Abstract
Hepatic infections by hepatitis B virus (HBV), hepatitis C virus (HCV) and Plasmodium parasites leading to acute or chronic diseases constitute a global health challenge. The species tropism of these hepatotropic pathogens is restricted to chimpanzees and humans, thus model systems to study their pathological mechanisms are severely limited. Although these pathogens infect hepatocytes, disease pathology is intimately related to the degree and quality of the immune response. As a first step to decipher the immune response to infected hepatocytes, we developed an animal model harboring both a human immune system (HIS) and human hepatocytes (HUHEP) in BALB/c Rag2-/- IL-2Rγc-/- NOD.sirpa uPAtg/tg mice. The extent and kinetics of human hepatocyte engraftment were similar between HUHEP and HIS-HUHEP mice. Transplanted human hepatocytes were polarized and mature in vivo, resulting in 20–50% liver chimerism in these models. Human myeloid and lymphoid cell lineages developed at similar frequencies in HIS and HIS-HUHEP mice, and splenic and hepatic compartments were humanized with mature B cells, NK cells and naïve T cells, as well as monocytes and dendritic cells. Taken together, these results demonstrate that HIS-HUHEP mice can be stably (> 5 months) and robustly engrafted with a humanized immune system and chimeric human liver. This novel HIS-HUHEP model provides a platform to investigate human immune responses against hepatotropic pathogens and to test novel drug strategies or vaccine candidates.
Highlights
Infectious diseases that target the liver, including Plasmodium parasites and hepatitis B and C viruses (HBV, hepatitis C virus (HCV)), affect over 600 million people worldwide
In order to establish an animal model in which human immune responses against human hepatotropic pathogens could be studied in vivo, we generated a novel recipient mouse strain that could be co-engrafted with human hematopoietic stem cells (HSC) and human hepatocytes
BALB/c Rag2-/-IL-2Rγc-/- NOD.sirpa (BRGS)-uPAtg/tg mice were engrafted in a two-step process to obtain human immune system (HIS)-human hepatocytes (HUHEP) mice: irradiated newborn pups (< 1 week old) were injected intrahepatic ally with human HSC, and at 4–8 weeks they were implanted with human adult hepatocytes (Fig. 1A)
Summary
Infectious diseases that target the liver, including Plasmodium parasites and hepatitis B and C viruses (HBV, HCV), affect over 600 million people worldwide. The specific roles of these authors are articulated in the ‘author contributions’ section
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