Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner

Casazza, Rebecca L.; Philip, Drake T.; Lazear, Helen M.

doi:10.1101/2022.01.04.475019

Cited by 2 publications

(2 citation statements)

References 73 publications

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“…Second, diarrheagenic MNV strains were not detected in intestinal epithelial cells which are the main site of type III IFN receptor expression. Yet our results are in line with an increasing appreciation for the capacity of type III IFNs to exacerbate disease associated with viral infections in situations where immune cell-derived type III IFNs reduce tissue repair [47][48][49] , raising the intriguing possibility that norovirus infection of intestinal immune cells leads to production of type III IFNs that impair epithelial barrier function, contributing to diarrhea, while type I IFNs protect from disease. Overall, this body of work illustrates the importance of translatable small animal models for understanding basic norovirus biology to elucidate disease mechanisms.…”

Section: Discussionsupporting

confidence: 83%

Infection of neonatal mice with the murine norovirus strain WU23 is a robust model to study norovirus pathogenesis

Karst

Peiper

Helm

et al. 2022

Preprint

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Noroviruses are the leading cause of severe childhood diarrhea and foodborne disease worldwide. While they are a major cause of disease in all age groups, infections in the very young can be quite severe with annual estimates of 50,000-200,000 fatalities in children under 5 years old. In spite of the remarkable disease burden associated with norovirus infections in people, very little is known about the pathogenic mechanisms underlying norovirus diarrhea, principally because of the lack of tractable small animal models. The development of the murine norovirus (MNV) model nearly two decades ago has facilitated progress in understanding host-norovirus interactions and norovirus strain variability. However, the model remains limited because MNV strains tested thus far either do not cause intestinal disease or were isolated from extraintestinal tissue, raising concerns about translatability of research findings to human norovirus disease. Consequently, the field lacks a strong model of norovirus gastroenteritis and determinants of norovirus pathogenesis remain poorly defined. Herein, we provide a comprehensive characterization of a new small animal model system for the norovirus field that overcomes prior weaknesses. Specifically, we demonstrate that the WU23 MNV strain isolated from a mouse naturally presenting with diarrhea causes reduced weight gain and acute self-resolving diarrhea in neonatal mice of several inbred mouse lines. Moreover, our findings reveal that norovirus-induced diarrhea is associated with infection of subepithelial cells in the small intestine and systemic spread. Finally, type I interferons (IFN) are critical to protect hosts from norovirus-induced intestinal disease whereas type III IFNs exacerbate diarrhea. This latter finding is consistent with other emerging data implicating type III IFNs in the exacerbation of some viral diseases. This new model system should enable a detailed investigation of norovirus disease mechanisms and serve as a platform for testing antivirals.

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Section: Discussionsupporting

confidence: 83%

Infection of neonatal mice with the murine norovirus strain WU23 is a robust model to study norovirus pathogenesis

Karst

Peiper

Helm

et al. 2022

Preprint

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“…DENV3 RNA was not detected. To test whether the vagina is permissive to other RNA viruses that generally are restricted by innate antiviral responses in wild-type mice (24, 25), we inoculated wild-type mice intravaginally with 1000 FFU of rubella virus ( Matonaviridae ) or 5 × 10 8 genome equivalents of hepatitis A virus ( Picornaviridae ) but detected no viral RNA in vaginal washes at any of the time points evaluated through 8 dpi (data not shown). Altogether, these data show that vaginal infection is not a unique property of ZIKV among flaviviruses.…”

Section: Resultsmentioning

confidence: 99%

Zika virus replicates in the vagina of mice with intact interferon signaling

López¹,

Dulson²,

Lazear³

2022

Preprint

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Zika virus (ZIKV) is unusual among flaviviruses in its ability to spread between humans through sexual contact, as well as by mosquitoes. Sexual transmission has the potential to change the epidemiology and geographic range of ZIKV compared to mosquito-borne transmission and potentially could produce distinct clinical manifestations, so it is important to understand the host mechanisms that control susceptibility to sexually transmitted ZIKV. ZIKV replicates poorly in wild-type mice following subcutaneous inoculation, so most ZIKV pathogenesis studies use mice lacking IFN-αβ signaling (e.g. Ifnar1-/-). However, we found that wild-type mice support ZIKV replication following intravaginal infection, although the infection remained localized to the lower female reproductive tract. Vaginal replication was not a unique property of ZIKV, as other flaviviruses that generally are restricted in wild-type mice also were able to replicate in the vagina. Vaginal ZIKV infection required a high-progesterone state (pregnancy or pre-treatment with depot medroxyprogesterone acetate (DMPA)), identifying a key role for hormonal status in susceptibility to vaginal infection. Progesterone-mediated susceptibility did not appear to result from a compromised epithelial barrier, blunted antiviral gene induction, or changes in vaginal leukocyte populations, leaving open the mechanism by which progesterone confers susceptibility to vaginal ZIKV infection. Progesterone treatment is a key component of mouse vaginal infection models for herpes simplex virus and Chlamydia, but the mechanisms by which DMPA increases susceptibility to those pathogens also remain poorly defined. Understanding how progesterone mediates susceptibility to ZIKV vaginal infection may provide insights into host mechanisms influencing susceptibility to diverse sexually transmitted pathogens.

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Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner

Cited by 2 publications

References 73 publications

Infection of neonatal mice with the murine norovirus strain WU23 is a robust model to study norovirus pathogenesis

Infection of neonatal mice with the murine norovirus strain WU23 is a robust model to study norovirus pathogenesis

Zika virus replicates in the vagina of mice with intact interferon signaling

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