virology blog
About viruses and viral disease
After infection with poliovirus, only about 1% of individuals develop paralysis. I have always wondered whether genetic polymorphisms underlie the rarity of this disease outcome. The results of study carried out in Denmark provide the first insights.
[Read more…] about The rarity of paralysis following poliovirus infection
Host behavior alteration by viruses is known to assist the development of another organism. An example is a parasitoid wasp that injects viruses along with eggs into a caterpillar. The viral genomes encode proteins that subvert the caterpillar immune response, allowing the wasp larva to develop. A similar strategy may enable safe development of a wasp by a ladybeetle.
The parasitoid wasp D. coccinellae lays its eggs inside a ladybeetle. After 20 days of larval development, a prepupa emerges from the ladybeetle and fabricates a cocoon between the beetle’s legs. At the same time, the ladybeetle becomes paralyzed. It remains on top of the cocoon (pictured; image credit), protecting it until an adult wasp emerges. Remarkably, some ladybeetles then resume their normal lives!
Given what we know about how parasitoid viruses can alter the manipulation of their hosts, it was only logical to search for a virus that paralyzes the ladybeetle. Sequencing of RNA from the heads of parasitized ladybeetles revealed the presence of an RNA virus which the authors call D. coccinellae paralysis virus, DcPV. The virus is a new member of a Iflaviruses, a family of picornavirus-like, (+) strand RNA viruses that infect insects. DcPV was found in wasps in Poland, Japan, and The Netherlands, confirming its cosmopolitain nature.
Viral particles were observed in cells lining the wasp oviducts, but not in the lumen. Viral genomes were undetectable in wasp eggs, became more abundant during hatching, and ceased to replicate in adult wasps. The levels of virus in the ladybeetle abdomen and head increase with time to egress, suggesting that it was transmitted from the wasp larvae to the host. In ladybeetles where the wasp egg did not develop, viral replication does not occur.
DcPV appears to be neurotropic. Before larval egression, no changes were observed in the nervous system of the ladybeetle, but glial cells were full of virus particles. After egression, vaculoles developed in glial cells and neurons degenerated. This damage was less severe in beetles that survived and recovered from paralysis. An expansion of glial cells in these hosts might explain how normal brain functions were restored.
Insects respond to infection with an RNA-based antiviral response. Components of the RNA based immune system were down-regulated during larval development, possibly by viral proteins, allowing virus to invade the nervous system. Resumption of the antiviral reponse might enable recovery of the ladybeetle after emergence of the wasp.
It appears that DcPV is a wasp symbiont that manipulates the behavior of the ladybeetle host to ensure development of wasp offspring. This hypothesis can be tested by removing DcPV from infected wasps, or by adding DCpV to uninfected hosts, and determining the effect on larval development.
We now realize that animals are actually holobionts: an aggregate of eukaryotes, bacteria, and viruses. Therefore host-parasite interactions are really holobiont-holobiont interactions.
Evidence is mounting that Zika virus is neurotropic (able to infect cells of the nervous system) and neurovirulent (causes disease of the nervous system) in humans.
The most recent evidence comes from a case report of an 81 year old French man who developed meninogoencephalitis 10 days after returning from a 4 week cruise to New Caledonia, Vanuatu, Solomon Islands, and New Zealand (meningoencephalitis is infection of the meninges - the membranes that cover the brain - and the brain). His symptoms included fever, coma, paralysis, and a transient rash. A PCR test revealed Zika virus genomes in the cerebrospinal fluid, and infectious virus was recovered after applying the CSF to Vero cells in culture.
A second case report concerns a 15 year old girl in Guadeloupe who developed left hemiparesis (weakness of one side of the body), left arm pain, frontal headache, and acute lower back pain. After admission she developed dysuria (difficulty urinating) that required catheterization. PCR revealed the presence of Zika virus genomes in her serum, urine, and cerebrospinal fluid; other bacterial and viral infections were ruled out.
Until very recently Zika virus was believed to cause a benign infection comprising rash, fever, joint pain, red eyes, and headache. There is now strong evidence that the virus can cause congential birth defects, and growing evidence that the virus is neurotropic and neurovirulent. Previously the entire Zika virus genome was recovered from brain tissue of an aborted fetus.
Zika virus is classified in the family Flaviviridae, and other members are known to be neurotropic, including West Nile virus, Japanese encephalitis virus, and tick-borne encephalitis virus. West Nile virus infection may lead to acute flaccid paralysis, meningitis, encephalitis, and ocular manifestations. Examination of additional cases of Zika virus infection will be needed to document the full spectrum of illness caused by this virus.
Update: Neurotropism of Zika virus is also indicated by the findings that the virus infects human cortical neural progenitors.
On episode #331 of the science show This Week in Virology, the TWiVÂ team discusses the possible association of the respiratory pathogen enterovirus D68 with neurological disease.
You can find TWiV #331 at www.microbe.tv/twiv.
An outbreak of respiratory disease caused by enterovirus D68 began in August of this year with clusters of cases in Missouri and Illinois. Since then 691 infections have been confirmed in 46 states in the US.
The number of confirmed infections is likely to increase in the coming weeks, as CDC has developed a more rapid diagnostic test. Previously it was necessary to amplify the viral genome by polymerase chain reaction, followed by nucleotide sequencing to determine the identity of the agent. The new test utilizes real time, reverse transcription PCR which is specific for the EV-D68 strains that have been circulating this summer.
Since its discovery in California in 1962, EV-D68 has been rarely reported in the United States (there were 26 isolations from 1970-2005). Beginning in 2009 it was more frequently linked to respiratory disease outbreaks in North America, Europe, Asia, and Africa. It seems likely that the virus was always circulating, but we never specifically looked for it.
The current EV-D68 outbreak is the largest ever reported in North America. Enterovirus infections are not rare – there are millions every year in the US – but why EV-D68 has been so frequently isolated this year is unknown. One possibility is that the CDC, after the initial outbreak in August 2014, began looking specifically for the virus.
Sequence analysis of the EV-D68 viral genomes indicate that 3 different strains are involved in the US outbreak. These viruses are related to EV-D68 strains that have previously circulated in the US, Europe, and Asia. The sequences are available at GenBank as follows: US-IL-14/18952, US-KY-14/18951, US-MO-14/18950, US-MO-14/18949, US-MO-14/18948, US-MO-14/18947, and US-MO-14/18946.
Most of the illness caused by EV-D68 in the US has been respiratory disease, mainly in children. Five of the 691 confirmed EV-D68 cases were fatal, but whether the virus was responsible is not known.
There have also been some cases of polio-like illness in children in several states associated with EV-D68. In Colorado the virus was isolated from four of 10 children with partial paralysis and limb weakness. Previously there had been one report of an association of EV-D68 with central nervous system disease. In this case viral nucleic acids were detected in cerebrospinal fluid. EV-D68 probably does not replicate in the human intestinal tract because the virus is inactivated by low pH. If the virus does enter the central nervous system, it may do so after first replicating in the respiratory tract, and then entering the bloodstream.
There are no vaccines or antivirals to prevent or treat EV-D68 infection. Most infections will resolve without intervention save for assistance with breathing. As the fall ends in North America, so will infections with this seasonal virus.
Vaccine-associated poliomyelitis caused by the oral poliovirus vaccine is rare, but its occurrence in a healthy, immunocompetent 6-month old child was highly unusual because the child had been previously immunized with two doses of the injected, inactivated poliovirus vaccine (IPV).
The three poliovirus vaccine strains developed by Albert Sabin (OPV, oral poliovirus vaccine) contain mutations which prevent them from causing paralytic disease. When the vaccine is ingested, the viruses replicate in the intestine, and immunity to infection develops. While replicating in the intestinal tract, the vaccine viruses undergo mutation, and OPV recipients excrete neurovirulent polioviruses. These so-called vaccine-derived polioviruses (VDPV) can cause poliomyelitis in the recipient of the vaccine or in a contact. During the years that the Sabin poliovirus vaccines were used in the US, cases of poliomyelitis caused by VDPV occurred at a rate of about 1 per 1.4 million vaccine doses, or 7-8 per year. Once the disease was eradicated from the US in 1979, the only cases of polio were caused by the Sabin vaccine.
To prevent vaccine-associated poliomyelitis, in 1997 the US switched to an immunization schedule consisting of two doses of IPV followed by one dose of OPV. The US then switched to using IPV exclusively in 2000. The child in this case essentially had a polio immunization course similar to that utilized in the US from 1997-2000: two doses of IPV, one dose of OPV. Why did the child develop poliomyelitis?
One clue comes from the fact that after the switch to an IPV-OPV schedule in 1997, there were still three cases of VAPP in 1998 and three in 1999. Another hint comes from a study of immune responses in children given multiple doses of IPV. Most of the children receiving two doses of IPV produced antibodies against types 1 and 2 poliovirus (92 and 94%), but only 74% of children produced antibodies against type 3 poliovirus.
The final piece of information needed to solve this puzzle is that the child in this case had vaccine-associated poliovirus caused by the type 3 strain, which was isolated from his feces.
Therefore, the child in this case most likely did not produce sufficient antibodies to type 3 poliovirus after receiving the two doses of IPV. As a consequence, when he was given OPV, he developed type 3 vaccine-associated poliomyelitis.
This case of VAPP could have been prevented: the child was born in Canada, and as customary in that country since 1995, he received two doses of IPV. At 5 months of age the child and his family visited China, where his parents decided to continue his immunizations according to the local schedule. China still uses OPV, so that is what the child received.