In vivo imaging in NHP models of malaria: Challenges, progress and outlooks

Abstract

Animal models of malaria, mainly mice, have made a large contribution to our knowledge of host-pathogen interactions and immune responses, and to drug and vaccine design. Non-human primate (NHP) models for malaria are admittedly under-used, although they are probably closer models than mice for human malaria; in particular, NHP models allow the use of human pathogens (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium knowlesi). NHPs, whether natural hosts or experimentally challenged with a simian Plasmodium, can also serve as robust pre-clinical models. Some simian parasites are closely related to a human counterpart, with which they may share a common ancestor, and display similar major features with the human infection and pathology. NHP models allow longitudinal studies, from the early events following sporozoite inoculation to the later events, including analysis of organs and tissues, particularly liver, spleen, brain and bone marrow. NHP models have one other significant advantage over mouse models: NHPs are our closest relatives and thus their biology is very similar to ours. Recently developed in vivo imaging tools have provided insight into malaria parasite infection and disease in mouse models. One advantage of these tools is that they limit the need for invasive procedures, such as tissue biopsies. Many such technologies are now available for NHP studies and provide new opportunities for elucidating host/parasite interactions. The aim of this review is to bring the malaria community up to date on what is currently possible and what soon will be, in terms of in vivo imaging in NHP models of malaria, to consider the pros and the cons of the various techniques, and to identify challenges.

A Review of Plasmodium coatneyi–Macaque Models of Severe Malaria

“…NHP models could address problems involving metabolic and physiologic changes (eg, the pathogenesis of coma and neurologic dysfunction) that are difficult to study in human patients. 7 Functional magnetic resonance imaging, intracranial pressure monitoring, and laser video microscopy of flow and electroencephalogram under controlled settings (and in response to potential adjuvant therapies) are difficult to perform in human patients with malaria. In comparison with the nonsequestration-dependent, immune-mediated encephalitis of experimental murine cerebral malaria, the similarities of the pathophysiologic tapestry of P. coatneyi to human disease should make its results more medically relevant.…”

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

“…the use of humanized mice in human malaria parasite Pe vaccine research P. falciparum and P. vivax PE stages exhibit a narrow host-cell tropism in which productive infection of host cells and complete liver-stage development is largely restricted to human and great ape hepatocytes [14]. This has been a significant hurdle for studying relevant liver-stage biology, immunology and vaccinology of these pathogens.…”

“…Importantly, NHPs are the only model in which tissue-resident immune responses to human malaria parasite infection and vaccination can be assessed through tissue sampling, and NHP models have proven critical in P. vivax research [76]. NHP studies perhaps remain underutilized because of their significantly higher logistical, ethical and financial barriers, and while their immune systems more closely resemble that of humans, their more diverse histocompatibility complex loci could potentially misinform vaccine efficacy [75][76][77]. Furthermore, P. falciparum and P. vivax malaria parasites must be adapted to NHP models, a process that has been shown to result in altered parasite biology [72,78].…”

“…Multi-epitope transgenic parasites have however recently been generated, and the advent of CRISPR/Cas9 usage in Plasmodium spp, may accelerate their creation by allowing direct replacement of essential genes without selection [73,82,83]. The predictive efficacy of the transgenic parasite screening approach remains unknown, and only once CHMI studies have been performed with antigens selected in this way will the utility of this model be determined definitively.the use of humanized mice in human malaria parasite Pe vaccine research P. falciparum and P. vivax PE stages exhibit a narrow host-cell tropism in which productive infection of host cells and complete liver-stage development is largely restricted to human and great ape hepatocytes [14]. This has been a significant hurdle for studying relevant liver-stage biology, immunology and vaccinology of these pathogens.…”

“…In this perspective, we will explore how traditional animal models of malaria infection, in combination with in vitro assays, have contributed to the advancement of PE vaccine candidates to human clinical trials. While we acknowledge the critical contribution made by non-human primate (NHP) models of malaria [4,14], we focus on the role of small rodent models given their greater accessibility and cost-effectiveness early in vaccine discovery. Furthermore, malaria vaccine research has the advantage of a human challenge model known as controlled human malaria infection (CHMI).…”