How mosquitoes survive dengue virus infection
Dengue fever and dengue hemorrhagic fever are major global public health burdens, with up to 100 million cases occurring annually, yet no vaccines or specific preventative medicines are currently available. Dengue viruses, globally the most prevalent arboviruses, are transmitted to humans by persistently infected Aedes aegypti mosquitoes. However, although DENVs can cause severe disease in humans, mosquito infections are non-pathogenic and persistent. Determining how the virus evades the mosquito’s defense is an important next step in research that aims to fight disease by interrupting the growth of dengue virus within the mosquito before it can be transmitted. Researchers have discovered that mosquitoes that transmit deadly viruses such as dengue avoid becoming ill by mounting an immediate, potent immune response. Because their immune system does not eliminate the virus however, they are able to pass it on to a new victim. The researchers showed that RNA interference – a mosquito immune response – is initiated immediately after they ingest blood containing dengue virus, but the virus multiplies in the mosquitoes nevertheless.
RNA interference is an evolutionarily ancient antiviral defense used by mosquitoes and other invertebrates to destroy the RNA of many invading arthropod-borne viruses. This team of researchers previously showed that ramping up the RNA interference response in mosquitoes prevented dengue infection, and now they show that temporarily impairing this immune response increased virus transmission. The investigators analyzed RNA from adult mosquitoes, finding that both the trigger and initiator molecules for RNA interference were formed after infection, yet viral RNA could readily be detected in the same mosquitoes. They also measured infectious virus rates in the mosquitoes’ saliva, which revealed levels whereby the mosquitoes could transmit the disease to humans. These findings indicate that genetic manipulation of RNA interference could be a significant weapon in stopping dengue virus transmission by Aedes aegypti.
Understanding the mechanisms mosquitoes use to modulate infections by these agents of serious human diseases should give us critical insights into virus–vector interactions leading to transmission. RNA interference (RNAi) is an innate defense mechanism used by invertebrates to inhibit RNA virus infections; however, little is known about the antiviral role of RNAi in mosquitoes. RNAi is triggered by double-stranded RNA, leading to degradation of RNA with sequence homology to the dsRNA trigger. Dengue virus type 2 (DENV2) infection of Ae. aegypti by the natural route generates dsRNA and DENV2-specific small interfering RNAs, hallmarks of the RNAi response; nevertheless, persistent infection of mosquitoes occurs, suggesting that DENV2 circumvents RNAi. DENV2 infection is also modulated by RNAi, since impairment by silencing expression of genes encoding important sensor and effector proteins in the RNAi pathway increases virus replication in the vector and decreases the incubation period before virus transmission.
Dengue Virus Type 2 Infections of Aedes aegypti Are Modulated by the Mosquito’s RNA Interference Pathway. PLoS Pathog 5(2): e1000299
A number of studies have shown that both innate and adaptive immune defense mechanisms greatly influence the course of human dengue virus (DENV) infections, but little is known about the innate immune response of the mosquito vector Aedes aegypti to arbovirus infection. We present evidence here that a major component of the mosquito innate immune response, RNA interference (RNAi), is an important modulator of mosquito infections. The RNAi response is triggered by double-stranded RNA (dsRNA), which occurs in the cytoplasm as a result of positive-sense RNA virus infection, leading to production of small interfering RNAs (siRNAs). These siRNAs are instrumental in degradation of viral mRNA with sequence homology to the dsRNA trigger and thereby inhibition of virus replication. We show that although dengue virus type 2 (DENV2) infection of Ae. aegypti cultured cells and oral infection of adult mosquitoes generated dsRNA and production of DENV2-specific siRNAs, virus replication and release of infectious virus persisted, suggesting viral circumvention of RNAi. We also show that DENV2 does not completely evade RNAi, since impairing the pathway by silencing expression of dcr2, r2d2, or ago2, genes encoding important sensor and effector proteins in the RNAi pathway, increased virus replication in the vector and decreased the extrinsic incubation period required for virus transmission. Our findings indicate a major role for RNAi as a determinant of DENV transmission by Ae. aegypti.
Related:
- MicrobiologyBytes: Dengue Virus
- Dengue Virus
- Clustering of dengue virus infections
- Wolbachia could combat dengue fever
- Dissecting the Cell Entry Pathway of Dengue Virus
Tags: Biology, Emerging disease, Health, Medicine, Microbiology, Science, Virology
How do you think the mosquitoes immune system protects it against the virus, if it is not actually killing the virus? I didn’t quite understand that point (as a layman); could you explain it a little more simply? I am extremely interested in this subject and have been for some years, so I will definitely appreciate any more clear response to me as a layperson.
Eileen
The mosquito serves as a vector for transmission of the virus to humans and therefore it is of evolutionary importance that the virus be able to infect but not kill the mosquito. Since the virus has not evolved to facilitate human to human transmission it must use the mosquito as a “dirty syringe” to keep replicating. It is really a battle of attrition between the virus evolving to replicate to a meaningful level in the mosquito so it is passaged in its silava, and the mosquito’s innate defense mechanisms evolving to keep the viral infection to low enough levels so as to not cause pathology. This work demonstrates that the innate immune mechanism of RNAi has evolved in the mosquito to keep the virus in check (i.e. not kill the mosquito), but not to eliminate all infection. If the virus is not hurting the mosquito’s fitness then why would it invest energy to fully eliminate it? The researchers were able to knock down the expression of genes required by the mosquito to turn on the RNAi pathway in order to see how it affected the virus’ ability to replicate. The results indicate that a reduction in the RNAi response correlates to an increase in virus replication. On the flip side, what if scientists were able to increase the expression of the RNAi genes? One could hypothesize that by doing so the virus would not be able to replicate to a high enough level to be transmitted from mosquito to human.
Hope this helps!
-Clayton
I was wondering if you’ve written anything like this for Chikungunya, and if this would apply to Chikungunya.
Thanks,
Lola
Try this: http://www.google.com/cse?cx=014911858250242089637%3Agrmiutwkd-g&ie=UTF-8&q=Chikungunya