Hantavirus-induced pathogenesis in mice with a humanized immune system

Abstract

Hantaviruses are emerging zoonotic pathogens that can cause severe disease in humans. Clinical observations suggest that human immune components contribute to hantavirus-induced pathology. To address this issue we generated mice with a humanized immune system. Hantavirus infection of these animals resulted in systemic infection associated with weight loss, decreased activity, ruffled fur and inflammatory infiltrates of lung tissue. Intriguingly, after infection, humanized mice harbouring human leukocyte antigen (HLA) class I-restricted human CD8+ T cells started to lose weight earlier (day 10) than HLA class I-negative humanized mice (day 15). Moreover, in these mice the number of human platelets dropped by 77 % whereas the number of murine platelets did not change, illustrating how differences between rodent and human haematolymphoid systems may contribute to disease development. To our knowledge this is the first description of a humanized mouse model of hantavirus infection, and our results indicate a role for human immune cells in hantaviral pathogenesis.

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

“…88 In humanized HLA-A2 mice, Hantavirus infection induces a dramatic decrease in total platelet count and infiltration of lymphocytes into the lungs, and increases weight loss. 89 Similarly, in Crimean-Congo haemorrhagic fever infection, there is distinct strain variability observed, liver and brain pathological changes, increased polyfunctionality of CD8 + T cells and viral RNA observed in the blood and tissues of infected mice. 90…”

“…The distinct pathogenesis of these infections can be recapitulated in humanized mice, which can display features such as Ebola virus antigen detection and liver‐specific histological changes and inflammatory cell infiltrates and species‐specific infection with Ebola virus or Reston virus . In humanized HLA‐A2 mice, Hantavirus infection induces a dramatic decrease in total platelet count and infiltration of lymphocytes into the lungs, and increases weight loss . Similarly, in Crimean–Congo haemorrhagic fever infection, there is distinct strain variability observed, liver and brain pathological changes, increased polyfunctionality of CD8 + T cells and viral RNA observed in the blood and tissues of infected mice …”

Humanized Mouse Models of Clinical Disease

“…To create a humanized mouse model for the study of Hantavirus, NSG-HLA-A2 mice were engrafted with HLA-A2 matched cord blood HSCs (61). Infected mice experienced weight loss, pulmonary inflammation, and ~75% loss of human platelets (but no loss of mouse platelets), providing another humanized mouse model for the study of BSL4 level infectious agents.…”

What Do We Know about How Hantaviruses Interact with Their Different Hosts?

“…The best animal model remains the macaque nonhuman primate for both New and Old World hantaviruses [35,36,37]. Recent data described possible infection of humanized SCID mice with hantaviruses [38]. Today, most data on the physiopathology of hantaviruses come from analyses of human clinical samples, or host reservoir samples, as well as from in vitro studies with cellular models.…”