The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system

Riel, Debby van; Verdijk, Robert M.; Kuiken, Thijs

doi:10.1002/path.4461

Cited by 337 publications

(320 citation statements)

References 103 publications

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“…Such an intra-axonal migration pathway has long been known for neurotropic viruses such as rabies virus, herpesviruses, morbilliviruses, West Nile virus, and poliovirus (45)(46)(47), and also, the bacterium Burkholderia pseudomallei is suspected to migrate along cranial nerves (48). Although, once L. monocytogenes has entered the brain, the intrathecal immune response is intense and develops rapidly, L. monocytogenes is able to efficiently replicate and spread within the brain, causing a progressive and frequently fatal neurological disease (17,29).…”

Section: Discussionmentioning

confidence: 99%

“…9). Transneuronal spread is a known pathway of intracerebral spread of rabies virus, measles virus, and herpesviruses and is a pathway suspected for many more viruses (47,(57)(58)(59). Proposed mechanisms include trans-synaptic transport, the establishment of microfusions, and non-trans-synaptic neuron-to-neuron transmission but remain to be elucidated for most of these viruses (47).…”

Section: Discussionmentioning

confidence: 99%

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Listeria monocytogenes Spreads within the Brain by Actin-Based Intra-Axonal Migration

et al. 2015

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e Listeria monocytogenes rhombencephalitis is a severe progressive disease despite a swift intrathecal immune response. Based on previous observations, we hypothesized that the disease progresses by intra-axonal spread within the central nervous system. To test this hypothesis, neuroanatomical mapping of lesions, immunofluorescence analysis, and electron microscopy were performed on brains of ruminants with naturally occurring rhombencephalitis. In addition, infection assays were performed in bovine brain cell cultures. Mapping of lesions revealed a consistent pattern with a preferential affection of certain nuclear areas and white matter tracts, indicating that Listeria monocytogenes spreads intra-axonally within the brain along interneuronal connections. These results were supported by immunofluorescence and ultrastructural data localizing Listeria monocytogenes inside axons and dendrites associated with networks of fibrillary structures consistent with actin tails. In vitro infection assays confirmed that bacteria were moving within axon-like processes by employing their actin tail machinery. Remarkably, in vivo, neutrophils invaded the axonal space and the axon itself, apparently by moving between split myelin lamellae of intact myelin sheaths. This intra-axonal invasion of neutrophils was associated with various stages of axonal degeneration and bacterial phagocytosis. Paradoxically, the ensuing adaxonal microabscesses appeared to provide new bacterial replication sites, thus supporting further bacterial spread. In conclusion, intra-axonal bacterial migration and possibly also the innate immune response play an important role in the intracerebral spread of the agent and hence the progression of listeric rhombencephalitis. Due to its resistance to hostile conditions, the Gram-positive bacterium Listeria monocytogenes is ubiquitously distributed in the environment and commonly contaminates food and animal feed (1-3). Upon oral uptake, L. monocytogenes may turn into an intracellular pathogen causing listeriosis, one of the deadliest foodborne infections in humans and ruminants (1,(4)(5)(6). Clinical syndromes associated with L. monocytogenes infection include febrile gastroenteritis, mastitis, septicemia, abortion, and central nervous system (CNS) infection, the latter accounting for the high mortality rates associated with listeriosis (1, 5-9). In most human patients, neurolisteriosis manifests as meningitis or meningoencephalitis, and L. monocytogenes is listed among the most common pathogens of bacterial meningitis (10-13). Further forms of neurolisteriosis include brainstem encephalitis (rhombencephalitis) occurring in 25% of cases and brain abscesses accounting for a further 10% of cases with CNS infection (11,14). Neurolisteriosis in ruminants occurs almost exclusively as rhombencephalitis (1, 15-17) and mimics its human counterpart in many respects (17, 18), lending itself as a spontaneous animal model.Although the intracellular life cycle of L. monocytogenes has been elegantly deciphered by in vitro st...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Listeria monocytogenes Spreads within the Brain by Actin-Based Intra-Axonal Migration

et al. 2015

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“…Moreover, spread of influenza viruses to the brain usually occurs by the hematogenic route and also through the olfactory nerve. 27 Decreased replication in the brain in birds infected with Hp-NS230 or Hp-NSLp may be due to decreased tropism to endothelial cells; which is an important feature of HPAIV in domestic poultry. 28 These results indicated that NS1 can (1) modulate tropism to different tissues limiting systemic spread of the virus and (2) truncation is involved in this restriction but also other mutations in the NS1 play an additional role.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens

et al. 2016

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(2016) Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens, Virulence, 7:5, 546-557, DOI: 10.1080/21505594.2016 protein sequences of all AIV subtypes in birds from 1902 to 2015 were analyzed to study the prevalence and distribution of CTE truncation (DCTE). Thirteen different DCTE forms were observed in NS1 proteins from 11 HA and 8 NA subtypes with high prevalences in H9, H7, H6 and H10 and N9, N2, N6 and N1 subtypes particularly in chickens and minor poultry species. With 88% NS217 lacking amino acids 218-230 was the most common DCTE form followed by NS224 (3.6%). NS217 was found in 10 and 8 different HA and NA subtypes, respectively, whereas NS224 was detected exclusively in the Italian HPAIV H7N1 suggesting relevance for virulence. To test this assumption, 3 recombinant HPAIV H7N1 were constructed carrying wild-type HP NS1 (Hp-NS224), NS1 with extended CTE (Hp-NS230) or NS1 from LPAIV H7N1 (Hp-NSLp), and tested in-vitro and in-vivo. Extension of CTE in Hp NS1 significantly decreased virus replication in chicken embryo kidney cells. Truncation in the NS1 decreased the tropism of Hp-NS224 to the endothelium, central nervous system and respiratory tract epithelium without significant difference in virulence in chickens. This study described the variable forms of DCTE in NS1 and indicated that CTE is not an essential virulence determinant particularly for the Italian HPAIV H7N1 but may be a host-adaptation marker required for efficient virus replication.

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“…Previous observations have shown that neurons in the olfactory epithelium can be targeted by influenza A virus in mice (29), ferrets (24), and humans (40), and that H5N1 avian influenza strains in ferrets can spread along olfactory and trigeminal nerves to the OBs and brainstem after intranasal infection (24). In humans, influenza virus antigens in neurons and glia in the OBs and tracts, and the gyrus rectus have recently been found in an immune-compromised child (41).…”

Section: Influenza Virus Targets Olfactory Epithelium and Sleep-wakementioning

confidence: 99%

“…For example, a mutant of vesicular stomatitis virus can target DRN neurons and cause lifelong selective serotonin depletion in the brain (46). It is therefore possible that the several viruses that can invade the brain along the olfactory route (40,46), include mutant virus strains, which could more selectively target Orx/Hcrt neurons and cause lifelong sleep pattern changes in susceptible individuals.…”

Section: Influenza Virus Targets Olfactory Epithelium and Sleep-wakementioning

confidence: 99%

H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep–wake regulatory neurons in mice

Tesoriero

Codita

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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An increased incidence in the sleep-disorder narcolepsy has been associated with the 2009-2010 pandemic of H1N1 influenza virus in China and with mass vaccination campaigns against influenza during the pandemic in Finland and Sweden. Pathogenetic mechanisms of narcolepsy have so far mainly focused on autoimmunity. We here tested an alternative working hypothesis involving a direct role of influenza virus infection in the pathogenesis of narcolepsy in susceptible subjects. We show that infection with H1N1 influenza virus in mice that lack B and T cells (Recombinant activating gene 1-deficient mice) can lead to narcoleptic-like sleep-wake fragmentation and sleep structure alterations. Interestingly, the infection targeted brainstem and hypothalamic neurons, including orexin/ hypocretin-producing neurons that regulate sleep-wake stability and are affected in narcolepsy. Because changes occurred in the absence of adaptive autoimmune responses, the findings show that brain infections with H1N1 virus have the potential to cause per se narcoleptic-like sleep disruption.

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The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system

Cited by 337 publications

References 103 publications

Listeria monocytogenes Spreads within the Brain by Actin-Based Intra-Axonal Migration

Listeria monocytogenes Spreads within the Brain by Actin-Based Intra-Axonal Migration

Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens

H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep–wake regulatory neurons in mice

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