Humanized Mice for Infectious and Neurodegenerative disorders

Abstract

Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.

Fig. 1

Development and characterization of humanized microglial mice. Humanized microglia mice serve as tool to elucidate neuroHIV pathobiology and to develop therapeutic and elimination antiretroviral strategies for HIV infections. IL-34 was transgenically introduced and at the same time CD34 + HSCs were injected into the liver of immunodeficient newborn mice. These mice developed a functional human lymphoid system comprised of B cells, T cells and macrophages and brain enriched with human microglial cells. Blue and red colored cells are human and mouse cells, respectively. In regards to the timing, human cells are introduced after birth to reconstitute lymphoid and solid organ tissues devoid of endogenous murine immunocytes. The human immunocytes show limited number reductions with time after injection as new cells are produced from progenitors. These exist, over time, less frequently in brain and periphery compared to mouse cells

Fig. 2

LASER ART and CRISPR-Cas9 therapies for HIV-1 elimination. Humanized mice developed (a) and HIV-1 infected humanized (b) mice were administered with sequential treatment of a combination of long-acting ART followed by CRISPR-Cas9 targeting specific sequences of the HIV-1 genome (c). Using sequential treatments, complete HIV-1 elimination from a subset of animals. This combinatorial approach is being developed for improved delivery of CRISPR-Cas9 to target the latent reservoirs in humanized mouse models (left panel), to improve the rates of viral elimination (right panel) (Color explanation: blue color cells are represented as human cells, red color cells are represented HIV-1 infected cells and green color represents the cells with complete elimitation of HIV-1)

Fig. 3

Immune transformation in neurodegenerative disorders. Pathogenic changes seen in the brains of AD include accumulation of intraneuronal neurofibrillary tangles of Tau and extracellular Aβ plaques. These induce activation of CNS resident microglia and astrocytes leading to neuroinflammation (top left). In contrast, transformation of an inflammatory microglia by medicines or immune modulation leads to neuronal protection and maintenance of CNS homeostasis (top right). Similarly in PD, aggregated self-protein α-synuclein activates microglia leading to neuronal damage within the substantia nigra pars compacta along with their connections into the striatum; brain subregions responsible for coordinate movement (bottom left). However, brain homeostasis achieved through neuroprotection (bottom right) can affect clinical improvements

Fig. 4

Potential of LASER ART for HIV-1 treatment and prevention. Based on extensive animal modeling, a single intramuscular injection of a nanoformulated stearoylated CAB ester prodrug (NM2CAB) can lead to sustained drug levels at the site of injection and within the reticuloendothelial system for up to one year (top panel). The formed CAB nanocrystals are absorbed from the injection site and undergo dissolution for prodrug that is subsequently hydrolyzed into active CAB in blood and tissue. CAB prodrug was recorded in all the tissues during a year-long observation in rodents and rhesus macaques after a singleNM2CAB injection. Top panel reflects how NM2CAB can be distributed after an intramuscular injection. By contrast, the nanoformulated NCAB is rapidly cleared from the site of injection and tissues. For NCAB, therapeutic drug levels are present in lymphoid tissues for one month (bottom panel)