virology blog
About viruses and viral disease
The TWiV team discuss the use of quantum dots to study uncoating of influenza virus in real time, and induction of endothelial dysfunction by flavivirus NS1 proteins in a tissue-specific manner.
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Show notes at microbe.tv/twiv
Mosquito saliva, which is injected into the host as a mosquito probes for a blood vessel, contains a collection of chemicals which include anticoagulants to prevent blood clotting, vasodilators to keep blood vessels wide, and anesthetics to prevent us from sensing the mosquito. Saliva also contains components that enhance viral replication, dissemination, and pathogenesis by inducing an inflammatory response that inadvertently promotes infection by providing new cell targets for infection (paper link).
To separate the bite from virus inoculation, mice were first exposed to Aedes aegyptii mosquitoes, and then infected at the bite site with two different mosquito transmitted viruses, Semliki Forest virus or Bunyamwera virus. Mosquito bites caused more virus replication at the inoculation site, greater dissemination of virus, and more lethality compared with control mice that received only virus.
How does mosquito saliva enhance virus replication and dissemination? Part of the story is that as the mosquito probes for a blood vessel, it causes damage that leads to vascular leakage and accumulation of fluid (edema) which inhibits movement of virus to draining lymph nodes.
But delaying dissemination of virus alone does not promote infection and disease. Mosquito bites cause an infiltration of neutrophils (a type of white blood cell) into the bite site. The edema at the bite site is enhanced by neutrophils, because depleting these cells from mice greatly reduced edema. This depletion also returned viremia to levels observed in unbitten control mice, and restored dissemination of virus to draining lymph nodes. Neutrophils are not susceptible to infection with Semliki Forest virus, and therefore cannot explain the increase in virus replication at the bite site.
Enhanced virus replication in the skin occurs because the neutrophils elaborate chemokines that attract macrophages, which can be infected by Semliki Forest virus and Bunyamwera virus. One of the chemokines produced by neutrophils that is a macrophage attractant – CCL2 – binds a receptor on macrophages. Mice lacking the gene encoding the CCL2 receptor are protected from bite enhancement of Semliki Forest virus enhancement.
When a mosquito bites a host, it delivers saliva along with a virus. The saliva induces an inflammatory response and attracts neutrophils into the bite site. The resulting edema holds virus at the bite site until chemokines produced by neutrophils attract macrophages, which are then infected. The virus produced disseminates widely, reaching secondary tissues and causing disease.
It seems likely that the ability to replicate in macrophages that are recruited to the bite site is a property that was selected during evolution of mosquito-transmitted viruses. By replicating in macrophages, the amount of virus in the blood is increased, as well as the likelihood that the virus will be picked up by another mosquito and transmitted to a new host – a powerful selection mechanism. The down side – increased disease in the mammalian host – is an accidental side effect.
Think about that the next time you are scratching that raised bump on your skin caused by a mosquito bite.
On episode #379 of the science show This Week in Virology, Scott Tibbetts joins the TWiVirate to describe his work on the role of a herpesviral nocoding RNA in establishment of peripheral latency, and then we visit two last minute additions to the Zika virus literature.
You can find TWiV #379 at microbe.tv/twiv, or listen below.
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The clinical signs of an acute viral infection – characterized by rapid onset of disease with a short but sometimes severe course – are often obvious. These include coughing, sneezing, rashes and poxes, or headache. What takes place within the body while these symptoms develop?
Examination of the time course of an acute infection such as poliomyelitis reveals significant differences in the onset of clinical symptoms and appearance of virus or antiviral antibodies. The data in the figure (click for a larger view) come from studies of the disease in humans, which was common in the US until the early 1960s and therefore was extensively described in many medical texts. Within 2 days of exposure, virus levels begin to rise in feces and throat secretions, but no signs of disease are evident until day 7, when headache, sore throat, and nausea develop. The appearance of these non-specific symptoms (e.g. not unique to infection with any particular viral infection) correspond with peak levels of virus in the blood. Both subside by day 10. Antiviral antibodies begin to accumulate in the blood at the end of the viremic stage, around days 9-10.
Ninety-nine percent of all poliovirus infections end at this stage. In the remainder, the virus enters the central nervous system where it multiplies rapidly and reaches peak levels at day 13-14. At this time, headache and nausea return, accompanied by stiffness, pain, and in some cases, paralysis. During this central nervous system phase of the infection, levels of virus in throat secretions decline but remain high in the feces.
This typical pattern of acute infection has several practical consequences. Shedding of virus soon after exposure, in the pre-symptomatic period, facilitates the spread of infection. These individuals do not develop serious illness and remain in contact with others. By the time symptoms appear – either the mild symptoms or paralysis – virus in the blood is already declining. An antiviral compound given at this time would have no effect on the outcome of disease. Antibodies peak late in infection – too late to have a significant impact on the course of disease. This finding provided the early clues that lymphocytes, not antibodies, play a major role in clearing many acute viral infections.
If this hand-drawn schematic looks dated, it is because it was taken from a 1959 book entitled “Viral and Rickettsial Infections of Man”, edited by Rivers and Horsfall. It contains chapters written by the virology luminaries of the time, including George Hirst, Igor Tamm, A.D. Hershey, John Enders, Edwin Lennette, Albert Sabin, Jonas Salk, and David Bodian. Much of the information is dated, but some of it – including the course of poliomyelitis – established the basic principles of viral pathogenesis that will never be obsolete.