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Coxsackievirus A16 induced neurological disorders in young gerbils which could serve as a new animal model for vaccine evaluation

View Article: PubMed Central - PubMed

ABSTRACT

Coxsackievirus A16 (CA16) is one of the major pathogens associated with human hand, foot, and mouth disease (HFMD) in the Asia-pacific region. Although CA16 infections are generally mild, severe neurological manifestations or even death has been reported. Studies on CA16 pathogenesis and vaccine development are severely hampered because the small animal models that are currently available show major limitations. In this study, gerbils (Meriones unguiculatus) were investigated for their suitability as an animal model to study CA16 pathogenesis and vaccine development. Our results showed that gerbils up to the age of 21 days were fully susceptible to CA16 and all died within five days post-infection. CA16 showed a tropism towards the skeletal muscle, spinal cord and brainstem of gerbils, and severe lesions, including necrosis, were observed. In addition, an inactivated CA16 whole-virus vaccine administrated to gerbils was able to provide full protection to the gerbils against lethal doses of CA16 strains. These results demonstrate that gerbils are a suitable animal model to study CA16 infection and vaccine development.

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Pathology of CA16-infected gerbil tissues.Gerbils aged 21 days were challenged with CA16-194 using a TCID50 of 105.5. (A) Representative images of control and CA16-infected gerbils four days post infection. The arrow indicates hind-limb paralysis observed in the CA16-infected gerbils. (B) Representative images of haematoxylin and eosin or Nissl stained brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. The arrows indicate focal shrunken neurons in the infected brainstem, swollen neurons and neuronophagia in the infected spinal cord, and inflammatory cell infiltration, severe necrotizing myositis, degeneration and swelling of skeletal muscle fibers in the infected muscle. (C) Representative images of brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. Presence of viral antigens (arrows) was visualized by incubation with peroxidase staining DAB followed by counterstaining with haematoxylin.
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f4: Pathology of CA16-infected gerbil tissues.Gerbils aged 21 days were challenged with CA16-194 using a TCID50 of 105.5. (A) Representative images of control and CA16-infected gerbils four days post infection. The arrow indicates hind-limb paralysis observed in the CA16-infected gerbils. (B) Representative images of haematoxylin and eosin or Nissl stained brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. The arrows indicate focal shrunken neurons in the infected brainstem, swollen neurons and neuronophagia in the infected spinal cord, and inflammatory cell infiltration, severe necrotizing myositis, degeneration and swelling of skeletal muscle fibers in the infected muscle. (C) Representative images of brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. Presence of viral antigens (arrows) was visualized by incubation with peroxidase staining DAB followed by counterstaining with haematoxylin.

Mentions: To investigate the pathological effects of CA16 on infected gerbil tissues, 21-day-old gerbils were infected with CA16-194 at a TCID50 of 105.5. At four days post-infection, the brainstem, spinal cord and muscle tissues were harvested and analyzed. Gerbils at this stage all showed typical clinical symptoms such as wasting and hind-limb paralysis (Fig. 4A). The brainstem and spinal cord were the most severely affected organs of the central nervous system (CNS) in the infected gerbils. In the infected brainstem, focal shrinking neurons were detected (Fig. 4B). In the spinal cord, neurons were found to be swollen and neuronophagia was detected (Fig. 4B). Finally, inflammatory cell infiltration and severe necrotizing myositis were observed in infected muscle tissues. Degeneration and swelling of skeletal muscle fibers were also detected, which resulted in muscle cell dead (Fig. 4B). In addition, widespread dissemination of the CA16 antigen was observed and corresponded with lesions present in the brainstem, spinal cord and muscle tissues (Fig. 4C). These results indicated that CA16-194 showed a strong tropism towards central nervous and skeletal muscle tissues.


Coxsackievirus A16 induced neurological disorders in young gerbils which could serve as a new animal model for vaccine evaluation
Pathology of CA16-infected gerbil tissues.Gerbils aged 21 days were challenged with CA16-194 using a TCID50 of 105.5. (A) Representative images of control and CA16-infected gerbils four days post infection. The arrow indicates hind-limb paralysis observed in the CA16-infected gerbils. (B) Representative images of haematoxylin and eosin or Nissl stained brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. The arrows indicate focal shrunken neurons in the infected brainstem, swollen neurons and neuronophagia in the infected spinal cord, and inflammatory cell infiltration, severe necrotizing myositis, degeneration and swelling of skeletal muscle fibers in the infected muscle. (C) Representative images of brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. Presence of viral antigens (arrows) was visualized by incubation with peroxidase staining DAB followed by counterstaining with haematoxylin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5035925&req=5

f4: Pathology of CA16-infected gerbil tissues.Gerbils aged 21 days were challenged with CA16-194 using a TCID50 of 105.5. (A) Representative images of control and CA16-infected gerbils four days post infection. The arrow indicates hind-limb paralysis observed in the CA16-infected gerbils. (B) Representative images of haematoxylin and eosin or Nissl stained brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. The arrows indicate focal shrunken neurons in the infected brainstem, swollen neurons and neuronophagia in the infected spinal cord, and inflammatory cell infiltration, severe necrotizing myositis, degeneration and swelling of skeletal muscle fibers in the infected muscle. (C) Representative images of brainstem, spinal cord and muscle tissues harvested from CA16-infected and control gerbils four days post infection. Presence of viral antigens (arrows) was visualized by incubation with peroxidase staining DAB followed by counterstaining with haematoxylin.
Mentions: To investigate the pathological effects of CA16 on infected gerbil tissues, 21-day-old gerbils were infected with CA16-194 at a TCID50 of 105.5. At four days post-infection, the brainstem, spinal cord and muscle tissues were harvested and analyzed. Gerbils at this stage all showed typical clinical symptoms such as wasting and hind-limb paralysis (Fig. 4A). The brainstem and spinal cord were the most severely affected organs of the central nervous system (CNS) in the infected gerbils. In the infected brainstem, focal shrinking neurons were detected (Fig. 4B). In the spinal cord, neurons were found to be swollen and neuronophagia was detected (Fig. 4B). Finally, inflammatory cell infiltration and severe necrotizing myositis were observed in infected muscle tissues. Degeneration and swelling of skeletal muscle fibers were also detected, which resulted in muscle cell dead (Fig. 4B). In addition, widespread dissemination of the CA16 antigen was observed and corresponded with lesions present in the brainstem, spinal cord and muscle tissues (Fig. 4C). These results indicated that CA16-194 showed a strong tropism towards central nervous and skeletal muscle tissues.

View Article: PubMed Central - PubMed

ABSTRACT

Coxsackievirus A16 (CA16) is one of the major pathogens associated with human hand, foot, and mouth disease (HFMD) in the Asia-pacific region. Although CA16 infections are generally mild, severe neurological manifestations or even death has been reported. Studies on CA16 pathogenesis and vaccine development are severely hampered because the small animal models that are currently available show major limitations. In this study, gerbils (Meriones unguiculatus) were investigated for their suitability as an animal model to study CA16 pathogenesis and vaccine development. Our results showed that gerbils up to the age of 21 days were fully susceptible to CA16 and all died within five days post-infection. CA16 showed a tropism towards the skeletal muscle, spinal cord and brainstem of gerbils, and severe lesions, including necrosis, were observed. In addition, an inactivated CA16 whole-virus vaccine administrated to gerbils was able to provide full protection to the gerbils against lethal doses of CA16 strains. These results demonstrate that gerbils are a suitable animal model to study CA16 infection and vaccine development.

No MeSH data available.


Related in: MedlinePlus