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Enterovirus 71 infection causes severe pulmonary lesions in gerbils, meriones unguiculatus, which can be prevented by passive immunization with specific antisera.

Xu F, Yao PP, Xia Y, Qian L, Yang ZN, Xie RH, Sun YS, Lu HJ, Miao ZP, Li C, Li X, Liang WF, Huang XX, Xia SC, Chen ZP, Jiang JM, Zhang YJ, Mei LL, Liu SL, Gu H, Xu ZY, Fu XF, Zhu ZY, Zhu HP - PLoS ONE (2015)

Bottom Line: However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models.Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination.EV71 viral titer was found to be peak at late stages of infection.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Vaccine against Hemorrhagic Fever with Renal Syndrome, Zhejiang Province Center for Disease Prevention and Control, Hangzhou, China.

ABSTRACT
Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs.

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Macroscopic pathological lung changes in EV71-infected 21-day-old gerbils following 1×105.5 TCID50 inoculation by IP route.Pictures correspond to the lung tissues from healthy or EV71-infected gerbils. Normal lung of a healthy gerbil (A, left; B, left), markedly red and congestion, extensive hemorrhage (A, right; B, right) in the lung were shown in EV71-infected gerbils.
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pone.0119173.g002: Macroscopic pathological lung changes in EV71-infected 21-day-old gerbils following 1×105.5 TCID50 inoculation by IP route.Pictures correspond to the lung tissues from healthy or EV71-infected gerbils. Normal lung of a healthy gerbil (A, left; B, left), markedly red and congestion, extensive hemorrhage (A, right; B, right) in the lung were shown in EV71-infected gerbils.

Mentions: For gerbils, the spinal cord, brainstem and skeletal muscle are the target organs of EV71-infection [26]. Neuronal degeneration, neuronal loss and neuronophagia in central nervous system (CNS) and necrotizing myositis in skeletal muscle were observed in the infected gerbils [26]. In this study, severe damage in lung tissues were also found in infected gerbils. Lung tissue from EV71-infected gerbils was observed to be more dark red than that from normal gerbils (Fig. 2). Microscopically, lung tissue from healthy gerbils showed normal alveoli, alveolar septa, and lining epithelium (Fig. 3A). In contrast, lung tissues of EV71-infected gerbils revealed diffused lesions and dysfunctions with varying degrees of severity. Pulmonary interstitial inflammatory and alveolar septum broadening was observed in all EV71-infected gerbils after EV71 inoculation at both high IP dosing in all three age groups (1×105.5 TCID50; 7 d, 14 d, 21d) (Fig. 3B). A thickened alveolar septum resulting from inflammation, scarring, or extra fluid (edema) was the main histological feature (Fig. 3C). Occasionally, lung tissue or alveolar space contained liquid instead of gas (Fig. 3D) and focal alveolar hemorrhaging was noted (Fig. 3E). One third of infected gerbils (6/18) developed focal alveolar consolidation and many neutrophilic infiltrates were found within the alveolar spaces (Fig. 3F). In addition, another one third developed diffuse alveolar hemorrhaging and lumina of alveoli with bronchioles minority filled with edema fluid (Fig. 3G). There was no obvious difference in histopathology in infected gerbils among the three age groups (Table 1). These data indicated gerbils aged from 7–21 days exhibited an age-independent response to lung tissue damage and death rate although the time to disease onset was different in each. Both 28-day-old and 35-day-old gerbils showed only pulmonary interstitial thickening, with no extensive pulmonary hemorrhaging observed (data not shown).


Enterovirus 71 infection causes severe pulmonary lesions in gerbils, meriones unguiculatus, which can be prevented by passive immunization with specific antisera.

Xu F, Yao PP, Xia Y, Qian L, Yang ZN, Xie RH, Sun YS, Lu HJ, Miao ZP, Li C, Li X, Liang WF, Huang XX, Xia SC, Chen ZP, Jiang JM, Zhang YJ, Mei LL, Liu SL, Gu H, Xu ZY, Fu XF, Zhu ZY, Zhu HP - PLoS ONE (2015)

Macroscopic pathological lung changes in EV71-infected 21-day-old gerbils following 1×105.5 TCID50 inoculation by IP route.Pictures correspond to the lung tissues from healthy or EV71-infected gerbils. Normal lung of a healthy gerbil (A, left; B, left), markedly red and congestion, extensive hemorrhage (A, right; B, right) in the lung were shown in EV71-infected gerbils.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359154&req=5

pone.0119173.g002: Macroscopic pathological lung changes in EV71-infected 21-day-old gerbils following 1×105.5 TCID50 inoculation by IP route.Pictures correspond to the lung tissues from healthy or EV71-infected gerbils. Normal lung of a healthy gerbil (A, left; B, left), markedly red and congestion, extensive hemorrhage (A, right; B, right) in the lung were shown in EV71-infected gerbils.
Mentions: For gerbils, the spinal cord, brainstem and skeletal muscle are the target organs of EV71-infection [26]. Neuronal degeneration, neuronal loss and neuronophagia in central nervous system (CNS) and necrotizing myositis in skeletal muscle were observed in the infected gerbils [26]. In this study, severe damage in lung tissues were also found in infected gerbils. Lung tissue from EV71-infected gerbils was observed to be more dark red than that from normal gerbils (Fig. 2). Microscopically, lung tissue from healthy gerbils showed normal alveoli, alveolar septa, and lining epithelium (Fig. 3A). In contrast, lung tissues of EV71-infected gerbils revealed diffused lesions and dysfunctions with varying degrees of severity. Pulmonary interstitial inflammatory and alveolar septum broadening was observed in all EV71-infected gerbils after EV71 inoculation at both high IP dosing in all three age groups (1×105.5 TCID50; 7 d, 14 d, 21d) (Fig. 3B). A thickened alveolar septum resulting from inflammation, scarring, or extra fluid (edema) was the main histological feature (Fig. 3C). Occasionally, lung tissue or alveolar space contained liquid instead of gas (Fig. 3D) and focal alveolar hemorrhaging was noted (Fig. 3E). One third of infected gerbils (6/18) developed focal alveolar consolidation and many neutrophilic infiltrates were found within the alveolar spaces (Fig. 3F). In addition, another one third developed diffuse alveolar hemorrhaging and lumina of alveoli with bronchioles minority filled with edema fluid (Fig. 3G). There was no obvious difference in histopathology in infected gerbils among the three age groups (Table 1). These data indicated gerbils aged from 7–21 days exhibited an age-independent response to lung tissue damage and death rate although the time to disease onset was different in each. Both 28-day-old and 35-day-old gerbils showed only pulmonary interstitial thickening, with no extensive pulmonary hemorrhaging observed (data not shown).

Bottom Line: However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models.Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination.EV71 viral titer was found to be peak at late stages of infection.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Vaccine against Hemorrhagic Fever with Renal Syndrome, Zhejiang Province Center for Disease Prevention and Control, Hangzhou, China.

ABSTRACT
Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs.

Show MeSH
Related in: MedlinePlus