To date, 18 Marburg virus disease (MVD) outbreaks have been reported, most recently in Tanzania and Ethiopia. From 1998 to 2000, a large MVD outbreak in Watsa/Durba region, Democratic Republic of the Congo (DRC), resulted in 154 cases and 128 deaths. Given the public health risks posed by MARV, the lack of approved vaccines and therapeutics, and unpredictability of future outbreaks, this study aimed to assess the anti-MARV seroprevalence in Watsa/Durba.MethodsSamples collected in May 2023 (n = 313) included known MVD survivors (n = 5), close contacts (n = 22), and other residents (n = 286). A multiplexed immunoassay was used to assess seroreactivity to MARV and other pan-filovirus targets.ResultsAmong the Watsa/Durba cohort, 4.5% and 1.6% were seroreactive to MARV glycoprotein (GP) and VP40, including only 1 known MVD survivor. No significant associations were found between MARV seroreactivity and risk factors: travel to Uganda, receiving injections, or employment as a gold miner. Of those 14 MARV GP-reactive individuals, 85.7% were cross-reactive to other filoviral targets.ConclusionsThis detected seroprevalence among individuals with no known exposure history may indicate continued exposure to MARV or MARV-like antigens 25 years after the conclusion of the outbreak; cross-reactivity to pan-filovirus targets further suggest the potential for undetected cases.

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Read the full paper: Subcellular Characterization of the Molecular Determinants of Ebola VP40 Trafficking and Assembly

Selective autophagy of the endoplasmic reticulum (ER-phagy) is critical for ER proteostasis and host defense, yet how ER quality-control pathways interface with ER-phagy to restrict viral glycoproteins remains poorly defined. Previously, the 1st known ER-phagy receptor gene RETREG1 (RETR1)/FAM134B gene was reported to restrict Ebola virus (EBOV) replication in vivo by inhibiting the viral glycoprotein (GP) and viral protein 40 kDa (VP40) expression, but this mechanism remains unknown. Here, we identify the truncated RETR1/FAM134B isoform 2 (RETR1-2), but not its full-length protein RETR1, as an ER-phagy receptor that targets EBOV-GP for degradation. RETR1-2 broadly triggers GP degradation across ebolavirus species but not Marburg virus and inhibits EBOV replication. Mechanistically, RETR1-2 recognizes EBOV-GP via its luminal domain, undergoes GP-induced oligomerization, and directs GP-containing ER membranes to lysosomes through canonical macro-autophagy. Using unbiased mass spectrometry, we identified TOLLIP as the key cytoplasm adaptor for RETR1-2, which also requires cooperation with the ER chaperone calnexin for EBOV-GP degradation. Notably, the PI3P-binding C2 domain of TOLLIP mediates its interaction with RETR1-2, and the EBOV-GP degradation occurs independently of ubiquitination, revealing an unexpected role for TOLLIP in ER-phagy. Furthermore, EBOV-VP40 antagonizes this pathway by selectively targeting RETR1-2 for macroautophagic degradation independently of TOLLIP, thereby restoring GP expression and viral infectivity. Nevertheless, RETR1-2 reciprocally degrades VP40 via a similar mechanism. Together, these findings define a calnexin-TOLLIP-RETR1-2 axis that links ER quality control to ER-phagy-mediated antiviral restriction and uncover a reciprocal host-virus arms race centered on selective macro-autophagy.

Orthomarburgvirus marburgense (MARV) causes infrequent but often fatal disease in humans, with recent outbreaks expanding into new regions including Tanzania, Rwanda and Ethiopia. To date, 18 Marburg virus disease (MVD) outbreaks have been reported, primarily in Sub-Saharan Africa. From 1998-2000, a large MVD outbreak in Watsa/Durba region, Democratic Republic of the Congo (DRC), resulted in 154 confirmed cases and 128 deaths (83% case fatality rate). Given the ongoing public health risks posed by MARV, the lack of approved vaccines and therapeutics, and unpredictable frequency of future outbreaks, this study aimed to assess the prevalence of anti-MARV antibodies in Watsa/Durba.MethodsSamples collected in May 2023, (n=313) included known MVD survivors (n=5), close contacts (n=22) and other residents (n=286). A multiplex immunoassay, was used to assess seroreactivity to MARV antigens and other pan-filovirus targets.ResultsAmong the Watsa/Durba cohort, 4.5% and 1.6% were seroreactive to MARV glycoprotein (GP) and VP40, respectively, including only one known MVD survivor. No significant associations were found between MARV seroreactivity and risk factors such as travel to Uganda, receiving injections or employment as a gold miner. Of those 14 MARV GP-reactive individuals, 85.7% were cross-reactive to other filoviral targets.ConclusionsThis detected seroprevalence among individuals with no known history of exposure may indicate continued exposure to MARV or MARV-like antigens almost 25 years after the conclusion of the outbreak. Beyond MARV reactivity, detected cross-reactivity to pan-filovirus targets further emphasize a need for increased surveillance, and the potential for asymptomatic, undetected cases in the region.