Respiratory viruses infect the human upper respiratory tract, mostly causing mild diseases. However, in vulnerable populations, such as newborns, infants, the elderly and immune-compromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, causing a more severe disease (e.g., pneumonia). Respiratory viruses can also exacerbate asthma and lead to various types of respiratory distress syndromes. Furthermore, as they can adapt fast and cross the species barrier, some of these pathogens, like influenza A and SARS-CoV, have occasionally caused epidemics or pandemics, and were associated with more serious clinical diseases and even mortality. For a few decades now, data reported in the scientific literature has also demonstrated that several respiratory viruses have neuroinvasive capacities, since they can spread from the respiratory tract to the central nervous system (CNS). Viruses infecting human CNS cells could then cause different types of encephalopathy, including encephalitis, and long-term neurological diseases. Like other well-recognized neuroinvasive human viruses, respiratory viruses may damage the CNS as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals (virus-induced neuro-immunopathology) and/or viral replication, which directly causes damage to CNS cells (virus-induced neuropathology). The etiological agent of several neurological disorders remains unidentified. Opportunistic human respiratory pathogens could be associated with the triggering or the exacerbation of these disorders whose etiology remains poorly understood. Herein, we present a global portrait of some of the most prevalent or emerging human respiratory viruses that have been associated with possible pathogenic processes in CNS infection, with a special emphasis on human coronaviruses.

Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?

Satellite glial cells in sensory ganglia: from form to function

Virus Infections in the Nervous System

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even thoug ...

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Microbes and Alzheimer's disease

Liposomes and liposome-derived nanovesicles such as archaeosomes and virosomes have become important carrier systems in vaccine development and the interest for liposome-based vaccines has markedly...

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Liposomes as vaccine delivery systems: a review of the recent advances

Olfactory receptor neurons are unique in their anatomical structure and function. Each neuron is directly exposed to the external environment at the site of its dendritic nerve terminals where it is exposed to macromolecules. These molecules can be incorporated into by olfactory receptor neurons and transported transsynaptically to the central nervous system. Certain neurotropic pathogens such as herpes simplex virus and Borna disease virus make use of this physiological mechanism to invade the brain. Here the authors review the olfactory transmission of infectious agents and the resulting hazards to human and animal health.

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Olfactory transmission of neurotropic viruses

Herpes simplex virus type 1 (HSV-1) has been proposed as an environmental risk factor for sporadic Alzheimer's disease, although this issue is still in dispute. The involvement of HSV-1 in the pathogenesis of familial Alzheimer's disease, the uncommon type of Alzheimer's disease, has not been addressed yet. We investigated formalin-fixed, paraffin-embedded, postmortem brain tissue sections of three patients with familial Alzheimer's disease for the presence of HSV-1 DNA. The nested polymerase chain reaction (PCR) detected the HSV-1 glycoprotein D gene in the brain of all three patients with familial Alzheimer's disease preferentially in the frontal and temporal cortices, whereas only one case out of six age-matched, non-Alzheimer's disease individuals could disclose the presence of HSV-1 gene. The PCR detected HSV-1 DNA in the frontal cortex of the two patients with sporadic Alzheimer's disease. The presence of HSV-1 was associated with beta-amyloid deposition in the cerebral cortex. To clarify the localization of HSV-1 in the brain tissue of patients with familial Alzheimer's disease, the in situ hybridization of the tyramide signal amplification system was used. It detected the HSV-1-specific signals predominantly in the cytoplasm of cortical neurons in a dot-like staining fashion. In addition, high-sensitivity immunohistochemistry revealed the existence of HSV-1 antigens in the cytoplasm of cortical neurons. This report provides the first evidence of reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease, associated with beta-amyloid deposition, and suggests the possible involvement of HSV-1 together with genetic factors in the pathogenesis of familial Alzheimer's disease.

Reactivation of HSV‐1 in the brain of patients with familial Alzheimer's disease

It is well accepted that vaccination by oral administration has many advantages over injected parenteral immunization. The present study focuses on whether oral vaccination with a DNA vaccine could induce protective immunity against respiratory challenge infection. The M1 gene of influenza A virus was used to construct DNA vaccine using pcDNA 3.1(+) plasmid, a eukaryotic expression vector. The cationic liposomes were used to deliver the constructed DNA vaccine. In vitro and in vivo expression of M1 gene was observed in the cell line and in the intestine of orally vaccinated C57BL/6 mice, respectively. It became clear that this type of oral DNA vaccination was capable of inducing both humoral and cellular immune responses, together with an augmentation of IFN-γ production. In addition, oral vaccination with liposome-encapsulated DNA vaccine could protect the mice against respiratory challenge infection. These results suggest that gastrointestinal tract, a constituent member of the common mucosal immune system, is a potent candidate applicable as a DNA vaccine route against virus respiratory diseases.

Oral vaccination with a liposome‐encapsulated influenza DNA vaccine protects mice against respiratory challenge infection

The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus

Extensive efforts have been made to elucidate mechanisms by which viruses induce apoptosis in cultured neuronal cells. However, little is yet understood about the mechanisms of neuronal apoptosis in vivo as well as interpretations of this active host response. Here we review recent advances toward understanding these topics. The c-Jun N-terminal protein kinase cascade may be an important apoptotic mediator in virally infected neurons, which comes in focus as a therapeutic target for protecting neurons from death. A novel concept can be proposed that virus-induced neuronal apoptosis in the central nervous system may represent a pathological host response, while that in the peripheral counterpart, especially olfactory receptor neurons, may mediate a protective host response.

Yoshinobu Kimura

Papers

Olfactory transmission of neurotropic viruses

Reactivation of HSV‐1 in the brain of patients with familial Alzheimer's disease

Oral vaccination with a liposome‐encapsulated influenza DNA vaccine protects mice against respiratory challenge infection

The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus

Virus-induced neuronal apoptosis as pathological and protective responses of the host