Biology subjects

Kotenko, S.

Publications and source records attributed to Kotenko, S..

2 recordsLinked to original sources

bioRxiv2020

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.

immunology↗

bioRxiv2018

Realtime 2-5A kinetics suggests interferons β and {lambda} evade global arrest of translation by RNase L

Cells of all mammals recognize double-stranded RNA (dsRNA) as a foreign material. In response, they release interferons (IFNs) and activate a ubiquitously expressed pseudokinase/endoribonuclease RNase L. RNase L executes regulated RNA decay and halts global translation. Here we developed a biosensor for 2,5-oligoadenylate (2-5A), the natural activator of RNase L. We found that 2-5A was acutely synthesized by cells in response to dsRNA sensing, which immediately triggered cellular RNA cleavage by RNase L and arrested host protein synthesis. However, translation-arrested cells still transcribed IFN-stimulated genes (ISGs) and secreted IFNs of types I and III (IFN-{beta} and IFN-{lambda}). Our data suggests that IFNs escape from the action of RNase L on translation. We propose that 2-5A/RNase L pathway serves to rapidly and accurately suppress basal protein synthesis, preserving privileged production of defense proteins of the innate immune system.\n\nSignificanceRNase L is a mammalian enzyme that can stop global protein synthesis during interferon response. Cells must balance the need to make interferons (which are proteins) with the risk to lose cell-wide translation due to RNase L. This balance can most simply be achieved if RNase L was activated late in the interferon response. However, we show by engineering a biosensor for the RNase L pathway, that on the contrary, RNase L activation precedes interferon synthesis. Further, translation of interferons evades the action of RNase L. Our data suggest that RNase L facilitates a switch of protein synthesis from homeostasis to specific needs of innate immune signaling.

cell biology↗