Human microglial models to study host-virus interactions

Abstract

Microglia, the resident macrophage of the central nervous system, are increasingly recognized as contributing to diverse aspects of human development, health, and disease. In recent years, numerous studies in both mouse and human models have identified microglia as a "double edged sword" in the progression of neurotropic viral infections: protecting against viral replication and cell death in some contexts, while acting as viral reservoirs and promoting excess cellular stress and cytotoxicity in others. It is imperative to understand the diversity of human microglial responses in order to therapeutically modulate them; however, modeling human microglia has been historically challenging due to significant interspecies differences in innate immunity and rapid transformation upon in vitro culture. In this review, we discuss the contribution of microglia to the neuropathogenesis of key neurotropic viral infections: human immunodeficiency virus 1 (HIV-1), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Herpes simplex virus (HSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We pay special attention to recent work with human stem cell-derived microglia and propose strategies to leverage these powerful models to further uncover species- and disease-specific microglial responses and novel therapeutic interventions for neurotropic viral infections.

Keywords: Herpes simplex virus (HSV); Human immunodeficiency virus 1 (HIV-1); Japanese encephalitis virus (JEV); Microglia; Neuroinfectious diseases; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); West Nile virus (WNV); Zika virus (ZIKV); iPSC-derived microglia (iMG).

Fig. 1.

Human microglial modeling of neurotropic viral infection. MG = microglia. (a) SARS-CoV-2 and WNV infect neurons but not microglia (Jacob et al., 2020; Cheeran et al., 2005), and WNV -infected hMG produce proinflammatory factors (Cheeran et al., 2005). (b) HIV-1 infects microglia in the CNS, which produce glutamate and other proinflammatory factors that contribute to neuronal death and recruitment of immune cells (Huang et al., 2011; Zhao et al., 2004; dos Reis et al., 2020; Ryan et al., 2020), and HIV-1 establishes latency in MG that survive cell death following HIV-1 CNS entry (Castellano et al., 2017) and can be reactivated by neuronal damage (Alvarez-Carbonell et al., 2019). (c) HSV-1, JEV, and ZIKV infect MG (Lokensgard et al., 2001; Kumar et al., 2020; Lannes et al., 2017; Retallack et al., 2016; Lum et al., 2017), which produce proinflammatory factors that may drive neuronal loss and immune infiltration (Lokensgard et al., 2001; Kumar et al., 2020; Lannes et al., 2017; Lum et al., 2017; Diop et al., 2018; Muffat et al., 2018; Mesci et al., 2018; Xu et al., 2021; Abreu et al., 2018), and JEV-infected MG may infect neighboring cells by cell-to-cell contact (Lannes et al., 2019). Created with BioRender.com.

Fig. 2.

Strategies to investigate neurotropic viral infections using human microglial models. (a) Primary microglia isolated from human post-mortem brain tissue can be immortalized through oncogenic transduction. (b) Microglia-like cells can be derived from primary monocytes, though they are derived from different progenitors. (c) hiPSC-derived microglia can be cultured in isolation or applied to a wide variety of multicellular and in vivo systems. Created with BioRender.com.