VP1 is the primary determinant of neuropathogenesis in a mouse model of enterovirus D68 acute flaccid myelitis.

Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory and neurologic disease [acute flaccid myelitis (AFM)]. Intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with US/IL/14-18952 (IL52), a clinical isolate from the 2014 EV-D68 epidemic, results in many of the pathogenic features of human AFM, including viral infection of the spinal cord, death of motor neurons, and resultant progressive paralysis. In distinction, CA/14-4231 (CA4231), another clinical isolate from the 2014 EV-D68 outbreak, does not cause paralysis in mice, does not grow in the spinal cord, and does not cause motor neuron loss following IM injection. A panel of chimeric viruses containing sequences from IL52 and CA4231 was used to demonstrate that VP1 is the main determinant of EV-D68 neurovirulence following IM injection of neonatal SW mice. VP1 contains four amino acid differences between IL52 and CA4231. Mutations resulting in substituting these four amino acids (CA4231 residues into the IL52 polyprotein) completely abolished neurovirulence. Conversely, mutations resulting in substituting VP1 IL52 amino acid residues into the CA4231 polyprotein created a virus that induced paralysis to the same degree as IL52. Neurovirulence following infection of neonatal SW mice with parental and chimeric viruses was associated with viral growth in the spinal cord. IMPORTANCE: Emerging viruses allow us to investigate mutations leading to increased disease severity. Enterovirus D68 (EV-D68), once the cause of rare cases of respiratory illness, recently acquired the ability to cause severe respiratory and neurologic disease. Chimeric viruses were used to demonstrate that viral structural protein VP1 determines growth in the spinal cord, motor neuron loss, and paralysis following intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with EV-D68. These results have relevance for predicting the clinical outcome of future EV-D68 epidemics as well as targeting retrograde transport as a potential strategy for treating virus-induced neurologic disease.

Molecular diversity and biennial circulation of enterovirus D68: a systematic screening study in Lyon, France, 2010 to 2016.

BackgroundUnderstanding enterovirus D68 (EV-D68) circulation patterns as well as risk factors for severe respiratory and neurological illness is important for developing preventive strategies. Methods: Between 2010 and 2016, 11,132 respiratory specimens from hospitalised patients in Lyon, France, were screened for EV-D68 by PCR. Phylogenetic relationships of the viral-protein-1 sequences were reconstructed using maximum-likelihood and Bayesian-Markov-Chain-Monte-Carlo approaches. Results: Overall, 171 infections with a biennial pattern were detected, including seven, one, 55, none, 42, one and 65 cases annually during 2010-16. Children (< 16 years-old; n = 150) were mostly affected and 71% (n = 121) of the total patients were under 5 years-old. In 146 patients with medical reviews, 73% (n = 107) presented with acute respiratory distress. Among paediatric patients with medical reviews (n = 133), 55% (n=73) had an asthma/wheezing history, while among adults (n = 13), 11 had underlying diseases. In total, 45 patients had severe infections and 28 patients needed intensive care unit stays. No acute flaccid myelitis (AFM) was detected. We found genotypes A, B1, B2 B3 and D circulating, and no associations between these and clinical presentations. During the study, new genotypes continuously emerged, being replaced over time. We estimated that ancestors of currently circulating genotypes emerged in the late-1990s to 2010. Rises of the EV-D68 effective population size in Lyon coincided with infection upsurges. Phylogenetic analyses showed ongoing diversification of EV-D68 worldwide, coinciding with more infections in recent years and increases of reported AFM paediatric cases. Conclusions: Reinforcement of diagnostic capacities and clinical-based surveillance of EV-D68 infections is needed in Europe to assess the EV-D68 burden.

Vaccine-associated paralytic poliomyelitis in a patient with acute lymphocytic leukemia.

We report a case of vaccine-associated paralytic poliomyelitis (VAPP) in an immunocompromised patient with acute lymphocytic leukemia who was initially diagnosed with aseptic meningitis. Isolation of Sabin-like type 1 poliovirus from the patient's cerebrospinal fluid made this a case of vaccine-related poliovirus (VRPV) infection. The patient developed paralysis and respiratory distress and deceased a few months after onset of paralysis with respiratory failure. This tragic case report highlights the emergence of VAPP and indicates the importance of timely diagnosis of VRPV infections to improve clinical management of VRPV-infected patients and to prevent the devastating consequences of silent introduction of VRPVs in treatment wards and eventually in the society.

Characterization of group B coxsackieviruses isolated from non-polio acute flaccid paralysis patients in Pakistan: vital assessment before polio eradication.

Pakistan is at the verge of polio eradication but isolation of non-polio enteroviruses (NPEVs) from acute flaccid paralysis (AFP) cases may result in serious or even fatal outcome. Many enteroviruses share similar symptoms and epidemiology as is the case with poliovirus and coxsackievirus (CV). The present study was designed to genetically characterize coxsackievirus B (CV-B) serotypes isolated from non-polio acute flaccid paralytic children, as well as to understand their probable role in paralysis. A total of 63 (20·1%) out of 313 stool samples during 2013 were found positive for NPEVs in rhabdomyosarcoma cells. Only 24 (38·0%) NPEVs were typed as CV-B by microneutralization assay and were further characterized by sequencing of the viral protein 1 (VP1) gene. Molecular phylogenetic analyses classified the study strains into six coxsackievirus B serotypes (coxsackievirus B1 to B6) with their respective prototype strains with evidence of epidemiological linkage and distinct clusters. Moreover, four major differences were found within the amino acid sequences of BC-loop in VP1 of CV-B strains. In conclusion, this study presented the molecular evolutionary genetic overview and distinct phylogenetic pattern of CV-B isolates from AFP cases in Pakistan, and explored the possible link between CV-B infections and AFP cases. Furthermore, our data reveal that these viruses might contribute to the incidence of paralysis in population and there is need of time to establish an enterovirus surveillance system for better understanding of epidemiological and virological characteristics of NPEV infections associated with AFP cases in the country.

Molecular characterization of echovirus 13 uncovering high genetic diversity and identification of new genotypes in Pakistan.

Echovirus 13 (E-13) is reported worldwide and is mostly related to aseptic meningitis but it is also isolated from cases of acute flaccid paralysis (AFP). Unfortunately, all studies conducted on non polio enterovirus in Pakistan only confirm E-13 isolation based on microneutralization assay but there is lack of molecular epidemiological data on this serotype. In this study, 113 stool samples were collected from AFP patients during 2008-2010. An enterovirus primer mediated real-time reverse transcriptase polymerase chain reaction, a standard microneutralization assay and sequencing of viral protein 1 gene (VP1) identified the predominant serotype E-13. For molecular characterization, genetic relationship between 12 clinical isolates of echovirus 13 was investigated by partial sequencing of viral protein 1 gene. These strains, combined with related sequences from GenBank were divided phylogenetically into two different genogroups A and B (>30% divergence) and were found genetically distinct from the circulating strains in the world. Additionally, phylogenic grouping pattern revealed that the study strains clustered into three distinct subgroups (A3, A7 and B3) having >23% nucleotide divergence representing three new genotypes. The genotype A7 seems to be restricted geographically. In conclusion, the current study provides an overview of the molecular epidemiology and evolution of E-13 in the country. This study strongly suggests that enterovirus surveillance system should be established in the country to determine the temporal and geographical trends and disease pattern of different enterovirus serotypes in the community.

[Investigation of adenovirus isolation frequency from the stool samples of patients suspected with acute flaccid paralysis]. / Akut flask paralizi süpheli olgularin diski örneklerinden adenovirus izolasyon sikliginin arastirilmasi.

Although adenoviruses (AdVs) generally cause upper respiratory tract infections, conjunctivitis/epidemic keratoconjunctivitis, gastroenteritis and pneumonia, they can lead to the involvement of central nervous system. Acute flaccid paralysis (AFP) is a type of seizure, characterized by rapid and sudden onset of extreme weakness in hands and feet, including (less frequently) weakness of respiratory and swallowing, representing with decreased muscle tone, especially in children below 15-year-old. The major viral cause of AFP is polioviruses, however non-polio enteroviruses, mumps virus, rabies virus and flaviviruses can also be responsible for AFP. The data of some recent studies have pointed out the probable aetiological role of AdVs in AFP. The aim of this study was to investigate the frequency of AdVs from stool samples of AFP-suspected patients and their contacts. A total of 6130 stool samples from patients (age range: 0-15 years) prediagnosed as AFP (n= 3185) and their contacts (n= 2945), which were sent to our laboratory from the health care centers located at different regions of Turkey for the monitorization of poliomyelitis as part of national AFP surveillance programme, between 2000-2014, have been retrospectively evaluated in terms of adenovirus isolation frequency. Samples were analyzed according to the algorithm recommended by World Health Organization and inoculated in Hep-2, RD, and L20B cell lines for cultivation. Apart from enteroviruses, in case of the presence of characteristic cytopathic effects for AdVs observed in L20B cells were confirmed by a commercial Adeno agglutination kit (Diarlex Adeno; Orion Diagnostica, Finland). It was noted that AdVs have been isolated from 1.6% (97/6130) of the samples, and out of positive samples 76.3% (74/97) were from AFP-suspected cases, while 23.7% (23/97) were from their contacts. Accordingly the frequencies of AdVs from AFP-suspected cases and their contacts were found as 2.3% (74/3185) and 0.8% (23/2945), respectively. The frequencies of Adenovirus positivity between the patients and their contacts were statistically significant (Z-Score 4.8347; p< 0.05). It was determined that 52.6% of the detected AdVs among AFP-suspected cases were between 1-4 age group and the positivity was 1.6 times more among males than the females. Although the data of this study are in agreement with the studies that support the relationship of AdVs with AFP, it is obvious that further molecular and clinical studies are needed.

Genomic characterization of coxsackievirus type A24 strains associated with acute flaccid paralysis and rarely identified Hopkins syndrome.

The full-length genome sequence analysis of four coxsackievirus A24 (CV-A24) strains, detected in three paralytic and one post-asthmatic paralytic (Hopkins syndrome) cases, is reported here for the first time. A phylogenetic tree constructed on the basis of entire genomes displayed topology similar to that of the full-VP1 tree, classifying the study strains in genogroup CV-A24vGIV along with their temporal counterparts in strains from non-paralytic cases. The strains of the study formed a single genetic cluster C4 within CV-A24vGIV and showed 3.5-19.4 % nucleotide sequence divergence, with 2-4 novel nucleotide mutations in the 5'NCR and 3-8 unique amino acid substitutions in the polyprotein, with respect to the CV-A24 strains associated with non-paralytic cases. Among the nucleotide mutations, A299U was identified in the 5'NCRs of all of the study strains. CV-A24v strains of the same genogroup with few genomic variations but different disease manifestations need to be explored to investigate the molecular basis of evolution of neurovirulence.

Complete genome sequence analysis of an enterovirus 75 isolate from China.

Enterovirus 75 (EV-B75) is a member of the species Enterovirus B (EV-B). So far, only the complete genome of the prototype strain from the United States is available. Here, we report the genome sequence of an EV-B75 isolate from an acute flaccid paralysis patient in China. Sequence analysis revealed high nucleotide sequence divergence from foreign EV-B75 strains and suggested several recombination events with other serotypes of EV-B.

[Serotype distribution of non-polio enterovirus in patients with acute flaccid paralysis during 2011-2012 in Hebei Province, China].

This study aims to investigate the serotype distribution of non-polio enterovirus (NPEV) isolated from patients with acute flaccid paralysis (AFP) during 2011-2012 in Hebei Province, China and to analyze the relationship between these viruses and AFP. NPEV strains were isolated from the stool specimens from AFP cases in Hebei using human rhabdomyosarcoma cells (RD) and the mouse cell line expressing the gene for the human cellular receptor for poliovirus (L20B) according to the WHO requirements. The nucleotide sequence of VP1 region was determined, and the serotypes of NPEV were identified by molecular typing. The results showed that among the 82 strains of NPEV isolated from the AFP cases during 2011-2012, 42 isolates (55.3%) were identified as human enterovirus A (HEV-A), which were classified into 4 serotypes, 34 (44.7%) as human enterovirus B (HEV-B), which were classified into 13 serotypes, 2 as adenovirus, and 4 were untyped; human enteroviruses C and D were not found in these cases. Enterovirus A71 (EV-A71) was the main type of HEV-A, accounting for 85.7% of all HEV-A strains. HEV-A, especially EV-A71, was predominant among the NPEV strains isolated from AFP patients during 2011-2012 in Hebei Province.

Fifteen years of acute flaccid paralysis surveillance in Hong Kong: findings from 1997 to 2011.

AIM: Acute flaccid paralysis (AFP) surveillance system was set up in Hong Kong in 1997 for World Health Organization's (WHO) certification of poliomyelitis eradication. This paper describes and reviews the demographic, clinical and virological characteristics of AFP cases reported to the system in its first 15 years. METHODS: All patients aged under 15 years presented with acute onset of paralysis of any limbs reported to the Department of Health from January 1997 to December 2011 were reviewed. Data on demographic characteristics, vaccination history, clinical presentation and virological investigation on stool specimens collected during investigation were analysed with descriptive statistics. RESULTS: Of the 247 cases reported, about 45% were aged under five. All cases were classified as non-polio AFP according to WHO classification. About 60% were identified with neurological disorders, with Guillain-Barré syndrome (25.9%) and myelitis (13.4%) being the most common. Viruses were detected in 14.0% of the AFP cases, with non-polio enteroviruses (NPEV) (60.0%) and adenoviruses (31.4%) accounted for most of the positive detections. Most performance indicators set by the WHO were fulfilled. CONCLUSIONS: The AFP surveillance facilitated the clinical, virological and epidemiological examination of paediatric AFP cases. From 1997 to 2011, Guillain-Barré syndrome and myelitis were the most common among paediatric AFP cases in Hong Kong. NPEV and adenoviruses accounted for most of the positive viral detections. No wild poliovirus was detected, and all cases were classified as non-polio AFP.

Spontaneous pneumomediastinum due to paralytic rabies

Rabies is a fatal disease resulting from rabies virus infection, causing severe neurological symptoms and ultimately death by destroying the nervous system. In general, a patient tends to see a neurologist or an infectious diseases physician, with very common and typical discipline-related signs and symptoms, such as hydrophobia, aerophobia, and mental disorders. However, we reported a rabies patient who was first admitted to see a thoracic surgeon with spontaneous pneumomediastinum.

Very virulent plus strains of MDV induce an acute form of transient paralysis in both susceptible and resistant chicken lines.

Marek's disease (MD) is a lymphoproliferative disease of domestic chickens caused by a highly cell-associated alpha herpesvirus, Marek's disease virus (MDV). Clinical signs of MD include depression, crippling, weight loss, and transient paralysis (TP). TP is a disease of the central nervous system that affects MD-susceptible chickens 8-11 days post-infection (dpi), normally resulting in recovery 1-3 d after the onset of clinical signs. In this study we inoculated chickens from lines 7(2) (MD-susceptible) and 6(3) (MD-resistant) with a very virulent plus strain of MDV at 2 wk of age, and collected brain samples from birds with and without TP at 5, 11, and 21 dpi for gene expression profiling and histological analysis. Data revealed that chickens inoculated with MDV had higher levels of IL-6, IL-10, IL-18, IFN-α, IFN-ß, IFN-γ, MHC I, and CD18 in their brains at 11 dpi compared to the uninfected control birds. In addition, the expression levels of IL-6, IL-10, IFN-α, IFN-ß, and IFN-γ were significantly higher in the brains of the birds showing clinical signs of TP than in asymptomatic chickens. Comparative analysis between the two chicken lines showed that the expression levels of IL-6, IL-10, IFN-ß, IFN-γ, IL-18, CD18, and MHC I were significantly higher in the brains of the birds from line 6(3) with TP than those of line 7(2) exhibiting neurological disorders. A differential expression pattern was observed for some of the tested genes at different time points post-inoculation. Histological analysis showed lymphocytic meningitis, perivascular cuffing, and neuronal degeneration within the brains of birds from both susceptible and resistant lines exhibiting TP at 11 dpi. Vaccination prevented development of TP and other MD-associated clinical symptoms. These observations are suggestive of an underlying immunological mechanism for viral-induced neurological dysfunction, and the differential responses of the two chicken lines to MDV infection.

Adenovirus isolation rates in acute flaccid paralysis patients.

Adenoviruses usually cause asymptomatic or mild infection, but occasionally they produce various severe syndromes including neurological disorders. Association of adenovirus infection with acute flaccid paralysis has been investigated. Shedding of adenovirus with feces was detected in 1.05% of young children (mostly infants) with acute flaccid paralysis syndrome versus 0.42% in healthy contact children (P < 0.01). However, 85% of adenoviruses in the pediatric AFP patients belonged to HAdV-C species, which does not have a known neuropathogenic potential. Also, 40% of adenoviruses were isolated from patients with consequently established diagnosis of traumatic neuritis at the discharge, which was not compatible with virus ethology of neurological lesions. Higher adenovirus prevalence in young neurological patients could be affected by an underlying immune deficiency or by congestion in children's hospitals. Indeed, among 70 patients (40 infants, 30 adults) with primary immune deficiencies, asymptomatic shedding of adenoviruses was found in 10-17%; in one adult patient a mixture of HAdV-C2 and HAdV-D15 persisted for several months. Adenoviruses also could be detected in feces of 12% and 57% of healthy young children from two orphanages, respectively. A significant fraction of samples in these groups contained adenovirus mixtures. Therefore, immune deficiencies and congested groups in children's facilities (orphanages and hospitals) could affect significantly the prevalence of adenovirus shedding. The role of adenoviruses in AFP requires further study.

Exogenous interleukin-6, interleukin-13, and interferon-γ provoke pulmonary abnormality with mild edema in enterovirus 71-infected mice.

BACKGROUND: Neonatal mice developed neurological disease and pulmonary dysfunction after an infection with a mouse-adapted human Enterovirus 71 (EV71) strain MP4. However, the hallmark of severe human EV71 infection, pulmonary edema (PE), was not evident. METHODS: To test whether EV71-induced PE required a proinflammatory cytokine response, exogenous pro-inflammatory cytokines were administered to EV71-infected mice during the late stage of infection. RESULTS: After intracranial infection of EV71/MP4, 7-day-old mice developed hind-limb paralysis, pulmonary dysfunction, and emphysema. A transient increase was observed in serum IL-6, IL-10, IL-13, and IFN-γ, but not noradrenaline. At day 3 post infection, treatment with IL-6, IL-13, and IFN-γ provoked mild PE and severe emphysema that were accompanied by pulmonary dysfunction in EV71-infected, but not herpes simplex virus-1 (HSV-1)-infected control mice. Adult mice did not develop PE after an intracerebral microinjection of EV71 into the nucleus tractus solitarii (NTS). While viral antigen accumulated in the ventral medulla and the NTS of intracerebrally injected mice, neuronal loss was observed in the ventral medulla only. CONCLUSIONS: Exogenous IL-6, IL-13, and IFN-γ treatment could induce mild PE and exacerbate pulmonary abnormality of EV71-infected mice. However, other factors such as over-activation of the sympathetic nervous system may also be required for the development of classic PE symptoms.

Polio / Polio

Polio continúa endémica en: Nigeria, Afganistán Pakistán e India. La iniciativa global de erradicación de polio de la OMS estableció que para 2013 no debe haber ningún niño paralítico en el mundo por el virus salvaje o por el virus derivado de la vacuna. En esta revisión se describen ambas vacunas contra el polio, la oral y la inactivada, su inmunogenicidad, seguridad y las condiciones a cumplir por un paíspara que cambie su esquema de vacunación de polio oral a inactivada. La vacuna polio oral ha permitido la erradicación de la enfermedaden varios continentes incluyendo América; sin embargo conlleva riesgos, tales como polio paralítica asociada a vacuna (VAP-siglas en inglés-) y parálisis producida por polio virus derivado de la vacuna (VDP-siglas en inglés-). La Vacuna Polio Inactivada (VPI) es segura e inmunogénica, puede ser administrada en combinaciones vacunales. Para que un país cambie a VPI debe tener cobertura y esquemaóptimo de esta vacuna, 90% de, cobertura de DTP3, vigilancia adecuada de parálisis flácida, no estar próximo en la actualidad o recientemente a un país con polio endémico. Altas coberturas vacunales son esenciales par asegurar una inmunidad adecuada de lapoblación

Polio remains endemic in Nigeria, Afghanistan, Pakistan, India. Strategic plan of Global Poliomyelitis Eradication Initiative (GPEI) of the WHO is that by 2013 no child will be paralyzed by a wild or vaccine derived poliovirus. This paper describes both oral and inactivated vaccine, safety concerns with the use of OPV, immunogenicity of IPV and the conditions to be full filled in order for a country to deliverIPV as a regular vaccine schedule. Oral polio vaccine has successfully contributed to global polio eradication in several continents including America. However, it carries risks, such as Vaccine Derived Poliovirus (VDP) and Vaccine Associated Paralytic Polio (VAPP). Inactivated Poliovirus Vaccine (IPV) is safe and immunogenic; it may be administered as monovalent or in a combined shot. Countries opting to switch from OPV to IPV should have: optimal IPV coverage and schedule, 90% of DTP 3 coverage, good surveillance of flaccid paralysis cases, and should not be near a country with endemic polio recently or at the present time. Are neither currently or were notrecently polio endemic nor has close contacts with such areas. High immunization coverage is essential to ensure adequate populationimmunity

Importance of macrophage inflammatory protein-1α and splenic macrophages in neurodegeneration induced by PVC-211 murine leukemia virus.

We recently reported that infection of rats with the neurodegenerative disease-causing retrovirus PVC-211 MuLV results in elevated levels of the chemokine MIP-1α followed by the accumulation of activated microglia in the brain. To investigate the importance of MIP-1α in recruitment of microglia to the brain, we treated rats with MIP-1α antibodies before and after PVC-211 MuLV infection. This caused a delay in the development of paralysis which was associated with a decrease in activated microglia without affecting virus expression. To determine the source of activated microglia, rats were splenectomized 4 days after virus infection. Splenectomized rats showed a delay in disease development that was associated with decreased numbers of activated microglia without affecting virus expression. Together, these results suggest that MIP-1α is directly involved in the neurodegeneration induced in rats by PVC-211 MuLV by recruiting macrophages/microglia from the periphery into regions of the brain that eventually become diseased.

Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice.

Many neurodegenerative diseases are associated with accumulation of misfolded proteins in cells of the central nervous system (CNS). We have previously reported that accumulation of the precursor envelope protein gPr80(env) of ts1, a mutant of Moloney murine leukemia virus (MoMuLV), in the endoplasmic reticulum (ER) of infected astrocytes, results in ER stress, oxidative stress and cell death, subsequently leading to ts1-mediated neurodegeneration in infected mice. In the present study, we assessed whether treatments that reduce the accumulation of gPr80(env) in the ER of ts1-infected astrocytes provided a protective effect against ER stress and cell death. We show that treatment with phenylbutyric acid (PBA) can prevent the unfolded protein response (UPR), ER stress and cell death in cultured ts1-infected astrocytes. The protective effect of PBA is associated with its ability to reduce gPr80(env) accumulation and to increase the expression of proteins involved in protein folding in the ER, such as protein disulfide isomerase (PDI) and ERp44, rather than by decrease mRNA levels of gPr80(env) or alter the proteasomal degradation process for gPr80(env). In infected mice treated with PBA we also noted a reduction in the severity of the neuropathology in brainstem tissues and a delayed onset of paralysis. These results show that PBA is a potentially effective drug for the treatment of neurodegeneration caused by protein accumulation in cells of the CNS.

Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus.

Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7-10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.