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An enhanced antiviral interferon (IFN) response combined with reduced inflammation might be linked to the apparent virus tolerance in bats. Lyssavirus phosphoproteins inhibit the IFN response with virus strain-specific efficiency. To date, little is known regarding the lyssavirus P-dependent anti-IFN countermeasures in bats, mainly due to a lack of <jats:italic>in vitro<\/jats:italic> tools. By using <jats:italic>E<\/jats:italic>. <jats:italic>helvum<\/jats:italic> bat cell cultures in a newly established bat-specific IFN-promoter activation assay, we analyzed the IFN-\u00df inhibitory activity of multiple lyssavirus P in <jats:italic>E<\/jats:italic>. <jats:italic>helvum<\/jats:italic> compared to human cells. Initial virus infection studies with a recently isolated <jats:italic>E<\/jats:italic>. <jats:italic>helvum<\/jats:italic>-borne Lagos bat virus street strain from Ghana showed enhanced LBV propagation in an <jats:italic>E<\/jats:italic>. <jats:italic>helvum<\/jats:italic> lung cell line compared to human A549 lung cells at later time points suggesting effective viral countermeasures against cellular defense mechanisms. A direct comparison of the IFN-\u00df inhibitory activity of the LBV-GH P protein with other lyssavirus P proteins showed that LBV-GH P and RVP both strongly inhibited the bat IFN-\u03b2 promotor activation (range 75\u201390%) in EidLu\/20.2 and an <jats:italic>E<\/jats:italic>. <jats:italic>helvum<\/jats:italic> kidney cell line. Conversely, LBV-GH P blocked the activation of the human IFN-\u03b2 promoter less efficiently compared to a prototypic Rabies virus P protein (range LBV P 52\u201368% vs RVP 71\u201395%) in two different human cell lines (HEK-293T, A549). The same pattern was seen for two prototypic LBV P variants suggesting an overall reduced LBV P IFN-\u00df inhibitory activity in human cells as compared to <jats:italic>E<\/jats:italic>. <jats:italic>helvum<\/jats:italic> bat cells. Increased IFN-\u00df inhibition by lyssavirus P in reservoir host cells might be a result of host-specific adaptation processes towards an enhanced IFN response in bat cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0264450","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T18:41:37Z","timestamp":1646764897000},"page":"e0264450","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Reduced IFN-\u00df inhibitory activity of Lagos bat virus phosphoproteins in human compared to Eidolon helvum bat 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