Interfering with interferons

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Science  16 Jan 2015:
Vol. 347, Issue 6219, pp. 233-234
DOI: 10.1126/science.aaa5056
Controlling persistent infection.

(A) Both wild-type mice and mice lacking the receptor for IFN-λ cannot clear murine norovirus (MNV) infection, but treatment with IFN-λ leads to virus elimination. (B) When the gut microbiota is eliminated by antibiotic treatment, MNV disappears from wild-type mice (and from mice that lack the adaptive immune system), but not from mice that lack IFN-λ signaling.


Living organisms must resist viral infection. In mammals, both infected cells and innate immune cells release signals (cytokines) that program the infected cells for antiviral defense, as well as alert neighboring cells that trouble is afoot. These signals—exemplified by the type I (α and β), type II (γ), and type III (λ) interferons (IFNs)—control the mammalian response against the vast majority of viruses. The host's control of an enteric pathogen, rotavirus, requires type III IFNs (1, 2). On page 269 and 266 of this issue, Nice (3) and Baldridge (4), respectively, show that protection provided by λ IFNs is generalizable to another enteric pathogen, norovirus. Notably, this protection is independent from the adaptive immune response, which has long thought to be absolutely required for clearing viral infection.

The principal difference between type I and type III IFNs lies in their cognate receptor (5, 6). Whereas type I IFNs are recognized by the IFNαR1-R2 heterodimer (also called IFNαβR), type III IFNs are recognized by a distinct heterodimeric receptor composed of IFNλR1 and interleukin-10 receptor beta (IFNλR1-IL10Rβ1 or IFNλR). Even though the IFNαβR and IFNλR are independent, both receptors signal through a series of common adaptors leading to an indistinguishable antiviral immune response. Unlike IFNαβR, which is ubiquitously expressed in all nucleated cells, IFNλR is primarily expressed by the mucosal epithelium, with the highest expression in the small and large intestine.

A common cause of gastroenteritis, human norovirus is notoriously difficult to study in vitro and in vivo. For this reason, murine norovirus (MNV) has been an invaluable tool for analyzing the relationship between enteric viruses and the host immune system. To uncover the antiviral mechanism controlling persistent MNV infection, Nice et al. used a genetic approach to discover that type III IFN, but not type I IFN, is required to control persistent MNV, as virus shedding was substantially increased in IFNλR-deficient mice but not in IFNαβR-deficient mice. Administration of IFN-λ to mice with persistent norovirus infection reduced virus shedding below detectable amounts (see the figure). Moreover, injection of exogenous IFN-λ cleared the virus from mice devoid of an adaptive immune system (thus, eliminating the possibility that the animals invoked norovirus antigen–specific targeting by T and B cells of the adaptive immune system). Similarly, the administration of exogenous IFN-λ also ablated acute rotavirus infection in vivo (2). Consequently, this finding may have far-reaching implications regarding “sterilizing” innate immunity against enteric viral infections.

Wild-type mice should be able to induce IFN-λ, so why did they fail to clear persistent norovirus infection? Baldridge et al. provide a possible link between the host's microbiota and the antiviral response governed by λ IFNs. The authors found that ablation of the gut microbiota by antibiotic treatment results in clearance of persistent murine norovirus infection; restoring gut microbiota with that from untreated mice (through fecal transplant) rescued virus replication. This result has been separately confirmed in both antibiotic-treated (7) and germ-free animals (8). By stark contrast, antibiotic-treated mice lacking IFN-λ signaling were unable to clear viral infection. Thus, IFN-λ is required to clear the virus, but its antiviral activity is diminished in the presence of the gut microbiota. This raises the possibility that the microbiota may directly or indirectly benefit the virus by inhibiting virally induced IFN-λ signaling. Indeed, another murine virus, mouse mammary tumor virus, exploits the host's gut microbiota by cloaking itself in bacterial lipopolysaccharide, a constituent of the outer membrane of Gram-negative bacteria (9). Virus-bound lipopolysaccharide triggers the pattern recognition receptor Toll-like receptor 4, which blocks the antivirus immune response by eliciting the production of IL-10, an immunosuppressive cytokine.

Enteric viruses, including reoviruses (10, 11), norovirus (4, 7, 8), and poliovirus (10, 12), are known now to require the gut microbiota for successful replication and transmission. The mechanisms through which the microbiota facilitates propagation of these viruses are not yet clear. In the case of murine norovirus, it may be that viral infection of B cells requires the presence of glycans, resembling histo-blood group antigens synthesized by specific types of enteric bacteria (7). Another possibility, suggested by the study of Baldridge et al., is that the gut microbiota may interfere with antiviral innate immunity, quenching IFN-λ signaling by an as-yet-undiscovered mechanism.

The findings of Nice et al. and Baldridge et al. prompt many questions. For example, it is unclear how MNV and other viruses elicit IFN-λ production, and what cell types sense this cytokine in the gut. Another question is why type I IFN production, which is triggered by MNV (8), does not contribute to the antivirus response in the gastrointestinal tract. One possibility is that the virus blocks the effects of both type I and type III IFNs with the help of the microbiota. It is also possible that a specific hierarchy exists through which IFNs control the virus, with IFN-λ providing superior protection in the gut whereas type I IFNs mainly protect systemic organs. That type III IFNs induce an antiviral response identical to that of type I IFNs and that their cognate receptor primarily lies within the intestinal epithelium can explain their essential role in the control of acute intestinal infections.

It appears that all orally transmitted viruses studied thus far exploit the gut microbiota for efficient transmission. However, many viruses enter the host through other surfaces, which also harbor commensal bacteria. Exploring the interaction between viruses and the surrounding microbial community should reveal how commensals contribute to the transmission of an array of viruses, not only enteric pathogens.


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