Norovirus immunology: Of mice and mechanisms

Abstract

Noroviruses (NoVs) are the most common cause of sporadic and epidemic gastroenteritis in the United States and Europe and are responsible for 20% of acute gastroenteritis worldwide. Over the past decade, the understanding of NoV immunology has grown immensely. Studies of the natural immune response to NoV in humans and animal models have laid the foundation for innovations in cell culture systems for NoV and development of new therapeutics. Evidence from animal models, NoV surrogates, observational human research, and human challenge studies suggest that the innate immune response is critical for limiting NoV infection but is insufficient for viral clearance. NoV may antagonize the innate immune response to establish or prolong infection. However, once a robust adaptive immune response is initiated, the immune system clears the infection through the action of T and B cells, simultaneously generating highly specific protective immunologic memory. We review here both the current knowledge on NoV immunity and exciting new developments, with a focus on ongoing vaccine development work, novel cell culture systems, and advances in understanding the role of the gut microbiome. These changes reinforce the need for a better understanding of the human immune response to NoV and suggest novel hypotheses.

Keywords: Animal models; Human; Microbiome; Norovirus; Vaccine.

Figure 1

Proposed schematic of norovirus infection in the gut and immune response. Noroviruses (NoV) may infect multiple cell types in the gut, and this may vary between humans and animal models. Three major hypothetical infection pathways are shown. (1) NoV may infect monocytes and other cells associated with Peyer’s patches in a microfold (M) cell-dependent manner, (2) NoV may infect epithelial cells directly, or (3) NoV may be transported across the epithelium, perhaps through interactions with commensal gut bacteria, where they may infect lymphoid cells. Infected cells produce IFNs. IFNs inhibit viral replication in infected cells and may stimulate CD4⁺ T-cell differentiation and activation, which may lead to CD8⁺ T-cell activation and B-cell maturation. This schematic is not intended to make suggestions on the host location of CD4⁺ and CD8⁺ differentiation and activation following NoV infection because these data are unknown. Cytokines may lead to inflammation of the gut epithelium and recruitment of neutrophils and monocytes. B cells produce NoV-specific antibodies that are critical for clearing the infection. NoV infection also generates memory B cells, which may protect against future infection by the same strain.

Figure 2

Proposed schematic of intracellular immune response to murine norovirus (MNV) infection. MNV may infect macrophages or dendritic cells in the gut. Infected cells sense MNV via MDA-5 and produce IFNs through this or the STAT-1 pathway. Type I IFNs inhibit MNV uncoating via ISG15 and may inhibit replication complex formation via an Atg complex. Type II IFNs block MNV translation via RNA-activated protein kinase (PKR). VF1-related immune suppression by MNV is not included in this schematic.