A Working Model of How Noroviruses Infect the Intestine

Human noroviruses (HuNoVs) cause a majority of gastroenteritis outbreaks across the globe and are the leading cause of severe childhood diarrhea and foodborne disease outbreaks in the United States [1,2]. In impoverished countries, they are estimated to cause over one million clinic visits and 200,000 deaths in young children annually [3]. However, the mechanisms used by noroviruses (NoVs) to infect the intestinal tract and cause disease are not well understood, primarily due to the paucity of cell culture and animal model systems. Recent major advances in developing such models now leave the field poised to tackle these critical questions. The goal of this opinion article is to propose a working model of early steps involved in intestinal infection by NoVs. In this model, NoVs bind carbohydrates on the surface of specific members of the intestinal microbiota and/or enterocytes and are then transcytosed across the intestinal epithelial barrier to gain access to their target immune cells. Evidence supporting each step of this model will be discussed. We also include a brief discussion of how NoVs cause disease as it relates to our model. NoVs Are Transcytosed Across Enterocytes in the Absence of Viral Replication HuNoV and murine NoVs (MuNoV) are transcytosed across intestinal epithelial cells in vitro [4,5], although they have not been shown to productively infect these cells in immunocompetent hosts (reviewed in [6]). Transcytosis of MuNoV across polarized murine intestinal epithelial cell monolayers does not disrupt tight junctions, is enhanced by B cell coculture, and is mediated by cells with characteristics of microfold (M) cells [4], a specialized cell type within the intestine responsible for sampling particulate antigen [7]. In a similar system, HuNoV virus-like particles were visualized on the basolateral side of cell nuclei from polarized Caco-2 cells [5], suggesting transport of particles through epithelial cells. However, whether particles were released from cells, whether particle transport modulated tight junction integrity, or whether a specialized cell type such as M cells mediated this process was not investigated. The importance of M cells for the efficient initiation of MuNoV infection in vivo was subsequently demonstrated by infecting mice depleted of M cells and observing reductions in viral titers in the intestine [8]. Furthermore, this partial, in contrast to complete, reduction of MuNoV infection in M cell-depleted mice suggests the presence of additional viral uptake routes across the intestinal barrier. Reovirus, a double-stranded RNA virus that infects enterocytes, similarly requires M cells for efficient infection [8], and other enteric pathogens also exploit M cells to infect the host [9]. Hence, we speculate that similar mechanisms are used by HuNoV to cross the intestinal epithelial barrier (Fig 1). Open in a separate window Fig 1 A working model for NoV intestinal infection. Multiple studies demonstrate that NoVs bind carbohydrates. These carbohydrates are expressed on enterocytes and secreted into the gut lumen. Furthermore, enteric bacteria can express similar carbohydrates. NoVs may bind to such carbohydrates in any of these contexts (1). NoVs are then transcytosed across the intestinal epithelium via M cells (2) and additional as-yet-to-be-identified pathways. Following transcytosis, NoVs infect dendritic cells, macrophages, and B cells (3). Depending on the species, infection can occur in the presence or absence of carbohydrates. Free carbohydrates or bacterially expressed carbohydrates may be cotranscytosed with the virus. Immune cell infection and putative concomitant viral-bacterial antigen presentation during NoV infections could have significant consequences on the nature and magnitude of antiviral immune responses.