Natural killer cell responses to emerging viruses of zoonotic origin

Abstract

Emerging viral diseases pose a major threat to public health worldwide. Nearly all emerging viruses, including Ebola, Dengue, Nipah, West Nile, Zika, and coronaviruses (including SARS-Cov2, the causative agent of the current COVID-19 pandemic), have zoonotic origins, indicating that animal-to-human transmission constitutes a primary mode of acquisition of novel infectious diseases. Why these viruses can cause profound pathologies in humans, while natural reservoir hosts often show little evidence of disease is not completely understood. Differences in the host immune response, especially within the innate compartment, have been suggested to be involved in this divergence. Natural killer (NK) cells are innate lymphocytes that play a critical role in the early antiviral response, secreting effector cytokines and clearing infected cells. In this review, we will discuss the mechanisms through which NK cells interact with viruses, their contribution towards maintaining equilibrium between the virus and its natural host, and their role in disease progression in humans and other non-natural hosts.

Figure 1

The immune response against zoonotic viruses in natural reservoirs compared to humans. Top: Zoonotic viruses can directly pass from natural hosts (e.g. bats, mice, monkeys) to humans, or be transmitted through intermediate hosts or vectors (e.g. mosquitoes, cattle). Middle and bottom: Some natural reservoirs have evolved enhanced interferon responses while reducing pro-inflammatory mediators. Increased NKR complexity and diversity, and improved NK cell responsiveness may also contribute to viral persistence while keeping the host asymptomatic. When zoonotic viruses jump to novel hosts such as humans, a slower interferon response and impaired early NK cell activation may lead to poor virus clearance, aberrant immune responses, heighten inflammation, and profound pathology.

Figure 2

Mechanisms of NK cell evasion or activation by zoonotic viruses. Left: Zoonotic viruses can avoid interferon responses by blocking PRR sensing, inhibiting interferon production, and dampening interferon receptor signalling. These viruses also evade NK cell recognition by upregulating ligands for inhibitory NKR, downregulating or shielding activating NKR ligands, and inducing anti-inflammatory cytokines. Right: When activating signals (green arrows) outweigh inhibitory signals (red flat-end arrows), NK cells become activated and secrete pro-inflammatory cytokines (e.g. IFN-γ), release cytotoxic granules to kill target cells, and undergo proliferation. See also Table 1 for a complete list of references. PRR, pattern recognition receptors. NKR, NK cell recognition receptors. ISG, interferon stimulated genes.