 virulence because this was required for trans-
REFERENCES Ayres, J.S., and Schneider, D.S. (2012). Annu. Rev. Immunol. 30, 271–294. Collin, N., Gomes, R., Teixeira, C., Cheng, L., Laughinghouse, A., Ward, J.M., Elnaiem, D.E., Fischer, L., Valenzuela, J.G., and Kamhawi, S. (2009). PLoS Pathog. 5, e1000441. Oliveira, F., Rowton, E., Aslan, H., Gomes, R., Castrovinci, P.A., Alvarenga, P.H., Abdeladhim, M., Teixeira, C., Meneses, C., Kleeman, L.T., et al. (2015). Sci. Transl. Med. 7, 290ra90. Pingen, M., Bryden, S.R., Pondeville, E., Schnettler, E., Kohl, A., Merits, A., Fazakerley, J.K., Graham, G.J., and McKimmie, C.S. (2016). Immunity 44, this issue, 1455–1469. Read, A.F., Baigent, S.J., Powers, C., Kgosana, L.B., Blackwell, L., Smith, L.P., Kennedy, D.A., Walkden-Brown, S.W., and Nair, V.K. (2015). PLoS Biol. 13, e1002198. Schneider, B.S., and Higgs, S. (2008). Trans. R. Soc. Trop. Med. Hyg. 102, 400–408. Vale, P.F., Fenton, A., and Brown, S.P. (2014). PLoS Biol. 12, e1001769.