Studying Hand, Foot, and Mouth Disease with Humanized Mice

Enterovirus-A71 (EV-A71), a member of the genus Enterovirus in the Picornaviridae family¹, is one of the most common causes of hand, foot, and mouth disease (HFMD) in younger children^2,3 and occasionally causes large-scale epidemics worldwide, especially within the Asia-Pacific region. In addition, EV-A71 is consistently associated with severe complications of the neurological and pulmonary system that may result in permanent paralysis or even death, especially among younger children⁴.

The underlying pathology of the immune system in response to EV-A71 infection is not fully understood, in part due to the lack of appropriate animal models that accurately recapitulate the human condition. This is because Homo sapiens is the only natural host for EV-A71 infection⁵. Inevitably, this hinders the development of promising vaccines and drugs. Understandably, EV-A71 is a public health concern and possesses significant socioeconomic burden⁶.

Using Humanized Mice to Model HFMD Infection

One approach for modelling EV-A71 infection is the use of human immune system-engrafted mice. In the present study, Ke et al. used human immune system-engrafted mice infected with a human isolate (non-mouse adapted) of EV-A71 strain 41⁷. They showed that EV-A71 infection was pathogenic and decreased the survival of humanized mice, but not of the corresponding non-humanized controls.

EV-A71-infected humanized mice presented with diminished neurobehavioral functions, as well as histopathological signs of cellular inflammation and tissue damage of the brain stem and spinal cord that were accompanied by high viral loads within these respective organ systems. Severe forms of EV-A71-associated neurological complications were found in EV-A71-infected moribund mice, which are similar to those reported in patients, such as aseptic meningitis, brainstem and cerebellar encephalitis⁸.

Together, these murine features phenocopy the clinical EV-AY1 syndrome and validate the in vivo humanized mouse as a model for human HFMD infection.

How the Immune System Reacts to HFMD

Ke et al. also utilized this mouse model to investigate the role of the human immune system during EV-A71 infection, demonstrating activation of human T-cells as well as an infiltration of human immune cells into the murine brains and lungs. Specifically, the authors reported a significant upregulation of circulating activated human CD4+ and CD8+ cells between three to seven weeks post-infection that were accompanied by EV-A71-specific human T cell responses.

Furthermore, the authors uncovered increased secretion of proinflammatory cytokines in the EV-A71-infected humanized mice, such as human IFN-γ, IL-8 and IL-17A, and proposed a contribution to the exacerbation of disease pathogenesis.

Studying Immune Responses to Infectious Disease

Collectively, this article demonstrates the utility of humanized mouse model to investigate the pathogenesis of EV-A71 infection and delineate the accompanying human immune responses. This humanized murine model will provide a platform for the evaluation of anti-EV-A71 therapeutics, and further insights into the human immune responses to infectious diseases for translational research.

References:

1. Pathinayake PS, Hsu AC, Wark PA. Innate Immunity and Immune Evasion by Enterovirus 71. Viruses. 7(12):6613-30 (2015).

2. McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 26(1):91-107. (2002).

3. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis. 129(3):304-9 (1974).

4. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med. 23;341(13):936-42 (1999).

5. Mandary MB and Poh CL. Changes in the EV-A71 Genome through Recombination and Spontaneous Mutations: Impact on Virulence. Viruses. 10(6):320 (2018).

6. Ryu WS, Kang B, Hong J, Hwang S, Kim J, Cheon DS. Clinical and etiological characteristics of enterovirus 71-related diseases during a recent 2-year period in Korea. J Clin Microbiol. 48:2490-4 (2010).

7. Ke Y, Liu WN, Her Z, Liu M, Tan SY, Tan YW, Chan XY, Fan Y, Huang EK, Chen H, Chang KTE, Chan JKY, Hann Chu JJ, Chen Q. Enterovirus-A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice. J. Virol. 2018 Nov 14.

8. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect. Dis. 10:778-90 (2010).