Polio, Still Lurking in the Shadows

The Journal of Neuroscience, January 16, 2013 • 33(3):855–862 • 855

Disease Focus

Editor’s Note: Disease Focus articles provide brief overviews of a neural disease or syndrome, emphasizing potential links to basic neural mechanisms. They are presented in the hope of helping researchers identify clinical implications of their research. For more information, see http://www.jneurosci.org/misc/ifa_minireviews.dtl.

Anthony N. van den Pol Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Introduction in the eventual elimination of this patho- nerves and thus interfering with breath- Iron lungs sucking breath into immobile gen. But recent events have reminded us ing, speaking, or swallowing. Since little bodies. Paralysis. Useless limbs. Forced that although the end of polio may be can be done to cure paralytic poliomyeli- separation of children from their families. near, it is not gone, and can return unex- tis, most efforts focus on prevention of in- Polio conjures up a nightmarish vision, in pectedly. A case in point is found in Tajik- fection, first by immunization and second part due to the rapid and unexpected on- istan, a country bordering Afghanistan by improving sanitation in regions at risk. set of paralysis, the inability to predict and China. Similar to the US, Tajikistan Intramuscular immunization with inacti- who might succumb, and the absence of had not had a reported case of polio in over a vated PV (Salk vaccine) is the safest vac- any cure for the potentially life-long decade from 1997 on. But two years ago cine approach, but requires skilled health poliovirus-associated paralysis. Sporadic (2010), polio showed a dramatic resurgence, professionals for administration, making cases of polio have plagued us for thou- with Ͼ450 cases of polio-induced paralysis it problematic in isolated communities sands of years. In the last 150 years, epi- identified (http://www.cdc.gov/mmwr/ lacking medical expertise. The oral (Sabin) demics of polio have generated fear and preview/mmwrhtml/mm6018a3.htm). But vaccine made from attenuated replication- confusion. Ironically, associated with in- the spread of the virus was worse than the competent PV is easily administered, partic- creased sophistication in clean water sup- 450 cases suggest. Fewer than 1% of those ularly in regions of the world with a paucity plies and sewage disposal in cities, the (nonimmunized) infected by PV show of health care experts, and has played a key immunity that had previously been generated paralytic symptoms (Mueller et al., 2005; role in controlling PV infections in both from early contact with the virus was delayed Modlin, 2010), suggesting that Ͼ45,000 large urban populations and also in remote until a later stage of development, leading to people may have been infected by the vi- villages. A major drawback of the Sabin vac- mass outbreaks of paralytic polio. In 1952 po- rus within only a few months. The out- cine, however, is that rare vaccinated indi- lio caused 3200 deaths, and Ͼ21,000 cases of break in Tajikistan may have arisen from a viduals can develop and even transmit the paralysis in the US alone (http://www.cdc. single infected traveler carrying the virus disease if the PV genome reverts from atten- gov/vaccines/pubs/pinkbook/downloads/ from a region of India where that strain of uated to potentially paralytic wild-type. polio.pdf). Rehabilitation centers such as PV had been endemic. From Tajikistan, Despite the enormous effort in eradi- the one shown in the photograph in Fig- the virus spread to Turkmenistan, Ka- cating poliovirus reaching every nation, ure 1 in 1953 were crowded with young zakhstan, and the Russian Federation. An there are still a surprisingly large number patients. aggressive and rapid vaccination program of mysteries related to the basic underly- After smallpox, poliovirus (PV) has successfully contained this unexpected PV ing mechanisms of PV infection and been on the road to potentially becoming outbreak. PV remains endemic in Paki- spread to the brain, and particularly to the second major human virus to be erad- stan and Afghanistan, and is most prob- spinal cord motor neurons. What is it icated from the planet. Many countries lematic in Nigeria where civil unrest and about human motor neurons that make have not seen a case of poliomyelitis in a suspicion about immunization safety and them selectively vulnerable to PV destruc- decade or longer, raising our confidence intent have complicated and arrested crit- tion, whereas most other neurons, includ- ical vaccination programs. ing sensory neurons, show little infection? The long-term paralysis that occurs in How does PV get into the brain, and how Received June 15, 2012; revised Sept. 7, 2012; accepted Nov. 1, 2012. ϳ This work was supported by NIH NCI 161048 and the Bill and Melinda 1% of patients is the result of PV infec- does it transit to the motor neurons? Why Gates Foundation Grand Challenge-polio vaccine award. I thank Drs. Mike tion and irreversible killing of motor neu- do only a very small percentage (Ͻ1%) of Robek,JustinPaglino,VincentRacaniello,andGuidoWollmannforsugges- rons in the anterior horn, resulting in those with active infections of type 1 PV tions on the manuscript. flaccid paralysis of denervated muscles, or show any neurological symptoms? The re- Correspondence should be addressed to Anthony N. van den Pol at the ϩ above address. E-mail: [email protected]. less commonly killing of motor neurons maining 99 % of those infected show ei- DOI:10.1523/JNEUROSCI.2861-12.2013 in the bulbar region of the brainstem, af- ther no symptoms at all, or in a small Copyright © 2013 the authors 0270-6474/13/330855-08$15.00/0 fecting muscles innervated by cranial percentage of those infected, mild tran- 856 • J. Neurosci., January 16, 2013 • 33(3):855–862 van den Pol • Poliovirus sient symptoms that might include a sore throat, diarrhea, headache, or stiff muscles. Type 2 PV, which may have recently been eradicated, was even less likely to cause paralysis, with Ͻ1 in 2000 infected people showing neurological symptoms (Nathanson and Martin, 1979). Some questions related to neurological dysfunction can be approached from a single-cell perspective. In contrast, events leading to paralytic PV-selective infection of spinal cord motor neurons cannot be understood in the absence of a broader perspective of PV infection within its human host, and within the global environment.

Cellular tropism of PV PV is a member of the picornavirus family and genus Enterovirus. Within this genus there are three serotypes of PV (1, 2, and Figure 1. Photo showing polio patients at Rancho Los Amigos National Rehabilitation Center in California in 1953. Used with 3), all of which can cause disease, and 60ϩ permission of Rancho Los Amigos. human serotypes of enteroviruses, dis- tributed among four virus species (A, B, C, and D). Immunity against one of the three PV serotypes does not protect against the other two, and so historically most effective polio vaccines contained 3 strains of attenuated (Sabin) or inactivated (Salk) virus (Racaniello, 2001). PV is a small (30 nm diameter) virus (Figs. 2, 3) with no surrounding membrane enve- lope. Its genome is a 7.5 kb single positive- sense strand of RNA (Fig. 2), surrounded and protected by the protein capsid. Translation of the PV genome generates a single polyprotein which is cut by viral proteases to generate four capsid proteins, VP1–VP4, and several nonstructural proteins. Nonstructural proteins here refers to proteins that are expressed in the infected cell, but are not incorporated into the virus particle. PV is one of the smallest viruses that causes human disease; in contrast, the DNA genomes of herpes and pox viruses are 20- and 30-fold larger, respec- tively, and these DNA viruses are also 5–10 times bigger than PV. The receptor for poliovirus (PVR) is a member of the Ig superfamily, CD155 (Mendelsohn et al., 1989); all three serotypes of PV use the same PVR. CD155 is necessary, but not sufficient to generate infection. A number of non-neuronal cells express CD155, but show little infection with PV, indicating that other cofactors also play critical roles. PVR is expressed in both human motor neurons, and in muscle end plates (Leon-Monzon et al., 1995). In humans, PVR is expressed in both a membrane-bound and releasable form. The membrane-bound recep- Figure 2. On the left is a schematic representation of the positive strand RNA genome of poliovirus. This is translated into a tor is the critical one for PV entry into a single polyprotein, which is then cleaved into a number of poliovirus proteins. In the upper right, a model of poliovirus is seen, cell. In contrast, the releasable PVR, pres- with the four capsid proteins combining to form the elements of the virus capsid. van den Pol • Poliovirus J. Neurosci., January 16, 2013 • 33(3):855–862 • 857

by the oral route (the critical one in humans; initially infects the throat, including the Zhang and Racaniello, 1997), to the non- tonsils, and gut. From the gut, the virus identical expression pattern of the PVR in may penetrate the lymph nodes. A num- humans and transgenic mice, and possibly ber of models of PV penetration of the to the lack of diffusible PVR in the mouse. CNS are based on the view that an inter- An ideal mouse model would express PVR mediate step between gut and spinal cord in both the same cell types and in approxi- infection requires the virus to move from mately the same concentration as in hu- the gut, possibly via the lymphatic system, mans. Crossing PVR-transgenic mice with into the blood stream (viremia). From mice lacking the type I interferon receptor there it might directly cross the blood– does generate a mouse model whereby PV brain barrier (BBB) into the CNS and ini- can target motor neurons after oral infec- tiate infection of neurons; it is, however, tion (Ida-Hosonuma et al., 2005). This is unusual for a virus, even a small one such consistent with the view that despite the un- as PV, to diffuse across the BBB, although derlying importance of the PVR, other fac- minor transient injury may enhance pen- tors play crucial roles in allowing or etration of some viruses into the CNS (van blocking spinal cord infections. den Pol, 2009a,b). Other potential mech- Another line of research has also raised anisms of PV movement across the BBB some interesting questions: by injection of include direct infection of the endothelial PV into the normal brain, mutant PVs cells, transendothelial transport, a Trojan Figure 3. A transmission electron micrograph shows the have been recovered that show a selective horse infection of macrophage or den- 30 nm poliovirus particles. Courtesy of the US Centers for Dis- infection and destruction of normal dritic cells that express the PVR and can be ease Control. mouse motor neurons in the absence of productively infected (Wahid et al., 2005) PVR binding (Jubelt et al., 1980a,b; Ford or other immune cells that subsequently et al., 2002), or more generalized infection enter the brain, or entry through one of ent in CSF and serum, may serve in part as of the CNS with mouse brain-derived mu- the regions of the brain such as the area a beneficial decoy, reducing the probabil- tant PV (Gromeier et al., 1995). A single postrema or median eminence with weak ity of PV attachment to the membrane- six amino acid sequence in the VP1 capsid BBBs and subsequent diffusion or trans- bound receptor (Baury et al., 2003). protein may enable PV to infect non-PVR port within the brain (Couderc et al., Because PV primarily infects human mouse motor neurons (Martin et al., 1990; Freistadt et al., 1993; Tyler and Na- cells, there is no latent reservoir of virus in 1988; Murray et al., 1988). The results thanson, 2001; Pfeiffer, 2010). animals, a key feature in the potential for suggesting selective motor neuron death Although infection of the gut is gener- the global eradication of the virus. Most support the view that PVR expression by ally seen as a prelude to more widespread animals, including mice, are refractory to motor neurons is not the only factor in dissemination of the virus, when incom- PV infection due to the absence of a cytolytic motor neuron targeting by the pletely inactivated (Salk) PV vaccine was human-type PVR. However, experimen- virus. given by intramuscular injection to hu- tal injection of the PV RNA into non- What mechanism underlies the PV- mans (Cutter incident), PV was subse- human cells does result in productive mediated death of infected cells? First, PV quently found in the gut and was secreted generation of the virus (Holland et al., reduces synthesis of cellular proteins in fa- fecally, causing additional cases of para- 1959a,b), underlining the importance of vor of virus proteins. Furthermore, the lytic poliomyelitis (Nathanson and Lang- the capsid-PVR binding in maintaining nontranslated 5Ј end of the PV genome muir, 1963ab; Offit, 2005). This indicates species selectivity to humans. Old World contains an internal ribosome entry site that the gut can become infected either by primates can also be infected by PV, with a (IRES) sequence which directs translation direct oral ingestion or by an indirect symptomatology not too different from of the PV RNA genome. The PV IRES se- route from other regions of the body. The that seen in humans; experimental pri- quence appears to play a critical role in gut plays a key role in virus dissemination mate PV infections were a great asset in neurotoxicity. Replacing the PV IRES in two contexts. It is here that the virus our initial understanding of PV infections with an IRES from another enterovirus gains an entry into the body, and is also leading to flaccid paralysis and in develop- attenuates the neurovirulence of the re- the source of infectious PV fecally released ing immunization strategies to combat combinant PV without blocking PV into the environment. The identity of the the virus (Bodian, 1954, 1955; Nathanson, translation or virus replication (Gromeier lower gut cells that productively generate 2008). et al., 1996). PV may also kill cells when PV for release into the gut lumen is not To enable the use of small animals in PV 2A, 2C, and 3C proteins induce apo- clear, but epithelial cells, cells of Peyer’s studies of PV actions and underlying mech- ptosis (Calandria et al., 2004; Buenz and patch, and lymphatic cells have been im- anisms, a number of lines of very useful Howe, 2006; Autret et al., 2007). Finally, plicated (Nathanson, 2008). After the ini- transgenic mice have been generated that PV can infect some cells which release tial infection, PV may be shed from the express the human PVR (Mendelsohn et al., progeny virus without generating a cyto- gut into feces for 2–8 weeks leading to vi- 1986; Ren et al., 1990; Koike et al., 1991; Ren pathic effect (Morrison et al., 1994). rus dispersal to other individuals. and Racaniello, 1992). These mice can be An alternative to the hypothesis that productively infected with PV resulting in Infection of the host organism and virus accesses the CNS via the blood- paralysis, and have proven a considerable spread to motoneurons stream is the possibility that virus may be asset in understanding some aspects of PV The virus enters the body by an oral route; retrogradely transported back to motor infection. Limitations of these mouse mod- unlike many other infectious organisms, neurons from a muscle group by innervat- els relate to the inability to infect these mice PV appears resistant to stomach acid, and ing axons. Direct injection of PV unilater- 858 • J. Neurosci., January 16, 2013 • 33(3):855–862 van den Pol • Poliovirus ally into limb muscles results in the 1998). Muscle injury may enhance PV exit sponse to inactivated PV blocks viremia ensuing paralysis of that limb, suggesting from the blood, may enhance retrograde and CNS infections with subsequent ex- selective direct retrograde axonal trans- axonal transport of the virus, or may in- posure to live PV, but may not block en- port of the PV from the injected muscle crease local virus replication. Another teric infection and production of the virus back to the innervating motor neuron possibility is that injury acts as a beacon (Nathanson, 2008). pool; this has been described in humans for cells of the systemic immune system injected with an incompletely inactivated and enhances PV infection of immune Neuronal plasticity and polio Salk vaccine (Nathanson and Langmuir, cells with subsequent entry of the infected Additional questions relate to the mecha- 1963a,b), in experimental monkeys (Bo- immune cell into the brain, followed by nisms underlying long-term aftereffects of dian, 1954, 1955), and in PVRϪ trans- PV release from the immune cell. Factors polio, termed the post-polio syndrome. genic mice (Ohka et al., 2009). Infection that reduce PV entrance into the brain Three to four decades after the initial PV of autonomic ganglia leading to axonal may include limited transport and repli- infection and signs of paralysis, ϳ25% of transport into the brain has also been pos- cation in peripheral neurons, and the poliomyelitis survivors show a recurrence tulated (Sabin, 1956). After PV injection awakening of the intrinsic immune sys- of the paralytic symptoms or muscle into a leg, transection of the sciatic nerve tem by PV infection, resulting in an up- weakening and fatigue, often affecting blocked the ensuing paralysis in PVR- regulation and release of interferon (IFN) muscle groups similar to those initially in- mice, indicating at least in this model, that locally which subsequently activates a volved. Although post-polio syndrome retrograde virus transport is one viable large number of antiviral genes (Lancaster has been suggested to be caused by a re- mechanism for PV entry into the spinal and Pfeiffer, 2010). surgence of latent virus, there is no sub- cord (Ohka et al., 1998). One early school Both the systemic and retrograde ax- stantive support for this perspective of thought suggested an olfactory nerve onal transport mechanisms may be viable, (Pallansch and Roos, 2001). Another pos- site of entry of PV into the brain; although and a key as to which mechanism under- sibility that may be relevant to post-polio PV can enter the brain through the olfac- lies a particular case of polio may relate to syndrome relates to mechanisms of tory nerve (Bodian, 1959), this does not different genotypes /substrains of virus. In short-term recovery after the initial acute appear to be its normal gate of access to an elegant set of experiments, Nathanson infection. Paralysis in some patients is the CNS in humans. and Bodian (1961, 1962) used two strains temporary, and over days or weeks, some Infection of motor neurons may be of PV, one neuroadapted strain with a recovery from partial paralysis ensues. enhanced by the association of the cyto- neurotropic tendency, and another with a The temporary nature of the paralysis plasmic domain of PVR with Tctex-1, a viremic tendency. Injection of the neu- here could be due to temporary silencing subunit of the dynein motor complex rotropic strain into a non-human primate of neurons by transient virus infection, (Mueller et al., 2002) which may underlie limb caused a high probability of ensuing neuronal response to transient inflamma- retrograde transport from axon terminals paralysis of that specific limb (suggesting tion, or to transient release of inhibitory back to the cell body; however, this view a mechanism based on direct retrograde neuroactive agents from diseased or dying may require revision given more recent axonal transport), whereas injection of neurons. Another potential scenario is data suggesting that the dynein-Tctex-1 the viremic strain also caused paralysis, that only a subset of motor neurons inner- complex may not bind cargo (Williams et but with no strong association of paralysis vating a particular set of muscles is killed, al., 2007). with the injected limb (arguing against ax- and the ensuing functional recovery is due Provocation poliomyelitis refers to the onal transport from the infected muscle). to local plasticity that allows remaining greater incidence of PV motor neuron tar- Furthermore, experimental sciatic nerve uninfected motor neurons to substitute geting and subsequent paralysis that oc- damage attenuated general paralysis for the ones that were lost by cytolytic vi- curs after muscle injury (Bodian, 1954). caused by the neurotropic strain, but did rus infection. This plasticity may involve An underlying mechanism may be en- not attenuate paralysis generated by the lateral growth of axons to reinnervate lo- hanced PV retrograde transport into the viremic strain. cal denervated muscles resulting in motor brain, possibly by a mechanism different neurons with expanded muscle fields, and from the one normally underlying PV en- Immune response may also involve some central reorganiza- try into the CNS (Gromeier and Wimmer, Local PV infection activates an IFN re- tion of systems signaling motor neurons. 1998). Injury to muscle or injection of un- sponse, in part through activation of One reason given for loss of motor neu- related antigens into a limb can enhance TLR3 receptors (Oshiumi et al., 2011; Abe rons years after PV infection is that the cell the probability of ensuing paralysis after et al., 2012). IFN release, activation of lo- is “overworked” and wears out. But what oral PV inoculation. In Romania, if chil- cal IFN receptors, and subsequent up- the actual mechanism is behind this is not dren received unrelated inoculations, regulation of the expression of scores of clear; understanding this may give us in- generally of antibiotics and often multiple IFN-stimulated genes is the first line of sight not only into post-polio syndrome, times, soon after receiving the oral PV immune defense against PV. PV is ulti- but also into other motor neuron diseases. vaccine, but not before the PV vaccine, the mately cleared from the body by antibod- The recovery found in some cases of likelihood of a paralytic response was en- ies against the virus that arise after the poliomyelitis touches on a key feature of hanced (Strebel et al., 1995). Similarly, af- systemic immune system is activated. The many neurological illnesses involving ter intravenous PV inoculation into PVR- antibodies generated against the PV are neuronal degeneration, that redundant transgenic mice, muscle injury increased the critical factor in preventing poliomy- cells and systems are available to take over the likelihood of paralysis of that leg, and elitis. The attenuated PV used in oral vac- functionally when some neurons are lost. the paralysis was attenuated by experi- cines shows little neurotoxicity in the But there is a limit to the redundancy, and mental sciatic nerve damage; further- brain, but maintains a strong replication after a certain percentage of neurons are more, there was an increased virus titer in potential in the gut (Sabin et al., 1954; Sa- lost, symptoms become progressively more the injured leg (Gromeier and Wimmer, bin, 1956). Interestingly, the antibody re- evident. A classic example of this is Parkin- van den Pol • Poliovirus J. Neurosci., January 16, 2013 • 33(3):855–862 • 859 son’s disease, where substantia nigra dopa- inent symptom (Rabinowitz et al., 1976; the world over the last few decades, and mine neurons are lost; in contrast to the Brown et al., 2009). Similarly, the unrelated with the epidemics have come a paralytic flaccid paralysis associated with PV, loss of positive strand RNA virus Sindbis virus also disease. During an outbreak of infectious dopamine neurons leads to muscle tremor can bind to many different cells in the ro- enterovirus 71 in Bulgaria in 1975, paralytic and rigidity. Similarly, the loss of hypocretin dent brain; in addition to other symptoms, disease occurred in ϳ21% of 700 patients neurons in narcolepsy can lead to transient Sindbis frequently causes hindlimb paraly- (Shindarov et al., 1979). E71 can also cause flaccid paralysis during cataplexy. Loss of sis due to motor neuron lytic infection (Kerr poliomyelitis-like paralysis in non-human less than ϳ50–60% of the critical neurons et al., 2002). primates (Hashimoto and Hagiwara, 1982; may be asymptomatic, but beyond that, the PV serves as an important example Johnson, 1998). In rare cases, related viruses severity of symptoms shows a positive cor- that helps us appreciate the complexity of including E70, coxsackie A7, B3, and others relation with the number of neurons lost. determining causation of neurological de- can cause paralytic disease in humans by In this context, post-polio syndrome terioration after viral infections. Similar mechanisms that are not yet clear (Grist et may be the manifestation of the combi- to PV, other viruses that cause CNS dys- al., 1978; Wadia et al., 1983; Pallansch and nation of cells initially killed by PV plus function seldom show a consistent CNS Roos, 2001). In mice coxsackie A can cause a the ongoing loss of neurons that occurs effect. For instance, West Nile virus is as- flaccid paralysis, and coxsackie B, a spastic with aging, resulting in an increased sociated with CNS disease in less than one paralysis (Pallansch and Roos, 2001). probability that insufficient motor neu- in a hundred of those infected, and can Amyotrophic lateral sclerosis (ALS) is rons are available to allow continued cause a poliomyelitis-like response in a a disease of unknown origin in which mo- normal functioning of those muscles minority of infected patients (Campbell et tor neurons are selectively lost. The cause initially affected by PV infection. An al- al., 2002). PV selectively infects motor of ALS remains unclear. Some studies ternate possibility is a PV-initiated low- neurons, and diagnosis is relatively have reported an elevated prevalence of grade autoimmune targeting of motor straightforward, based on paralysis and enterovirus RNA in patients with ALS neurons. detection of the virus by PCR. On the (Berger et al., 2000; Giraud et al., 2001; A number of viruses, for instance, cy- other hand, viruses that infect the limbic Woodall and Graham, 2004; Vandenber- tomegalovirus, are more dangerous to the system, with the potential to cause shifts ghe et al., 2010); however, in other studies developing human brain than to the adult. in mental state, depression, mood, and enterovirus RNA has not been found in In contrast, despite the enhanced matu- anxiety disorders with a disease-causing the spinal cord or motor cortex of patients ration of the systemic immune system, potential similar to PV of Ͻ1%, would be with ALS (Swanson et al., 1995; Walker et PV is more likely to cause a debilitating substantially more difficult to detect and al., 2001; Nix et al., 2004). Thus the possi- paralysis in adults than in young chil- interpret. For instance, Borna disease vi- ble role of enteroviruses in ALS remains dren. Why? The alternate name for po- rus (BDV) infects the limbic system and unclear. Although no specific virus has liomyelitis of “infantile paralysis” was causes a large number of behavioral dis- been identified as contributing to the due to the fact that adults had a greater turbances in a wide variety of mammalian pathogenesis of ALS, the parallels between probability of having previous contact and avian species (Lipkin et al., 2011). poliomyelitis/post-polio syndrome and with, and immunity from, the virus, BDV has been associated with mental dis- ALS may present opportunities for cross- whereas an encounter with PV in young ease in humans, but whether this is merely fertilization of information relating to children was more likely to be the first a correlation or causation is not yet clear. mechanisms underlying both diseases. contact, thereby increasing the proba- Importantly, the fact that the majority of With polio, the paralytic symptoms of bility of paralysis. However, if one com- humans can be infected by a particular vi- poliomyelitis appear relatively fast (days), pares the severity of an encounter with rus and not show neurological symptoms and are related primarily to infection PV, nonvaccinated adults are more cannot be used as an argument that a par- and destruction of spinal motor neu- likely to show some form of paralysis ticular virus does not cause neurologic or rons. In contrast, ALS is a slow and pro- than young children. The reason behind psychiatric dysfunction in others, as PV so gressive disease that leads to continued this developmental difference in suscep- eloquently shows us. motor neuron deterioration over years, tibility is not well understood, but may Other enteroviruses besides PV cause and includes both spinal and upper mo- in part relate to a greater degree of plasticity paralysis as well. As we hopefully near the tor neurons. in the developing brain after PV-induced final chapter of endemic PV, attention is Another symptomatically related syn- damage, enhancing the potential for recov- turning to other viruses closely related to drome is primary lateral sclerosis which ery from symptoms. PV that may also cause paralysis in hu- affects the corticospinal neurons, and de- mans, possibly based on mechanisms sim- terioration over several years leads to Poliomyelitis and other ilar to those used by PV. One potentially spasticity and muscle weakness. Stiff- neuromuscular syndromes problematic virus is enterovirus 71 which person syndrome also affects motor neu- Motor neurons are sometimes targeted causes hand, foot, and mouth disease rons, and may be caused by a poorly by completely unrelated viruses, for rea- which, similar to PV, may cause only mi- understood autoimmune dysfunction. In sons that are not clear, but may relate to nor or no symptoms, but in some cases this disorder, a progressive intermittent some specific sensitivity of motor neu- can cause flaccid paralysis after motor muscle rigidity can be associated with a rons to some factor associated with infec- neuron infection, as well as encephalitis or heightened sensitivity to a number of sen- tion. Vesicular stomatitis virus (VSV), a meningitis. Interestingly, this virus does sory inputs, some leading to muscle spasms. membrane-bound negative strand RNA vi- not bind to the PVR, but instead uses differ- Stiff-person syndrome is associated with rus, binds to receptors found on most cells, ent receptors, including human P-selectin antibodies against the GABA-synthesizing and can be neurotoxic. But in a subset of glycoprotein ligand-1 (Nishimura et al., enzyme, glutamate decarboxylase, and syn- rodents infected with VSV, hindlimb paral- 2009). Enterovirus 71 has caused a number aptic molecules synaptophysin, amphiphy- ysis after motor neuron infection is a prom- of localized epidemics in many regions of sin, synaptobrevins, and gephyrin (Butler et 860 • J. Neurosci., January 16, 2013 • 33(3):855–862 van den Pol • Poliovirus al., 1993, 2000; Levy et al., 1999; Geis et al., to other positive stranded RNA viruses, need to be destroyed or raised to a high 2009). Whether stiff-person syndrome is PV replication is based on an error-prone biohazard level to prevent accidental rein- caused by an immune response to a single RNA polymerase, leading to frequent mu- troduction of the virus from experimental epitope or multiple targeted antigens is not tations in the PV genome. Attenuated ac- stocks, or from possible clinical use in clear. The immune involvement in stiff- tive PV can revert back to wild-type cancer treatment. Elimination of attenu- person syndrome also raises the question of infectious neurotropic virus, in rare cases ated PV vaccine would prevent accidental whether post-polio syndrome could also infecting motor neurons and causing po- reintroduction into the environment, but arise from a latent immune memory of PV- liomyelitis in either the inoculated indi- the vaccine may still be needed in the infected motor neurons. vidual, or in others in contact with the event that another unexpected PV out- immunized person (Kew et al., 2002). break occurs from an unexpected source. Therapeutic uses of PV A second risk factor is the potential for One positive twist that merits further ex- recombination of the attenuated PV ge- References ploration is the finding that the PVR, nome with genomes from other enterovi- Abe Y, Fujii K, Nagata N, Takeuchi O, Akira S, CD155, is also expressed on several forms ruses, particularly human enterovirus Oshiumi H, Matsumoto M, Seya T, Koike S of cancer cells, including glioblastoma, C/coxsackie viruses. Such a recombina- (2012) The toll-like receptor 3-mediated antiviral response is important for protection medulloblastoma, and colorectal cancer. tion can result in novel recombinant vi- against poliovirus infection in poliovirus re- The PVR may play an important role in ruses with disease potential in causing ceptor transgenic mice. J Virol 86:185–194. cancer invasiveness and glioma migra- paralysis (Rakoto-Andrianarivelo et al., CrossRef Medline tion, a key problem in eliminating high- 2008; Combelas et al., 2011), and viruses Autret A, Martin-Latil S, Mousson L, Wirotius A, grade gliomas from the brain. CD155 is derived from recombination of attenu- Petit F, Arnoult D, Colbe`re-Garapin F, Esta- reported to be recruited to the leading ated vaccine PV with coxsackie A17 are quier J, Blondel B (2007) Poliovirus induces edge of migrating cells where it colocalizes now circulating in some regions of the Bax-dependent cell death mediated by c-Jun NH2-terminal kinase. J Virol 81:7504–7516. with actin; experimental reduction in the world (Jegouic et al., 2009). In patients CrossRef Medline expression of CD155 reduces migration of orally inoculated with all 3 serotypes of Baury B, Masson D, McDermott BM Jr, Jarry A, glioma cells in vitro (Sloan et al., 2004, PV, recombinant PVs are commonly gen- Blottie`re HM, Blanchardie P, Laboisse CL, 2005); PVR expression is upregulated by erated, with some single recombinants Lustenberger P, Racaniello VR, Denis MG sonic hedgehog, a possible clue to the role containing unique sequences from all 3 (2003) Identification of secreted CD155 iso- of PVR during development (Solecki et parent PVs (Cammack et al., 1988). Re- forms. Biochem Biophys Res Commun 309: 175–182. CrossRef Medline al., 2002). If PVR can be downregulated in combination is most common among vi- Berger MM, Kopp N, Vital C, Redl B, Aymard M, glioma in vivo, this may possibly reduce ruses with the most similar sequence Lina B (2000) Detection and cellular local- the neuroinvasive potential of these tu- homologies. The mechanism may be re- ization of enterovirus RNA sequences in spi- mor cells and potentially increase the lon- lated to RNA polymerase copying the 3Ј nal cord of patients with ALS. Neurology 54: gevity of the patient. That brain tumors end of one parental positive RNA strand, 20–25. CrossRef Medline express the PVR raises the possibility that after which the polymerase switches Bledsoe AW, Jackson CA, McPherson S, Morrow CD (2000) Cytokine production in motor recombinant oncolytic PV strains lacking copying to a second parental template, re- neurons by poliovirus replicon vector gene neurotoxicity may prove useful in combat- sulting in a chimeric negative strand anti- delivery. Nat Biotechnol 18:964–969. ing some forms of brain cancer, a promising genome (Kirkegaard and Baltimore, 1986; CrossRef Medline path for future study (Gromeier et al., Racaniello, 2001). It is difficult to fully Bodian D (1954) Viremia in experimental po- 2000). Replacing the PV IRES with a human predict the final disease-phenotype of PV- liomyelitis. II. Viremia and the mechanism of rhinovirus type 2 IRES blocks PV neurotox- coxsackie recombinations even if the nu- the provoking effect of injections or trauma. icity, but does not block the ability of the cleotide sequence can be determined. Am J Hyg 60:358–370. Medline Bodian D (1955) Emerging concept of poliomy- recombinant PV to infect human glioma As we approach the end of wild-type elitis infection. Science 122:105–108. (Gromeier et al., 1996; Merrill et al., 2004; PV infections across the globe, there re- CrossRef Medline Goetz and Gromeier, 2010). main some complications that merit con- Bodian D (1959) Poliomyelitis: pathogenesis PV replicons, which contain a partial sideration. First, even after some regions and histopathology. In Viral and rickettsial virus genome without the genes coding of the world have been without active PV infections of man, Ed 3 (Rivers TM, Horsfall for the capsid, may have promise for selec- infections, PV has still been recovered FL Jr, eds), pp 479–498. Philadelphia: Lippincott. tive gene delivery to the same motor neu- from local water, suggesting either a la- Brown CW, Stephenson KB, Hanson S, Kucharc- rons or other cells that active PV infects. tency of virus deterioration, or that some zyk M, Duncan R, Bell JC, Lichty BD (2009) The capsid protein is provided in trans immunized or asymptomatic humans are The p14 FAST protein of reptilian reovirus during vector production, thereby re- still releasing active PV in feces. Inacti- increases vesicular stomatitis virus neuro- stricting infection and replication to a sin- vated PV immunization may protect pathogenesis. J Virol 83:552–561. CrossRef gle generation of cells, and allowing the against viremia and motor neuron- Medline Buenz EJ, Howe CL (2006) Picornaviruses and transient amplified expression of genes of mediated paralysis without completely cell death. Trends Microbiol 14:28–36. interest in the infected cells (Bledsoe et al., blocking PV infection and release in the Medline 2000; Jackson et al., 2003). gut. A further concern is that rare individ- Butler MH, Solimena M, Dirkx R Jr, Hayday A, De uals with Ig deficiencies (agammaglobu- Camilli P (1993) Identification of a domi- Eradication of PV linemia) that may not be able to eliminate nant epitope of glutamic acid decarboxylase Although the oral vaccine has carried us a PV completely may show ongoing fecal (GAD-65) recognized by autoantibodies in large step toward eliminating PV infec- release of PV for years (Minor, 2004; Mar- stiff-man syndrome. J Exp Med 178:2097– 2106. CrossRef Medline tions, as we approach the potential global tín, 2006), potentially acting as a source Butler MH, Hayashi A, Ohkoshi N, Villmann C, eradication of polio, two risk factors of the for PV resurgence. Another concern is Becker CM, Feng G, De Camilli P, Solimena M oral vaccine have emerged. First, similar that at some point PV in laboratories may (2000) Autoimmunity to gephyrin in Stiff- van den Pol • Poliovirus J. Neurosci., January 16, 2013 • 33(3):855–862 • 861

Man syndrome. Neuron 26:307–312. keys. Acta Neuropathol 58:125–132. CrossRef Leon-Monzon ME, Illa I, Dalakas MC (1995) CrossRef Medline Medline Expression of poliovirus receptor in human Calandria C, Irurzun A, Barco A, Carrasco L Holland JJ, McLaren JC, Syverton JT (1959a) spinal cord and muscle. Ann N Y Acad Sci (2004) Individual expression of poliovirus The mammalian cell virus relationship. III. 753:48–57. Medline 2Apro and 3Cpro induces activation of Production of infectious poliovirus by non- Levy LM, Dalakas MC, Floeter MK (1999) The caspase-3 and PARP cleavage in HeLa cells. primate cells exposed to poliovirus ribonu- stiff-person syndrome: an autoimmune disor- Virus Res 104:39–49. CrossRef Medline cleic acid. Proc Soc Exp Biol Med 100: der affecting neurotransmission of gamma- Cammack N, Phillips A, Dunn G, Patel V, Minor 843–845. Medline aminobutyric acid. Ann Intern Med 131: PD (1988) Intertypic genomic rearrange- Holland JJ, McLaren JC, Syverton JT (1959b) 522–530. Medline ments of poliovirus strains in vaccines. Virol- The mammalian cell virus relationship. IV. Lipkin WI, Briese T, Hornig M (2011) Borna ogy 167:507–514. CrossRef Medline Infection of naturally insusceptible cells with disease virus—fact and fantasy. Virus Res 162: Campbell GL, Marfin AA, Lanciotti RS, Gubler DJ enterovirus ribonucleic acid. J Exp Med 110: 162–172. CrossRef Medline (2002) West Nile virus. Lancet Infect Dis 65–80. CrossRef Medline Martin A, Wychowski C, Benichou D, Crainic R, 2:519–529. CrossRef Medline Ida-Hosonuma M, Iwasaki T, Yoshikawa T, Na- Girard M (1988) Construction of a chima- Combelas N, Holmblat B, Joffret ML, Colbe`re- gata N, Sato Y, Sata T, Yoneyama M, Fujita T, eric type1/type2 poliovirus by genetic recom- Garapin F, Delpeyroux F (2011) Recombi- Taya C, Yonekawa H, Koike S (2005) The al- bination. Ann Inst Pasteur 139:79–88. nation between poliovirus and coxsackie A pha/beta interferon response controls tissue CrossRef viruses of species C: A model of viral genetic tropism and pathogenicity of poliovirus. J Vi- Martín J (2006) Vaccine-derived poliovirus plasticity and emergence. Viruses 3:1460– rol 79:4460–4469. CrossRef Medline from long term excretors and the end game of 1484. CrossRef Medline Jackson CA, Messinger J, Palmer MT, Peduzzi JD, polio eradication. Biologicals 34:117–122. Couderc T, Barzu T, Horaud F, Crainic R (1990) Morrow CD (2003) Gene expression in the CrossRef Medline Poliovirus permissivity and specific receptor muscle and central nervous system following Mendelsohn CL, Wimmer E, Racaniello VR expression on human endothelial cells. Virol- intramuscular inoculation of encapsidated or (1989) Cellular receptor for poliovirus: ogy 174:95–102. CrossRef Medline naked poliovirus replicons. Virology 314: molecular cloning, nucleotide sequence, and ex- Ford DJ, Ropka SL, Collins GH, Jubelt B (2002) 45–61. CrossRef Medline pression of a new member of the immunoglobulin The neuropathology observed in wild-type Jegouic S, Joffret ML, Blanchard C, Riquet FB, superfamily. Cell 56:855–865. CrossRef Medline mice inoculated with human poliovirus mir- Perret C, Pelletier I, Colbere-Garapin F, Mendelsohn C, Johnson B, Lionetti KA, Nobis P, rors human paralytic poliomyelitis. Microb Rakoto-Andrianarivelo M, Delpeyroux F Wimmer E, Racaniello VR (1986) Transfor- Pathog 33:97–107. CrossRef Medline (2009) Recombination between polioviruses mation of a human poliovirus receptor gene Freistadt MS, Fleit HB, Wimmer E (1993) Polio- and co-circulating coxsackie A viruses: role in into mouse cells. Proc Natl Acad Sci U S A virus receptor on human blood cells: a possi- the emergence of pathogenic vaccine-derived 83:7845–7849. CrossRef Medline ble extraneural site of poliovirus replication. polioviruses. PLoS Pathog 5:e1000412. Merrill MK, Bernhardt G, Sampson JH, Wik- Virology 195:798–803. CrossRef Medline CrossRef Medline strand CJ, Bigner DD, Gromeier M (2004) Geis C, Beck M, Jablonka S, Weishaupt A, Toyka Johnson R (1998) Viral infections of the nervous Poliovirus receptor CD 155-targeted oncoly- KV, Sendtner M, Sommer C (2009) Stiff per- system, Ed 2. Philadelphia: Lippincott-Raven. sis of glioma. Neuro Oncol 6:208–217. son syndrome associated anti-amphiphysin anti- Jubelt B, Gallez-Hawkins G, Narayan O, Johnson CrossRef Medline bodiesreduceGABAassociated[Ca(2ϩ)](i)risein RT (1980a) Pathogenesis of human poliovi- Minor PD (2004) Polio eradication, cessation of embryonic motoneurons. Neurobiol Dis 36:191– rus infection in mice. I. Clinical and patholog- vaccination and re-emergence of disease. Nat 199. CrossRef Medline ical studies. J Neuropathol Exp Neurol 39: Rev Microbiol 2:473–482. CrossRef Medline Giraud P, Beaulieux F, Ono S, Shimizu N, Chazot 138–148. CrossRef Medline Modlin JF (2010) Poliovirus. In Mandell, Doug- G, Lina B (2001) Detection of enteroviral se- Jubelt B, Narayan O, Johnson RT (1980b) las, and Bennett’s principles and practice of quences from frozen spinal cord samples of Pathogenesis of human poliovirus infection in infectious diseases, Ed 7, Vol 2 (Mandell GL, Japanese ALS patients. Neurology 56:1777– mice. II. Age-dependency of paralysis. J Neu- Bennett JE, Dolin R, eds), pp 2345–2351. Phil- 1778. CrossRef Medline ropathol Exp Neurol 39:149–159. CrossRef adelphia: Churchill Livingstone Elsevier. Goetz C, Gromeier M (2010) Preparing an on- Medline Morrison ME, He YJ, Wien MW, Hogle JM, Racan- colytic poliovirus recombinant for clinical ap- Kerr DA, Larsen T, Cook SH, Fannjiang YR, Choi iello VR (1994) Homolog-scanning muta- plication against glioblastoma multiforme. E, Griffin DE, Hardwick JM, Irani DN (2002) genesis reveals poliovirus receptor residues Cytokine Growth Factor Rev 21:97–203. BCL-2 and BAX protect adult mice from le- important for virus binding and replication. Grist NR, Bell EJ, Assaad F (1978) Enteroviruses thal Sindbis virus infection but do not protect J Virol 68:2578–2588. Medline in human disease. Prog Med Virol 24:114– spinal cord motor neurons or prevent paraly- Mueller S, Cao X, Welker R, Wimmer E (2002) 157. Medline sis. J Virol 76:10393–10400. CrossRef Medline Interaction of the poliovirus receptor CD155 Gromeier M, Wimmer E (1998) Mechanism of Kew O, Morris-Glasgow V, Landaverde M, Burns with the dynein light chain Tctex and its im- injury-provoked poliomyelitis. J Virol 72: C, Shaw J, Garib Z, Andre´ J, Blackman E, Free- plication for poliovirus pathogenesis. J Biol 5056–5060. Medline man CJ, Jorba J, Sutter R, Tambini G, Venczel Chem 277:7897–7904. CrossRef Medline Gromeier M, Lu HH, Wimmer E (1995) Mouse L, Pedreira C, Laender F, Shimizu H, Mueller S, Wimmer E, Cello J (2005) Poliovirus neuropathogenic poliovirus strains cause Yoneyama T, Miyamura T, van Der Avoort H, and poliomyelitis: a tale of guts, brains, and an damage in the central nervous system distinct Oberste MS, et al. (2002) Outbreak of polio- accidental event. Virus Res 111:175–193. from poliomyelitis. Microb Pathog 18:253– myelitis in Hispaniola associated with circu- CrossRef Medline 267. CrossRef Medline lating type 1 vaccine-derived poliovirus. Murray MG, Bradley J, Yang XF, Wimmer E, Gromeier M, Alexander L, Wimmer E (1996) Science 296:356–359. CrossRef Medline Moss EG, Racaniello VR (1988) Poliovirus Internal ribosomal entry site substitution Kirkegaard K, Baltimore D (1986) The mecha- host range is determined by a short amino acid eliminates neurovirulence in intergeneric po- nism of RNA recombination in poliovirus. sequence in neutralization antigenic site I. Sci- liovirus recombinants. Proc Natl Acad Sci Cell 47:433–443. CrossRef Medline ence 241:213–215. CrossRef Medline U S A 93:2370–2375. CrossRef Medline Koike S, Taya C, Kurata T, Abe S, Ise I, Yonekawa Nathanson N (2008) The pathogenesis of polio- Gromeier M, Lachmann S, Rosenfeld MR, Gutin H, Nomoto A (1991) Transgenic mice sus- myelitis: what we don’t know. Adv Virus Res PH, Wimmer E (2000) Intergeneric poliovi- ceptible to poliovirus. Proc Natl Acad Sci 71:1–50. CrossRef Medline rus recombinants for the treatment of malig- U S A 88:951–955. CrossRef Medline Nathanson N, Bodian D (1961) Experimental nant glioma. Proc Natl Acad Sci U S A 97: Lancaster KZ, Pfeiffer JK (2010) Limited traf- poliomyelitis following intramuscular virus 6803–6808. CrossRef Medline ficking of a neurotropic virus through inef- injection. The effect of neural block on a neu- Hashimoto I, Hagiwara A (1982) Studies on the ficient retrograde axonal transport and the rotropic and pantropic strain. Bull Johns pathogenesis of the propagation of enterovi- type I interferon response. PLoS Pathog Hopkins Hosp 108:308–319. Medline rus 71 in poliomyelitis-like disease in mon- 6:e41000791. Nathanson N, Bodian D (1962) Experimental 862 • J. Neurosci., January 16, 2013 • 33(3):855–862 van den Pol • Poliovirus

poliomyelitis following intramuscular virus tem disease produced by wild-type and vaccine-associated paralytic poliomyelitis. injection. III. The effect of passive antibody on temperature-sensitive mutants of vesicular N Engl J Med 332:500–506. CrossRef Medline viremia and paralysis. Bull Johns Hopkins stomatitis virus. Infect Immun 13:1242–1249. Swanson NR, Fox SA, Mastaglia FL (1995) Hosp 111:198–220. Medline Medline Search for persistent infection with poliovirus Nathanson N, Langmuir AD (1963a) The Cutter Racaniello VR (2001) Picornaviridae: the vi- or other enteroviruses in amyotrophic lateral incident. Poliomyelitis following formaldehyde- ruses and their replication. In Fields virology, sclerosis-motor neurone disease. Neuromus- inactivated poliovirus vaccination in the United Ed 4, Vol 1 (Knipe DM, Howley PM, eds), pp cul Disord 5:457–465. CrossRef Medline States during the spring of 1955. I. Background. 685–722. Philadelphia: Lippincott, Williams Tyler KL, Nathanson N (2001) Pathogenesis of Am J Hyg 78:16–28. Medline & Wilkins. viral infections. In Fields virology, Ed 4, Vol 1 Nathanson N, Langmuir AD (1963b) The Cutter Rakoto-Andrianarivelo M, Gumede N, Jegouic S, (Knipe DM, Howley PM, eds), pp 199–244. incident. Poliomyelitis following formaldehyde- Balanant J, Andriamamonjy SN, Rabem- Philadelphia: Lippincott, Williams & Wilkins. inactivated poliovirus vaccination in the anantsoa S, Birmingham M, Randriamanalina van den Pol AN (2009a) Brain trauma enhances United States during the spring of 1955. II. B, Nkolomoni L, Venter M, Schoub BD, transient cytomegalovirus invasion of the Relationship of poliomyelitis to Cutter vac- Delpeyroux F, Reynes JM (2008) Reemer- brain only in mice that are immunodeficient. cine. Am J Hyg 78:29–60. Medline gence of recombinant vaccine-derived polio- J Virol 83:420–427. CrossRef Medline Nathanson N, Martin JR (1979) The epidemiol- virus outbreak in Madagascar. J Infect Dis van den Pol AN (2009b) Viral infection leading ogy of poliomyelitis: enigmas surrounding its 197:1427–1435. CrossRef Medline to brain dysfunction: more prevalent than ap- appearance, epidemicity, and disappearance. Ren R, Racaniello VR (1992) Human poliovirus preciated? Neuron 64:17–20. CrossRef Am J Epidemiol 110:672–692. Medline receptor gene expression and poliovirus tissue Medline Nishimura Y, Shimojima M, Tano Y, Miyamura tropism in transgenic mice. J Virol 66: Vandenberghe N, Leveque N, Corcia P, Brunaud- T, Wakita T, Shimizu H (2009) Human 296–304. Medline Danel V, Salort-Campana E, Besson G, Tran- P-selectin glycoprotein ligand-1 is a func- Ren RB, Costantini F, Gorgacz EJ, Lee JJ, Racan- chant C, Clavelou P, Beaulieux F, Ecochard R, tional receptor for enterovirus 71. Nat Med iello VR (1990) Transgenic mice expressing Vial C, Broussolle E, Lina B (2010) Cerebro- 15:794–797. CrossRef Medline a human poliovirus receptor: a new model for spinal fluid detection of enterovirus genome Nix WA, Berger MM, Oberste MS, Brooks BR, poliomyelitis. Cell 63:353–362. CrossRef in ALS: a study of 242 patients and 354 con- McKenna-Yasek DM, Brown RH Jr, Roos RP, Medline trols. Amyotroph Lateral Scler 11:277–282. Pallansch MA (2004) Failure to detect en- Sabin AB (1956) Pathogenesis of poliomyelitis: CrossRef Medline terovirus in the spinal cord of ALS patients reappraisal in light of new data. Science 123: Wadia NH, Katrak SM, Misra VP, Wadia PN, using a sensitive RT-PCR method. Neurology 1151–1157. CrossRef Medline Miyamura K, Hashimoto K, Ogino T, Hikiji T, 62:1372–1377. CrossRef Medline Sabin AB, Hennessen WA, Winsser J (1954) Kono R (1983) Polio-like motor paralysis Offit PA (2005) The Cutter incident, 50 years Studies on variants of poliomyelitis virus. I. associated with acute hemorrhagic conjuncti- later. N Engl J Med 352:1411–1412. CrossRef Experimental segregation and properties of vitis in an outbreak in 1981 in Bombay, India: Medline avirulent variants of three immunologic types. clinical and serologic studies. J Infect Dis 147: Ohka S, Yang WX, Terada E, Iwasaki K, Nomoto J Exp Med 99:551–576. CrossRef Medline 660–668. CrossRef Medline A (1998) Retrograde transport of intact po- Shindarov LM, Chumakov MP, Voroshilova MK, Wahid R, Cannon MJ, Chow M (2005) Virus- liovirus through the axon via the fast transport Bojinov S, Vasilenko SM, Iordanov I, Kirov ϩ ϩ system. Virology 250:67–75. CrossRef ID, Kamenov E, Leshchinskaya EV, Mitov G, specific CD4 and CD8 cytotoxic T-cell re- Medline Robinson IA, Sivchev S, Staikov S (1979) sponses and long-term T-cell memory in Ohka S, Sakai M, Bohnert S, Igarashi H, Dein- Epidemiological, clinical, and pathomorpholog- individuals vaccinated against polio. J Virol hardt K, Schiavo G, Nomoto A (2009) ical characteristics of epidemic poliomyelitis-like 79:5988–5995. CrossRef Medline Receptor-dependent and -independent ax- disease caused by enterovirus 71. J Hyg Epidemiol Walker MP, Schlaberg R, Hays AP, Bowser R, onal retrograde transport of poliovirus in mo- Microbiol Immunol 23:284–295. Medline Lipkin WI (2001) Absence of echovirus se- tor neurons. J Virol 83:4995–5004. CrossRef Sloan KE, Eustace BK, Stewart JK, Zehetmeier C, quences in brain and spinal cord of amyo- Medline Torella C, Simeone M, Roy JE, Unger C, Louis trophic lateral sclerosis patients. Ann Oshiumi H, Okamoto M, Fujii K, Kawanishi T, DN, Ilag LL, Jay DG (2004) CD155/PVR Neurol 49:249–253. CrossRef Medline Matsumoto M, Koike S, Seya T (2011) The plays a key role in cell motility during tumor Williams JC, Roulhac PL, Roy AG, Vallee RB, TLR3/TICAM-1 pathway is mandatory for in- cell invasion and migration. BMC Cancer Fitzgerald MC, Hendrickson WA (2007) nate immune responses to poliovirus infec- 4:73. CrossRef Medline Structural and thermodynamic characteriza- tion. J Immunol 187:5320–5327. CrossRef Sloan KE, Stewart JK, Treloar AF, Matthews RT, tion of a cytoplasmic dynein light chain- Medline Jay DG (2005) CD155/PVR enhances gli- intermediate chain complex. Proc Natl Acad Pallansch MA and Roos RP (2001) Enterovi- oma cell dispersal by regulating adhesion sig- Sci U S A 104:10028–10033. CrossRef ruses: polioviruses, coxsackieviruses, echovi- naling and focal adhesion dynamics. Cancer Medline ruses, and newer enteroviruses. In Fields Res 65:10930–10937. CrossRef Medline Woodall CJ, Graham DI (2004) Evidence for virology, Ed 4, Vol 1 (Knipe DM, Howley PM, Solecki DJ, Gromeier M, Mueller S, Bernhardt G, neuronal localisation of enteroviral sequences eds), pp 723–775. Philadelphia: Lippincott, Wimmer E (2002) Expression of the human in motor neurone disease/amyotrophic lateral Williams & Wilkins. poliovirus receptor/CD155 gene is activated sclerosis by in situ hybridization. Eur J His- Pfeiffer JK (2010) Innate host barriers to viral by sonic hedgehog. J Biol Chem 277:25697– tochem 48:129–134. Medline trafficking and population diversity: lessons 25702. CrossRef Medline Zhang S, Racaniello VR (1997) Expression of the learned from poliovirus. Adv Virus Res 77:85– Strebel PM, Ion-Nedelcu N, Baughman AL, Sutter poliovirus receptor in intestinal epithelial cells 118. CrossRef Medline RW, Cochi SL (1995) Intramuscular injec- is not sufficient to permit poliovirus replica- Rabinowitz SG, Dal Canto MC, Johnson TC tions within 30 days of immunization with tion in the mouse gut. J Virol 71:4915–4920. (1976) Comparison of central nervous sys- oral poliovirus vaccine—a risk factor for Medline